FINDINGS OF

DRUG ABUSE

RESEARCH

An annotated bibliography of NIMH

and NIDA-supported extramural grant

research 1967-74 in two volumes

Volume 1

July 1975

National Institute on Drug Abuse

11400 Rockville Pike

Rockville, Maryland 20852
The NIDA Research Monograph Services is property by the

Division of Research of the National Institute on Drug Abuse. Its

primary objective is to provide critical reviews of research problem

areas and techniques, the content of state-of-the-art conferences,

integrative research reviews and significant original research. Its

dual publication emphasis is rapid and targeted dissemination to the

scientific and professional community.

EDITORIAL ADVISORY BOARD

Avram Goldstein, M.D.

Jerome Jaffe, M.D.

Reese T. Jones, M.D.

William McGlothlin, Ph.D.

Jack Mendelson, M.D.

Helen Nowlis, Ph.D.

Lee Robins, Ph.D.

Addiction Research Foundation

Palo Alto, California

College of Physicians and Surgeons

Columbia University, New York

Langley Porter Neuropsychiatric Institute

University of California

San Francisco, California

Department of Psychology, UCLA

Los Angeles, California

Alcohol and Drug Abuse Research Center

Harvard Medical School

McLean Hospital

Belmont, Massachusetts

Office of Drug Education, DHEW

Washington, D.C.

Washington University School of Medicine

St. Louis, Missouri

NIDA RESEARCH MONOGRAPH series

Robert DuPont, M.D. DIRECTOR, NIDA

William Pollin, M.D. DIRECTOR, DIVISION OF RESEARCH, NIDA

Robert C. Petersen, Ph.D. EDITOR-IN-CHIEF

Eunice L. Corfman, M.A. EDITOR

Rockwall Building 11400 Rockville Pike Rockville, Maryland, 20852
PREFACE

Nearly eight years have elapsed since the inauguration of a

high priority Federal research program directed toward better

understanding and coping with drug abuse. When that program

was begun, estimates of the extent of drug abuse were more

frequently based on speculation than on hard data. The basic

materials for studying such drugs as marihuana were frequently

lacking and research was in its infancy. Opiate research,

while it had a much longer history through pioneering work of

the Addiction Research Center, the U.S. Public Health Hospitals

at Lexington and Fort Worth a and other programs, also underwent

a much needed expansion.

The research infant has now become a strapping adolescent.

While much remains to be learned, this bibliography comprising

some 3,500 titles and abstracts attests to the productivity

of over 650 researchers whose work was directly supported

through grants from the National Institute on Drug Abuse and

its predecessor program in the National Institute of Mental

Health. Its publication represents an attempt to give some

sense of the diversity and scope of the Federal impact on drug

abuse research. It is our hope that it will prove to be a

valuable source of scientific information in itself and will

also serve as a source document for later analysis of the

Federal role in its extramural grant program towards shaping

and contributing to the overall drug abuse literature.

Preparation of these volumes inevitably leaves us indebted to

many individuals and organizations. First and foremost, special

thanks are owed to the hundreds of researchers who took time

from their busy schedules to give us detailed accounting of the

papers they have published arising from our grant support.

Without their generous cooperation a reasonably complete accounting would not have been possible. Thanks are also due to the

staffs of some twenty libraries, information services and

clearinghouses which provided assistance in many ways.

The actual production of the volumes demands thanks to many

individuals whose commitment to the detailed preparation

required testifies to their fine level of professionalism.

Special thanks are due to the staff of Koba Associates, Inc.,

particularly to Georgette Semick, the project director, ably

assisted by Carol Tuckerman and to their research assistants

Tina Lindegren and Kath Nesper. Susan Lachter, Acting Chief

of the National Clearinghouse for Drug Abuse Information here

at NIDA provided necessary assistance as did other members of

the NIDA staff.

Robert C. Petersen

Assistant Director, Research Division

NATIONAL INSTITUTE ON DRUG ABUSE

iii
Introduction

PURPOSE

Since September, 1973, the Division of

Research of the National Institute on

Drug Abuse (NIDA) has been responsible

for the coordination of extramural,

grant-supported research into tke

effects of drug use/abuse and for funding projects to examine possibe prevention and treatment modalities for

its control. NIDA-supported work has

its origins in the research program

supported and coordinated since the

1960’s by the National Institute of

Mental Health. The bulk of the Federally funded research has been undertaken since 1967 and the results have

been documented in numerous journals,

books and other scientific publications.

A listing of published drug abuse literature including synopses of the content was considered necessary in order

to provide NIDA with a resource for

planning future research directions and

for examining the impact of this literature on the scientific community.

Thus, the purpose of tkis annotated

bibliography is twofold: 1) to kelp

NIDA program personnel review the findings of previous drug abuse grants in

order to plan future research strategies, and 2) to serve as a retrospective indication of the findings

from supported research that have been

disseminated to the scientific community

and the general public.

The publication, Findings of Drug Abuse

Research 1967-1974, is a two-volume

work that lists the drug abuse research

literature supported by NIMH and NIDA

and provides abstracts or summaries of

the articles when these are provided

by the author. Each volume may be used

independently and each is indexed.

PREPARATION OF THE BIBLIOGRAPHY

Having defined the scope of the final

product as research literature produced

under NIMH-NIDA grants during the

period 1967-1974. the first major task

was to identify the relevant grants and

their principal investigators (PIs).

The methodology for collecting the materials was based on the assumptions

that the Principal Investigator would,

at minimum, be familiar witk the literature produced as a result of his/her

grant and in most cases would also have

copies of that literature. Lists of

principal investigators were developed

by utilizing NIMH and NIDA files of

grantees and the Research Grants Index

published by tire Public Health Service.

Each identified Principal Investigator

tken received a personally addressed

letter explaining the project and requesting lists (and copies) of literature produced as a result of drug use/

abuse grants for which s/he was designated as PI.

PIs were also asked to identify in a

preliminary way which of ten program

areas of drug use/abuse research would

best classify their literature. By

receiving this additional information

from the PIs themselves, the project

staff was provided with a firmer foundation for designing the final product.

The first request to PIs yielded an

approximate 50 percent response rate

within a period of one month. To augment, these responses the project staff

sent outfollow-up reminders to nonrespondents while concurrently contacting information resources such as the

National Clearing House for Drug Abuse

Information, the Student Association

for the Study of Hallucinogens, Inc.

(STASH) and the Addiction Research

Foundation to obtain lists of articles/

books published by those PIs who were

not located by the principal contact

method, Final response was from approximately 60 percent of all PIs.

These’ sources produced the remainder.

To monitor tke communication with PIs

and other information sources and to
organize information received, detailed

recordkeeping systems were developed.

File systems recorded the number of

articles identified and submitted, classified or unclassified, and listed the

literature identified but not accompanied by abstracts or articles. Literature received was checked for complete

publication information and filed by

its appropriate classification category.

Using the prepared resource list of rug

abuse research and medical libraries,

information services and clearinghouses,

the project staff attempted to locate

the several hundred articles which PIs

identified but which were not forwarded

or classified by the investigators.

Once found, these were screened, classified and filed in accordance with

project specifications.

Following the’ collection of all identified articles and/or books, the final

classification system and entry format

were defined. Each entry was then

formatted (accompanied by its authorprepared abstract or summary where

available), cross-referenced where

necessary and prepared for final submission to NIDA.

FORMAT AND ANNOTATION SYSTEM

In order to create a bibliography of

optimal use, several questions were

kept in mind throughout the design

stages : “What format most readily

would facilitate the bibliography‘s

use ?” and “What information about each

item is necessary for subsequent location by users?” These questions were

carefull considered throughout the

bibliography design process.

The format design reflects the bibliography‘s principal, in tended use (i.e.,

for program planning and evaluation) by

organizing the material into program/

subject areas. Within each category

the entries are organized alphabetically by author. To facilitate identification of new entries and location of

cross-references, the author’s(s‘)

name(s) appears in capital letters.

Publication and descriptive information

about each item is provided in a standard bibliographic format which supplies

information about the author(s) or

editor(s), title of the chapter or article, source (book, proceedings or

journal) including volume numbers and

pages where applicable, book’s publisher

and dates of publication or presentation.

v

Following the entry‘s bibliographic

information the author-prepared abstract or summary is included.

Whenever possible, author-prepared

summaries, abstracts or short conclusions are used to describe the articles,

books and proceedings. Since authorprepared abstracts are not always required by the publisher, both annotated

and nonannotated citations are found in

the bibliography. The intended use of

the bibliography required that the

findings be consistently validated.

There fore, when no author-prepared

abstract was available, the project

staff did not attempt to summarize the

findings. In the same vein, no attempt

has been made to change or edit the

abstracts and summaries for consistent

language; thus, words such as ‘our’ and

‘I’ still remain.

Missing abstracts are not available for

a number of reasons: the articles are

out of print; literature is now “in

press”; papers presented at meetings,

conferences and symposia have not to

date been published; short summaries

were never required. In such cases the

unannotated bibliographic information

has, nonetheless, been provided.

CLASSIFICATION OF ENTRIES

The classification system was designed

to dovetail with the-primary intended

use of the bibliography; to review the

progress of the NIMH-NIDA supported

drug abuse research programs. Thus,

the sections of the bibliography

parallel the program areas of ‘NIDA research: To determine whether the eleven categories are descriptive of the

existing literature, the PIs were requested to indicate which of the

suggested categories were most applicable for their articles and abstracts.

Suggestions of alternative classification categories and systems were

encouraged. A review of the replies

received from the PIs showed that, for

the most part, the program areas also

adequately classified the grantsupported literature.

The ten subject-program categories

that correspond with the first ten

sections of the bibliography are:

I. Methodology of Drug Research

II. Drug Chemistry and Metabolism

III. Mechanisms of Action of

Different Drugs

IV. Behavioral Studies
V. Adverse Effects, Toxicity and

Genetic Effects

VI. Drug Use/Abuse Prevention

VII. Treatment-Related Research

VIII. Psychosocial Studies

IX. Education

X. Epidemiological Studies and

Surveys

INDEXES

The eleventh section, “Peripherally

Related”, was included to list those

materials that do not pertain exclusively to drug abuse research, but which

are produced as an offshoot of NIMH and

NIDA-supported drug abuse projects.

For this reason entries in this category

include references to subcategories such

as therapeutic aspects of various abusable drugs, analytical techniques for

more generalized behavioral research

and the body’s receptors for psychoactive drugs.

CROSS REFERENCES

Because many of the articles and books

summarize findings related to several

of the ten program areas, a crossreference system was developed. In

this way entries could be included in

all relevant subject categories without duplicating the abstracts for each

listing. The annotation for any crossreferenced entry can be found with the

first citation. In subsequent categories the entry includes complete bibliographic information; however, for the

abstract the reader is then referred

to the earlier section.

To increase the usefulness of the

bibliography, indexes have been provided for author/editor and for

subject/drugs, So that the two volumes may be used independently, these

indexes have been inserted at the end

of both volumes. Virtually all index

and cross references are to sections

within the same volume.

CONTENTS OF VOLUME 1

The first volume of Findings of Drug

Abuse Research offers three sections of

entries pertaining to the methodology

of drug abuse research and findings of

basic research into the chemical and

metabolic characteristics of drugs and

their mechanisms of action.

CONTENTS OF VOLUME 2

The second volume of Findings of Drug

Abuse Research includes entries on the

behavioral and clinical aspects of

drug abuse research including results

of studies of adverse effects, prevention and treatment systems and the

literature on human and psychosocial

factors of drug abuse research (i.e.,

psychosocial studies, education and

epidemiology of drug abuse).

The final section, entitled “Peripherally Related”, contains findings from

NIDA-supported drug abuse projects

which do not pertain exclusively to

that subject.
CONTENTS

VOLUME 1

Preface

Introduction

I . Methodology of Drug Research

II. Drug Chemistry and Metabolism

III. Mechanisms of Action of Different Drugs

Index

Author/Editor

Subject/Drugs

iii

iv

5

79

185

324i

VOLUME 2

Preface iii

Introduction iv

IV. Behavioral Studies 385

V . Adverse Effects, Toxicity and Genetic Effects 523

VI. Drug Use/Abuse Prevention 585

VII. Treatment - Related Research 595

VIII. Psychosocial Studies 627

IX. Education 661

X . Epidemiological Studies and Surveys 665

XI. Peripherally Related 691

Index

Author/Editor

Subject/Drugs

729

I

Methodology of

Drug Research

ABBOTT, S.R., ABU-SHUMAYS, A., LOEFFLER, K.O. and FORREST, I.S. High pressure

liquid chromatography of cannabinoids as their fluorescent dansyl derivatives. Research

Communications in Chemical Pathology and Pharmacology (in press)

Four different cannabinoids were converted to their 1-dimethylaminonaphthalene5-sulfonate (dansyl) derivatives. Standard mixtures were separated by high pressure

liquid chromatography and detected with an experimental filter fluorometer with subnanogram sensitivity. The effect of solvent properties on fluorescence spectra and

quantum yields was also studied.

ABRAMS, L.A., GARFIELD, E. and SWISHER, J., editors. Accountability in Drug Education:

A Model for Evaluation. Washington, D.C.: Drug Abuse Council, 1973.

ADLER, F.L. Detection of dependence-producing drugs in body fluids. World Health Organization Technical Report Series, No. 556. Geneva, Switzerland: World Health Organization,

1974.

ADLER, F.L. Drug testing by hemagglutination-inhibition. Immunoassays for Drugs Subject

to Abuse. Edited by S.J. Mule, I. Sunshine, M. C. Braude and R.E. Willette.

Cleveland, Ohio: Chemical Rubber Company Press, Inc., 1974. Pp. 37-43.

ADLER, F.L. and LIU, C-T. Detection of morphine by hemagglutination-inhibition. Journal

of Immunology 106(6): 1684-1685 (1971)

The production of antibodies reactive with morphine and a radioimmunoassay

sensitive to 0.5 ng of the drug has been described. This note confirms these findings

and describes a rapid, simple and inexpensive hemagglutination-inhibition test of equal

or greater sensitivity which appears to be adaptable to the screening of large numbers

of urine specimens with a minimum of effort and equipment. The specific activities of

methadone and of morphine were markedly different. Using one technique, morphine

was 60,000 times more effective an inhibitor than methadone.

5
ADLER, F.L., LIU, C-T. and CATLIN, D.H. Immunological studies on heroin addiction. I.

Methodology and application of a hemagglutination inhibition test for detection of morphine. Clinical Immunology and Immunopathology 1(1): 53-68 (1972)

Hemagglutination-inhibition techniques have been applied to measure morphine

in sera and urines. A rapid screening test and a quantitative test, each capable of detecting 25 pg morphine, have been described. The former allows analysis of 50 specimens/

hr, and both tests require only basic laboratory equipment. Methadone does not interfere;

“false positive” reactions occur in urines from patients receiving codeine, meperidine,

or dihydromorphinone. Dextromethorphan interferes slightly; diphenoxylate and dextropropoxyphene interfere slightly but not consistently. Ingestion of large amounts of poppy

seeds results in positive urine tests. The applicability of hemagglutination-inhibition

and other serological tests to the recognition of heroin abuse has been discussed. It is

concluded that hemagglutination-inhibition merits consideration for the screening of

specimens. and for the quantitation of morphine. The extreme sensitivity of hemagglutination-inhibition and other serological tests highly qualify these procedures for use

as exclusion tests.

ADLER, F.L., LIU, C-T. and CATLlN, D.H. A rapid serological screening test for morphine.

Federation Proceedings 31(2): 807 (March-April. 1972)

A hemagglutination inhibition test for the detection of morphine has been developed into a semi-quantitative rapid screening test that permits 50 analyses/hour/

person. Serum from rabbits immunized with carboxymethylmorphine (CMM) - BSA and

tanned sheep red blood cells coated with CMM-RSA are the test reagents. When adjusted

to a lower sensitivity level of 50 nanograms morphine/ML urine, the test detects heroin

use in serum for 36 hours and in urine for 72-96 hours after last admitted use of the

drug. Methadone in customary maintenance doses does not interfere. Codeine reacts

strongly and dextromethorphan weakly; the cross reactivity of these haptens with antiCMM sera varies with individual animals, suggesting immunochemical complexity.

Cross reactions also occur with meperidine, with aqueous extracts of poppy seeds and,

to a lesser degree, with propoxyphene. It is recommended that this serological

screening test be used for the purposes of determining heroin non-use rather than for

proof of drug abuse.

ADLER, M.W., LIN, C., SMITH, K.P., TRESKY, R. and GILDENBERG, P.L. Lowered

seizure threshold as a part of the narcotic abstinence syndrome in rats. Psychopharmacologia 35: 243-247 (1974)

A decrease in threshold to flurothyl-induced seizures in rats is a sensitive

measure of the morphine primary abstinence syndrome. The test is easy to perform,

yields highly reproducible results, allows for simple statistical group comparisons and

correlates well with the usual methods of assessing withdrawal.

6
AGHAJANIAN, G.K. and BUNNEY, B.S. Central clopaminergic neurons: Neurophysiological

identification and responses to drugs. Frontiers in Catecholamine Research. Edited

by E. Usdin and S.H. Snyder. New York: Pergamon Press, 1973. Pp. 643-648.

By combined neurophysiological and histochemical methods, dopaminergic

neurons of the zona compacta (ZC) of the substantia nigra and the adjacent ventral

tegmental (VT) areas were found to be clearly distinguishable from adjacent nondopaminergic neurons such as zona reticulata (ZR). Of particular interest was the

finding that ZC and VT cells are inhibited by microiontophoretic doparnine (DA) but

are insensitive to acetylcholine. On the other hand, ZR neurons are relatively

insensitive to DA but are excited by acetylcholine at very low ejection currents.

This suggests that if there are cholinergic afferents to the substantia nigra they

would need to impinge upon ZR rather than upon ZC cells to produce a physiological

effect. Drugs which either increase DA availability at DA receptors

such as amphetamine or have a direct DA agonist action such as apomorphine inhibit

the firing of dopaminergic neurons; these results are consistent with the operation of

a compensatory negative feedback system. Conversely, presumed DA receptor

blockers are consistent with the operation of a compensatory positive feedback system.

The soma of dopaminergic neurons appear to have DA receptors since they are responsive to the direct, microiontophoretic application of either DA or the DA agonist

apomorphine. If the terminals of dopaminergic neurons also have such DA receptors,

presynaptic DA receptors then this might explain the postulated receptor mediated

feedback control of striatal tyrosine hydroxylase activity at dopaminergic synapses.

ALTSHULER, H.L. and BURCH, N.R. Period analysis of the electroencephalogram of subhuman

primates. Behavior and Brain Electrical Activity. Edited by N.R. Burch and H.L.

Altshuler. New York: Plenum Press, 1974.

These studies demonstrate that closely related pairs of drugs, cocaine versus

d-amphetamine and chlorpromazine versus pentobarbital, may be distinguished from

one another on the basis of the period-analytic descriptors of the EEG. The differences

observed were in both magnitude and direction of change. In addition, different EEG

characteristics in response to high or low doses or pentobarbital were clearly observed.

These preliminary studies suggest that the period-analytic methodology should prove

useful in future, more detailed studies of the mechanism of action of these and other centrally active drugs.

BADEN, M.M., VALANJU, N.N., VERMA, S.K. and VALANJU, S.N. Confirmed identification

of biotransformed drugs of abuse in urine. American Journal of Clinical Pathology 57(1):

43-51 (January, 1972)

A procedure that has been developed over a 6-year period at the office of chief

medical examiner in New York City for rapid routine identification of drugs of abuse in

urine is described. The urine is extracted at acidic, strongly basic, and weakly basic

ph: the last, ph 8. 5, fraction is hydrolyzed to increase extractable morphine and

codeine. The residues are subjected to thin layer chromatography and suspected spots

scraped from the plates and confirmed by microcrystal examination or spectrofluorometry.

Amphetamines, quinine, methadone, meperidine, propoxyphene, pentazocine, cocaine,

and phenothiazine are present in the strongly basic extract. The acidic drugs, in particular barbiturates and glutethimide, are confirmed by gas liquid chromatography.

This procedure has proved effective for the routine analysis of more than 300 urine

specimens daily for court purposes as well as for a variety of drug abuse identification,

treatment, and followup programs. A rapid sensitive microchromatographic method

for detection of marihuana components from teeth and fingers is also described.

7
BAILEY, D.N. and JATLOW, P.I. Methaqualone, a new drug of abuse: Studies of

analytical methodology and interpretation of serum drug levels in overdose.

Clinical Chemistry 19: 666 (1973)

Methaqualone intoxication is being seen in epidemic proportions in out

community. Serum drug levels were determined in 15 documented cases of methaqualone

overdose seen at our medical center from June to December 1972. Analyses were

performed by gas-liquid chromatography (GLC) by a modification of the method of

Berry (J. Chromatogr. 42, 39, 1969) and by ultraviolet spectrophotometry (UV)

using both chloroform and hexane extraction. Levels obtained by GLC were

significantly lower than those obtained by UV following chloroform extraction

but correlated well with those following hexane extraction. Our studies of serum and

urine indicate that at least one chloroform extractable methaqualone metabolite has

an ultraviolet spectrum similar to that of the unchanged drug. This may in part

explain the higher results obtained by ultraviolet spectrophotometric analysis using

a more polar solvent (chloroform) and may also account for discrepancies in the

literature. This study emphasizes the importance of proper choice of solvent in

the ultraviolet determination of methaqualone.

Since ultraviolet spectrophotometric analysis using hexene extraction

followed by back extraction into 1 N hydrochloric acid yields results that are equal

to those obtained by GLC, it presumably measures only unchanged drug. This

procedure is suitable for emergency use.

Following methaqualone overdose, levels of unchanged drug in serum

ranged From 0.2 mg/100 ml to 2.2 mg/100 ml; levels above 0.8 mg/100 ml were usually

associated with coma in this series. All patients recovered with supportive therapy

only.

BAILEY, D.N. and JATLOW. P.I. Methaqualone overdose: Analytical methodology, and

the significance of serum drug concentrations. Clinical Chemistry 19: 615-629

(1973)

Methaqualone abuse and overdose have recently become “epidemic.” We

determined concentrations of The drug in scrum in 15 cases of overdose by gasliquid chromatography (GLC) and ultraviolet spectrophotometry (UV). Values

by GLC were consistently lower than those determined by UV after chloroform

extraction, but correlaled well with those obtained by UV after hexane extraction.

Our studies show that at least one chloroform extractable metabolite has a

spectrum very similar to that, of the parent drug, This may in part explain the

lower results obtained by GLC and suggests that other reported data based on

UV analysis of chloroform and ether extracts may be too high. Extraction with

hexane, a less polar solvent, followed by back extraction into HCL provides an

accurate UV method suitable for emergency use. Concentration of unchanged

methaqualone in serum after overdose ranged from 2 mg/liter to 22 mg/liter in

this series; those greater than 8 mg/liter were usually associated with unconsciousness.

8
BALL, J.C., ENGLANDER. D.M. and CHAMBERS, C.D. The incidence and prevalence of

opiate addiction in the United States. The Epidemiology of Opiate Addiction in the

United States. Springfield, Illinois: Charles C. Thomas, 1970. Pp. 68-78.

A method for estimating the extent of opiate addiction in the U.S. is described.

It is based upon a combination of the 3 most comprehensive sources of data pertaining

to addicts, that of the Bureau of Narcotics, the New York City Narcotics Register, and

the hospitals. A separate method for calculating the incidence and the prevalence of

addiction was derived. These estimation procedures can he employed for any recent

time period, and they are subject to verification. In 1967 it was calculated that there

were 108,424 known opiate addicts in the U.S. Of this number, 30,885 were first reported during 1967.

BARRY, H. Classification of drugs according to their discriminahle effects in rats. Federation

Proceedings 33(7): 1814-1824 (July, 1974)

Drugs were classified according to their discriminable effects in rats. A discriminative response was established by differential reinforcement in a series of training

sessions under the drug and nondrug conditions or under 2 different drugs. Drug conditions with stimulus characteristics resembling one of the training conditions were

identified by consistent choice of one of the alternative responses during tests under

novel doses or drugs. These tests of discriminative stimulus properties have identified

the following categories of drugs. 1) Central sedatives, including barbiturates and the

minor tranquilizers (chlordiazepoxide and meprobamate); 2) Central anticholinergics

(antimuscarinics); 3) nicotine; 4) marihuana or its component delta-9-tetrahydrocannabinol; and 5) hallucinogens (mescaline, LSD). Drugs with apparently weaker discriminahle effects include 1) chlorpromazine and the other phenothiazines; 2) amphetamine;

and 3) morphine. The discriminative stimulus seems to be a central drug effect, and

the differential response is difficult to estahlish with peripheral drug effects.

BENTLER. P.M. and EICHBERG, R.H. A social psychological approach to substance abuse

construct validity: Prediction of adolescent drug use from independent data sources.

Presented at the National Institute on Drug Abuse Drug Lifestyles Conference, St.

Simons, Georgia, January, 1975.

Some metatheoretical and metaempirical issues in predictive drug abuse

research are reviewed first. The relation of ethics to research in this area, the

importance of possible future applied uses of the research, the role of discriminant

validation in prediction, and the relevance of research to public policy are considered.

The criterion to he predicted is discussed in the context of decisions that need to be

made with respect to its univariate or multivariate nature, the measurement of use vs.

abuse, the possible role of variables correlated with use, and the importance of

operational definitions. Structural considerations related to the measurement of

predictors are discussed next, as related to measures obtained by self-report, peer

and parent-report, behavior observation, performance testing, psychophysiological

methods, archives, and sociological procedures. Principles of prediction relevant

to the design of research in this area are reviewed in the next section. Finally,

empirical drug research using independent peer and parent data sources is reviewed

for its relevance to future NIDA predictive research.

BEN-ZVI. Z., MECHOULAM, R. and BURSTEIN, S. Identification through synthesis of an

active delta-1(6)-tetrahydrocannabinol metabolite. Journal of the American Chemical

Sociey 92: 3468-3469 (1970)

9
BLACKFORD, L.S-C. Surveillance of levels of drug use in a student population. Drug Forum

1(3): 307-313 (April, 1972)

A method of developing comparable rates of drug use in student populations

is outlined. Tested by five large surveys, a set of standardized methods, procedures

and forms makes it possible to produce such information with a minimum of time and

money. The comparability of survey results between years or between areas is

stressed.

BONNET, K. A. and PETERSON, K. E. A modification of the jump-flinch technique for

measuring pain sensitivity in rats. Pharmacology Biochemistry and Behavior

(in press)

The jump-flinch procedure provides a sensitive alternative to the hot-plate

and tail-flick procedures. Analysis of the components of motor responses to

increasing intensity of foot shock presentation has allowed the observational

discrimination of five reliably elicited categories of unlearned responses to

inescapable foot shock. Morphine sulfate differentially altered response category

thresholds in rats. Response category thresholds also differed between Wistar and

Fisher strain rats in analgesic effects of morphine sulfate.

BORGATTA, E.A., LEVENTHAL, H., RITTENHOUSE, J. and BALL, S. Symposium: Problems

in Evaluation Research of Drug Information Programs. Report to the National Academy

of Sciences, 1973.

BORGEN, L.A. and DAVIS, W.M. Vehicle and route of administration as parameters affecting

operant behavioral effects of delta-9-tetrahydrocannabinol. Journal of Pharmaceutical

Sciences 62(3): 479-480 (March, 1973)

Four vehicles for delta-9-tetrahydrocannabinol were compared after intraperitoneal and subcutaneous administrations, using the disruption of food-reinforced,

operant behavior of rats as the test system for cannabinoid activity. Aqueous suspensions based on polyvinylpyrrolidone, polysorbate 80, and a polysorbate 65-

sorbitan monolaurate combination all were effective vehicles for intraperitoneal or

subcutaneous absorption of the cannabinoid. An olive oil solution was poorly effective.

The polyvinylpyrrolidone dispersion appeared to have the most rapid onset of action,

while the polysorbate 65-sorbitan monolaurate combination had the longest duration of

action.

10
BRADY, J.V., GRIFFITHS, R. and WINGER, G. Drug-maintained performance procedures and

the evaluation of sedative hypnotic dependency potential. Presented at the Upjohn Conference on Hypnotics, Kalamazoo, Michigan, July, 1974.

Behavioral procedures for evaluating the abuse potential of pharmacological

agents have received increasing experimental attention over the past decade since the

publication of the classic drug self-infusion studies in the early 1960’s (Weeks, 1961).

For the most part, methodological developments have focused upon the assessment of

a broad range of chemical substances in laboratory animals under conditions which

provide continuous access to the drug (Schuster and Thompson, 1969). and a high

correlation between the compounds self-administered under such conditions and those

abused by man has been demonstrated (Schuster and Balster, 1973). Of more recent

interest has been the concern with evaluations of a given drug’s abuse liability relative

to the range of compounds with demonstrated dependency potential, and with procedures

for ordering the reinforcing properties of such compounds. Behavioral assessment

techniques previously developed for measuring the differential reinforcing effects of

stimuli other than drugs have begun to be applied to the determination of the relative

reinforcing properties of various doses of a single compound, as well as to the rank

ordering of different compounds. In general, experimental drug self-administration

approaches to the problem have focused upon three broad performance measurement

categories: 1) relative rates of responding; 2) progressive ratio or “response cost”

values; and. 3) preference or choice determinations.

BRAESTRUP, C. Gas chromatographic evidence for the presence of 3-methoxy-4-hydroxyphenylethanol in rat brain. Biochemical Pharmacology 21: 1775-1776 (1972)

BRAESTRUP, C. Identification of free and conjugated 3-methoxy-4-hydroxyphenylglycol

(MOPEG) in rat brain by gas chromatography and mass fragmentography. Analytical

Biochemistry 55: 420-431 (1973)

BRAESTRUP, C. 3-Methoxy-4-hydroxyphenylethanol in the rat brain. Journal of Neuropharmacology 20: 519-527 (1973)

The neutral dopamine metabolite, 3-methoxy-4-hydroxypenylethanol (MOPET)

can be measured in the rat brain by a GLC method using a pentaflouropropionic derivative

and electron capture detector. The identity of MOPET is verified by mass spectrographic

analyses.

The endogenous level of MOPET of 16.6 ng/g whole rat brain can be raised

more than four-fold by intraperitoneal injection of L-DOPA, dopamine or MOPET. In

contrast intraventricular injection of dopamine or intraperitoneal injection of L-DOPA

plus a peripheral decarboxylase inhibitor (Ro 4-4602), results in small and insignificant

increase of MOPET in the CNS.

It is concluded that MOPET is probably of low significance to central dopamine

metabolism and that MOPET found in the rat brain is predominantly of peripheral origin.

BRATTIN, W.J. and SUNSHINE, I. Immunological assays for drugs in biological samples.

American Journal of Medical Technology 39(6): 223-230 (June, 1973)

A number of immunological assay systems for the detection of drugs of abuse

in biological samples have become commercially available recently. The general

theory of immunological assays and the specific principles of each assay are discussed.

The advantages and limitations of these methods with respect to non-immunological

techniques are also discussed, and some of the important features of the immunoassays

(sensitivity, reliability, cost, speed) are compared.

11
BROCHMANN-HANSSEN, E. Opium alkaloids XII: Quantitative determination of morphine in

opium by isotope dilution. Journal of Pharmaceutical Sciences 61: 1118-1119 (1972)

A method was developed for quantitative determination of morphine in opium

based on the isotope dilution technique. Morphine-2-3H and morphine N-14CH3 are used

as radioactive standards. A mixture of opium and the radioactive morphine standard

is triturated with dimethyl sulfoxide, dispersed on diatomaceous earth and acidic

aluminum oxide, and suspended in water. The aqueous suspension is transferred to a

chromatographic column of acidic aluminum oxide, and the alkaloids are eluted with

water. Alternatively, the mixture of opium and radioactive morphine is triturated

with a little water and dispersed on diatomaceous earth, and the alkaloid bases are

liberated with ammonia. The powder mixture is transferred to a column of neutral

aluminum oxide and eluted with chloroform-isopropyl alcohol (3:1). Phenolic and

nonphenolic alkaloids are separated by extraction at pH 13, and morphine crystallizes

from the aqueous phase after adjustment of pH to 9. The crystals are collected and

recrystallized to constant radioactivity. Both extraction methods gave the same results. No loss of tritium occurred during the assay, and morphine-2-3H and morphineN-14CH3

 were equally satisfactory as radioactive standards. The method is specific

for morphine, has good precision (0.4%), and requires no elaborate technique.

BROCHMANN-HANSSEN, E., CHEN, C.H., CHIANG, H.C., FU, C-C. and NEMOTO, H.

Opium alkaloids XIV: Biosynthesis of aporphines -- detection of orientaline in opium

poppy. Journal of Pharmaceutical Sciences. 62(8): 1291-1293 (August, 1973)

Orientaline was detected in the opium poppy by an isotope dilution method

based on its biosynthesis from norlaudanosoline. Administration of labeled orientaline

revealed that this alkaloid was not a precursor of isoboldine, and the experimental

results provided no evidence for a pathway involving norprotosinomenine. No conclusion was possible relative to the origin of magnoflorine in the opium poppy.

BROCHMANN-HANSSEN, E., FU, C-C. and ZANATI, G. Opium alkaloids IX: Detection of

coreximine in papaver somniferum L. Based on its biosynthesis from reticuline.

Journal of Pharmaceutical Sciences 60(6): 873-876 (June, 1971)

Protoberberines are biosynthesized in plants from reticuline in such a way

that the N-methyl group of reticuline becomes the methylene group in the 8-position.

It was demonstrated in this study that coreximine, a tetrahydro-psi-berberine, is

also derived from reticuline. (±)-Reticuline-(3-14C) administered to intact opium

poppies was incorporated into coreximine to an extent of 0.174% and controlled

degradation showed that the radioactivity was located at the C-6 position. Consequently, it could be concluded that the opium poppy is capable of converting reticuline

to coreximine, and that coreximine, like scoulerine and isocorypalmine, is a normal

member of the opium alkaloids. In the same way, it was shown that canadine, tetrahydropalmatine, stylopine, and berberine were not present in the plants in detectable

amounts.

12
BROCHMANN-HANSSEN, E., LEUNG, A. T. and RICHTER., W. J. Opium alkaloids

XIII. Isolation of 160 hydroxythebaine. Journal of Organic Chemistry

37: 1881 (1972)

The hydrophenathrene alkaloids of opium have been studied extensively,

and their biosynthesis in the living plant has been established in considerable

detail. Investigation of the minor alkaloid constituents of opium has led to the

isolation of a new alkaloid of this group. It was isolated from the nonphenolic

alkaloid fraction of opium and purified by preparative thin-layer chromatography

(TLC) on a sicica gel and by column chromatography on neutral aluminum oxide.

BURKS, T.F. Vascularly perfused isolated intestine. Proceedings of the 4th International

Symposium on Gastrointestinal Motility, Banff, Alberta, Canada, September 6-8, 1973.

Segments of dog, cat or monkey small intestine were vascularly perfused in

vitro with a physiological salt solution. Motility was measured by intraluminal balloons

or open catheters or by extraluminal strain gages. All three methods gave similar results. The isolated segments maintained viability, judged by electrical and motor

activity and responses to drugs, for up to several hours of isolation. Reasonably

reproducible graded responses to stimulatory agonists were obtained. Quantitative

responsiveness to stimuli remained stable for at least 0. 5 hr. This preparation is

offered as a simple and economical technique for in vitro studies with the intestine.

BURSTEIN, S. and ROSENFELD, J. The isolation and characterization of a major metabolite

of delta-1-THC. Acta Pharmaceutica Suecica 8:699 (1971)

The purpose of the experiments reported here is the identification of the

urinary metabolites of delta-1-THC. These results are a continuation of this project

in our laboratory, some of which have been previously reported. These findings suggest

the possibility than an aldehyde may be an intermediate between 7-OH-delta-1-THC and

the acid. The sensitivity of the conjugates to base indicates that they may be either

esters or amides.

BUSH, M. T. and SANDERS-BUSH, E. Phenobarbital, mephobarbital, and metharbital,

and their metabolites. Chemistry and methods for determination. Antiepileptic

Drugs. Edited by D. M. Woodbury, J. K. Penry and R. P. Schmidt. New York:

Raven Press, 1972. Pp. 293-302.

Those barbiturates which are important anticonvulsants (phenobarbital.

mephobarbital, and metharbital) have structural similarities to a number of other

classes of anticonvulsants (the hydantoins and oxazolidinediones), as well as to

primidone. The chemical and physical properties of all of these compounds have

enough in common to require that procedures for their detection and quantitation

be carefully designed in order to minimize interference. It seems desirable,

therefore, to discuss those physicochemical properties which are important in

the present context, so far as the available data permit.

These properties are basic to all of the methodologies which have been

developed for the separation, identification, and quantification of these drugs.

The subsequent discussion of methodologies will involve their careful consideration.

13
CASHAW, J.L., McMURTHEY. K.D., BROWN, H. and DAVIS, V.E. Identification of catecholamine-derived alkaloids in mammals by gas chromatography and mass spectrometry.

Journal of Chromatography 99: 567-573 (1974)

Tetrahydropapaveroline. the tetrahydroisoquinoline alkaloid derived from

dopamine, is converted in vivo by rats and by rat-liver and brain preparations to

tetrahydroprotoberberine alkaloids. The latter alkaloids have also been identified for

the first time in the urine of parkinsonian patients receiving L-DOPA therapy. These

findings suggest that man, like plants, may have the ability to elaborate several classes

of alkaloids with potentially important pharmacological consequences.

CASHAW, J.L., WALSH, M.J., YAMANAKA, Y. and DAVIS, V.E. Simultaneous determination of biogenic amines and narcotic alkaloids by gas-liquid chromatography.

Journal of Chromatographic Science 9: 98-104 (February, 1971)

A GC method has been developed for the simultaneous determination of

catecholamines. simple tetrahydroisoquinolines, a complex benzyltetrahydroisoquinoline alkaloid as well as the phenanthrene (opium) alkaloids. These chemical

classes of pharmacologically active bases were separated and identified as

trimethylsilylether derivatives on a six ft. 3% OV-1 column. Morphine, normorphine, and codeine were completely separated from each other as well as

from their biosynthetic precursor in the opium poppy. tetrahydropapaveroline

(THP). Additionally, THP is a known alkaloid metabolite of the neuroamine,

dopamine, in animal systems. By this procedure dopamine. its O-methylated

metabolite 3-methoxytyramine. a simple isoquinoline alkaloid derivative of

dopamine formed by condensation with acetaldehyde salsolinol, and THP, as

well as the narcotic alkaloids could be analyzed on a single sample, This method

should be of general applicability to several diverse biomedical problems. GLC

analysis of these compounds would be useful in such areas as alkaloid metabolism

in plant and mammalian systems. drug abuse detection. biogenic amine metabolic

pathway studies, investigations involving the interaction of narcotic alkaloids with

neurotransmitter stores, and especially in alcoholism research concerning the

interaction of alcohol with neuroamine metabolism.

CATLIN, D.H., ADLER, F.L. and LIU. C-T. Immunological studies on heroin addiction.

II. Applications of a sensitive hermagglutination-inhibition test for detecting

morphine to diagnostic problems in chronic heroin addiction. Clinical Immunology and Immunopathology 1(4): 446-455 (1973)

A sensitive hemagglutination-inhibition (HI) assay has been applied to

the detection of morphine (morphine equivalents) in urine or serum. Samples

obtained from 117 known chronic heroin addicts were analyzed in a clinical

trial. Positive results were found in 98% of urine samples collected between

3 and 48 hr after the last admitted use of heroin, while of those analyzed by

the less-sensitive thin-layer chromatography only 56% were positive for the

same time interval. The extreme sensitivity of HI and other serological tests

highly qualify these procedures for excluding the possibility of recent heroin

use. It is concluded that HI merits consideration for the screening of urine

or serum for morphine. The significance of the findings with regard to the

diagnosis of chronic heroin addiction is discussed.

14
CHATTERJIE. N., FUJIMOTO, J.M., INTURRISI, C.E., ROERIG. S., WANG. R.I.H.,

BOWEN. D.V., FIELD. F.H. and CLARKE, D.D. Isolation and stereochemical

identification of a metabolite of naltrexone from human urine. Drug Metobolism

and Disposition 2(5): 401-405 (1974)

Pooled urine samples from patients receiving 100-200 mg of naltrexone

per day orally were extracted; the basic (alkaloid) compounds derived were

isolated by preparative thin-layer chromatography. The major metabolite of

naltrexone was found to be an epimer of N-cyclopropylmethyl-14-hydroxy-7,

8-dihydronormorphine wherein the 6-keto group of naltrexone had been reduced

to yield the 6 beta-hydroxy epimer (an isomorphine). This conclusion was

based on infrared, mass, and nuclear magnetic resonance spectra studies.

Furthermore, the reduction product formed in vitro in a soluble chicken

liver enzyme system from naltrexone and an in vivo metabolite of naloxone

derived from the chicken were found to have the more commonly expected

6 alpha-hydroxy orientation.

CHATTERJIE. N., INTURRISI. C.E., FUJIMOTO, J.M. and ROERIG. S. Species variation in the stereochemistry of a metabolite of naltrexone. The Pharmacologist

16(2) (Fall. 1974)

A major metabolite of naltrexone (I), isolated from human urine was

found to be an epimer of N-cyclopropylmethyl-14-hydroxy-7, 8-dihydronormorphine or EN-2260 (II), wherein the 6-OH group was found to be beta due to

metabolic reduction of the 6-keto group of I. This conclusion was based on

infrared, mass and nuclear magnetic resonance (NMR) spectra studies. The

reduction product of I obtained in vitro using a soluble liver enzyme system

derived from the chicken was found to have a 6 alpha-OH orientation as in II.

while that product from the rabbit was found to have a 6 beta-OH orientation

similar to the stereochemistry of the human metabolite or I. The rabbit liver

enzyme system reduces naloxone to the corresponding 6 beta-OH metabolite.

The in vivo reduction product of naloxone isolated from chicken urine was

found to be the 6 alpha-OH metabolite. These data demonstrate species of

differences in the metabolism of these narcotic antagonists.

CHOULIS, N.H. and PAPADOPOULOS, H. Gas chromatographic determination of methadone

sustained release tablets. Journal of Chromatography (in press)

CICERO, T.J. and MEYER, E.R. Morphine pellet implantation in rats: Quantitative

assessment of tolerance and dependence. The Journal of Pharmacology and

Experimental Therapeutics 184(2): 404-408 (1973)

The development of tolerance to and physical dependence on morphine was

quantitatively examined in rats implanted s. c. with 75-mg morphine pellets. The

animals were maintained for up to seven days after pellet implantation and tolerance

and physical dependence were assessed at daily intervals. Both tolerance and

dependence peaked after three days of pellet implantation and then declined gradually

after this time. The withdrawal reaction precipitated by naloxone in morphinedependent rats was characterized by lacrimation. salivation, an ejaculate-like

discharge, diarrhea, hyperactivity and most notably by wet-dog shakes. Since the

observed withdrawal syndrome included virtually every response which had previously been associated with morphine abstinence in the rat, it appears that morphine pellet implantation produces a degree of physical dependence which is at

least as great as that which can be obtained with more commonly used techniques.

On the basis of these data, it was concluded that the technique of pellet implantation can be used in the rat as a rapid and reliable means of producing a high degree

of tolerance and physical dependence on morphine which are readily quantifiable.

15
COCHIN, J. Methods for the appraisal Of analgesic drugs for addiction liability. Selected

Pharmacological Testing Methods, Vol. 3. Edited by A. Burger. Medicinal

Research Series. New York: Marcel Dekker. Inc., 1968.

The efforts of many investigators, especially those at Lexington and Ann

Arbor, have resulted in methods which permit valid assessments and judgments

to be made regarding the physical-dependence liability, and more recently the

psychological-dependence liability, of new therapeutic agents. Until the day

comes when we have analgetic agents without addiction liability, these methods

will perform a necessary and useful function despite the limitations of their

highly specialized nature and their high cost in time, effort, and money.

COCHIN, J. The use of the animal model in assessing analgesic potency and dependence

liability. Research Animals in Medicine. Washington, D.C.: National Heart

and Lung Institute, NIH, HEW (Publication no. 72-333). Pp. 701-707.

There is no question that the use of animal models will permit investigators to study, assess and evaluate many facets of the phenomenon of addiction in

animals which we were not able to do previously. It is quite possible that the

importance of evaluation of subjective drug effects will decrease as such animal

techniques become more refined and sophisticated and this is, after all, what

animal models are for--to avoid doing in man what can be done in animals and

to help us to understand what happens in man.

COHEN. M. and KLEIN, D. F. A measure of severity of multi-drug use among psychiatric

patients. International Pharmacopsychiatry 6:83-91 (1971)

A method for measuring the severity of multi-drug use among psychiatric

patients has been developed which takes into consideration the three basic criteria

of drug abuse; number of different drugs used, frequency of use and length of use.

The procedure initiated with several mental health professionals rating the druguse patterns of 117 young psychiatric patients with a history of drug abuse. These

ratings were then used to develop scoring criteria for each individual drug and

combinations of drugs. The final result is a method which systematically categorizes drug users as either mild, moderate or heavy users.

COUSSENS, W.R., CROWDER, W.F. and DAVIS, W.M. Morphine induced saccharin

aversion in alpha-methyltyrosine pretreated rats. Psychopharmacologia

29: 151-157 (1973)

Rats pretreated with L-alpha-methyltyrosine (AMT) and then given

pairings of saccharin drinking and morphine infusion subsequently showed a reduced preference for saccharin over water, when compared with control rats.

Control conditions were AMT pretreatment with saccharin-saline pairings,

saline pretreatment with saccharin-morphine pairings, and saline pretreatment with saccharin-saline pairings. A second experiment also showed significantly greater saccharin aversion with morphine-infused, AMT-pretreated rats

than with saline-infused AMT-pretreated rats although the morphine dosage was

lower than that used in Experiment 1. These results suggest that morphine is

aversive to rats that have been treated with AMT.

DAVIDOW, B. Drug testing: A little urine goes a long way. Medical Laboratory

Observer 40 (September-October, 1971)

16
DAVIDOW, B., LIPETRI. N. and QUAME, B. A thin-layer chromatographic screening

procedure for detecting drug abuse. American Journal of Clinical Pathology

50(6): 714-719 (December, 1968)

An efficient screening procedure for the detection of drug abuse is

described. Using a single solvent system, acidic (barbiturates), neutral

(glutethimide), and basic drugs (morphine, amphetamine), are extracted

simultaneously from urine. The drugs are separated by means of thin-layer

chromatography, using a single developing solvent, and are made visible by

spraying with a series of compatible chromogenic reagents. The method is

rapid, sensitive, and suitable for screening a large number of specimens.

DAVIDOW, B. and QUAME, B. Extraction of drugs from urine using disposable

chromatographic columns. The Pharmacologist 13: 309 (1971)

The increasing demand for drug screening analysis has stimulated

investigation directed toward the development of more efficient detection methods.

Using a commercially available disposable chromatographic column, drugs such

as amphetamines, barbiturates, morphine, methadone. and quinine could be

extracted from urine and subsequently eluted with an organic solvent. The column

could also be used for the serial sampling of an individual’s urine over a period

of time. In this manner a single analysis would indicate whether an individual has

taken drugs during this time period. The commercial columns were found to be

convenient, rapid to process and equivalent in sensitivity to the conventional extraction procedures. In addition, columns containing the extracted drugs were easier

to transport to the laboratory than were the urines.

DAYTON, H.E. and INTURRISI, C.E. Urinary excretion of naltrexone and its metabolites

in man, rabbit, monkey and rat. Federation Proceedings 34 (1975)

A GLC method has been developed for the simultaneous determination

of Naltrexone (I). 6-beta-OH Naltrexone (II) and B-alpha-OH Naltrexone (III) as

the TMS-derivatives. Analysis of urine from rabbit, monkey and rat demonstrate that, like man, these species reduce I to II but not I to III. In three Naltrexone maintenance patients (125 mg., p.o., 3x/wk.) an average of 37% of a dose

was recovered in the 48 hour urine as free I (0.8%). conjugated I (7.6%), free II

(16.8%) and conjugated II (11.8%). Approximately 34% of the

dose appeared in the urine during 0-24 hours with only 3% recovered during

24-48 hours. The ratio of II/I rose from 2 at 0-4 hours to 34 at 24-48 hours

post drug. In a rabbit given 30 mg/kg/day (i.p.) for 4 days, 9.7% of the daily

dose was recovered in the 24 hour urine as free I (0.1%), conjugated I (7.6%).

free II (0.15%) and conjugated II (1.9%). The ratio of II/I rose from 0.1 at

0-4 hours to 2.7 at 20-24 hours post drug. In monkeys given 30 mg/kg

(p.o. or s.c.) the ratio of II/I increased 10-fold from 0.6 at 0-4 hours to

6.0 at 24-36 hours post drug. Thus, in man and monkey, II is the predominant and persistent urinary metabolite.

17
DeCATO, L., JR. and ADLER, F.L. Recurrence of morphine excretion after single

and multiple dose administration. Federation Proceedings 33(3): 473

(March, 1974)

Extended urinary excretion patterns for morphine HCL (MO) were

studied by means of hemagglutination inhibition (HI). This immunologic

technique can detect the presence of MO plus antigenically similar metabolites (morphine equivalents (ME)) with NG/ML sensitivity. Assays of

individual 24 hr urine specimens from 16 Swiss Webster mice after single

i.p. injections of MO showed a rapid decline in ME/ML to below HI sensitivity

levels within 4 days. Administration of naloxone HCL to 8 mice on day 6 did

not increase their ME excretion. Between days 10-13 about 20 percent of the

mice exhibited a recurrence of ME excretion which was not dependent upon

prior naloxone treatment. More complex excretion patterns were noted

after multiple increasing MO injections. A rapid decrease in ME/ML over

the first 4 days after cessation of injections was followed by a slowly declining plateau for 14 days. Approximately 40 percent of the 16 mice

exhibited large sporadic increases in ME excretion starting 10 days after

the first MO injection. The results suggest that MO or antigenically related

metabolites are sequestered and sporadically released for long time periods

and that this could have significance for current concepts of opioid tolerance.

DeFLEUR, L.B. Biasing influences on drug arrest records: Implications for deviance

research. American Sociological Review (February, 1975)

Despite repeated demonstrations that a variety of factors bias official

records. such records are widely used in deviance research. The crucial

issue relating to such use is whether biasing factors are random (tending to

cancel each other out) or systematic (reducing validity for research to

unacceptable degrees). Deviance statistics are generated in contexts whose

numerous biasing factors can distort the occurrence rates of deviant acts.

This study examines the influence of such factors on drug arrest records in

Chicago. Three decades of arrests were studied and related to findings from

extensive field research in the Narcotics Division of the Chicago Police. Drug

arrest statistics for both whites and nonwhites revealed distinct trends and distributions over time and space. These patterns reflect systematic biases in the

operations of police assigned to the Narcotics Division. These and other such

biases argue that we ought not to rely on indices of drug activity derived from

arrest records.

DENEAU, G.A. The measurement of addiction potential by self-injection experiments in

monkeys. Drug Abuse: Current Concepts and Research. Edited by W. Keup.

Springfield, Illinois: Charles C. Thomas. 1972. Pp. 73-79.

To determine addictional potential, Rhesus monkeys were allowed to

initiate and maintain intravenous self-administration of various drugs. The

monkey’s responses to centrally acting drugs were in most cases similar to

those in man, with the exception of hallucinogens. It was concluded that the

narcotic agents, short-acting sedatives, and stimulants would all have high

abuse liability: However, it was also concluded that mescaline and LSD

would not present serious abuse problems. Hence the procedure should not

be used as the only basis for predicting abuse liability.

18
DENEAU, G.A. Use of the monkey colony in studies of tolerance and dependence.

University of Michigan Medical Center Journal 36: 212-215 (1970)

DEWEY, W.L. Behavioral procedures: An overview. Narcotic Antagonists. Edited by

M.C. Braude, L.S. Harris, E.L. May, J.P. Smith and J.E. Villarreal.

Advances in Biochemical Pharmacology, Vol. 8. New York: Raven Press, 1973.

Operant behavior techniques can be used to obtain potency estimates,

determine duration of action, and study the ability to produce tolerance and/or

physical dependence of narcotic agonists or antagonists. These techniques can

be used to differentiate between those narcotic antagonists producing positive

and those producing negative reinforcing properties. Pentazocine, propiram

fumarate, and cudeine show positive reinforcement properties whereas

nalorphine and cyclazocine show negative reinforcement properties. A

clear distinction is seen in the potency of narcotic antagonists to produce

adverse effects in drug free as opposed to post dependent monkeys. Much

less naloxone or nalorphine is required to produce apparently adverse effects

in post dependent monkeys than in previously drug naive animals. The

problem of adverse effects of narcotic antagonists in treatment of postopiate, addicts may be mininized since tolerance appears to develop to many

of the subjective effects of cyclazocine rather than to its antagonistic

property. The narcotic antagonist analgesics cyclazocine, levallorphan,

and pentazocine increased the response rates in an avoidance schedule and

increased spontaneous activity while producing a decrease in rat whole brain

norepinephrine levels. Naloxone did not block the effect of these drugs on

locomotor activity or on the decrease in whole brain norepinephrine, but did

antagonize their stimulatory effect on operant behavior. This suggests that

only the stimulatory effect of these drugs on operant behavior was specific.

DEWEY, W.L. Narcotic-antagonist assay procedures in dogs. Narcotic Antagonists.

Edited by M.C. Braude, L.S. Harris. E.L. May, J.P. Smith and J.E.

Villarreal. Advances in Biochemical Pharmacology, Vol. 8. New York: Raven

Press, 1973. Pp. 263-272.

Assays of antagonists against overt behavioral effects or respiratory

depression produced by narcotic analgesics in dogs are useful in predicting

narcotic antagonist activity in man. Anesthetized dogs have been used to

test the ability of compounds to antagonize the respiratory depression produced by narcotic analgesics. There is correlation between the activity of

antagonists in reversing respiratory depression caused by opiates in dogs

and their potency in reversing many of the effects of opiates in man.

Physical dependence on narcotic analgesics can be produced in dogs by a

1 day I.V. infusion of an opiate. This model can be used for studying addiction liability of an unknown compound or for the ability of pretreatment with

an antagonist to inhibit dependence development. Though time consuming

and expensive, dog assays are reproducible. However, quantification of

dog responses has presented difficulties.

19
DIAB, I.M., FREEDMAN, D.X. and ROTH, L.J. lysergic acid diethylamide:

Cellular autoradiographic localization in rat brain. Science 173: 1022-1024

(September, 1971)

Intravenous administration of lysergic acid diethylamide (LSD)

to rats resulted in accumulation of the drug in the brain within 15 minutes.

Autoradiographic methods were used to differentiate free and bound LSD

in brain tissue. Free LSD was generally distributed in the pituitary and

pineal glands, cerebellium, hippocampus, and choroid plexus. Bound

LSD was localized in neurons of the cortex, caudate nucleus, midbrain, and

medulla, as well as in choroid plexus epithelium.

DIAB, I.M. and ROTH, L.J. Cellular autoradiography of 3H-LSD in brain, 3H-thymidine

in intestine, WR-2529-14C in bone utilizing dry mounted, frozen, freeze-dried

sections. Journal of Microscopy 96(Part 2): 155-164 (October, 1972)

An autoradiographic technique utilizing freeze-dried frozen sections

dry mounted on dry photographic emulsion was used in conjunction with conventional histological tissue processing, i.e. fixed, dehydrated, cleared,

embedded, de-embedded, and wet-mounted on photographic emulsion. to

differentiate between the free and the bound form of the compounds. The

freeze-dried frozen section method was extended to include undecalcified,

unfixed, unembedded hardbone, cartilage and bone marrow with good

histological details. The compounds utilized were 3H-thymidine in the

intestinal tissue and 3H-LSD in brain tissue and the radio-protective agent

WR-2529-14C in bone. The localization of 3H-LSD in the various regions

of the brain are also described. Solid-liquid nitrogen slush -210°C, having

increased temperature gradient and good thermal conductivity was used for

freezing tissue samples without ice crystal formation or tissue destruction.

DOORENBOS, N.J., FETTERMAN, P.S., QUIMBY, M.W. and TURNER, C.E.

Cultivation, extraction, and analysis of Cannabis sativa L. Annals of the

New York Academy of Sciences 191: 3-14 (December. 1971)

DROPPLEMAN, L.F. and McNAIR, D.M. Screening for anticholinergic effects of

atropine and chlordiazepoxide. Psychopharmacologia 12: 164-169 (1968)

Mild tranquilizers are suspected of having anticholinergic as well as

anti-anxiety effects; if so, a reduction in palmar sweating in response to a

tranquilizer cannot be interpreted simply as an anti-anxiety effect. A simple,

reliable, and valid technique for measuring palmar sweating was used to compare the response curves of placebo; a known anti-cholinergic agent, atropine

sulfate; and a mild tranquilizer, chlordiazepoxide, in a double-blind, balanced,

repeated measures design. A significant atropine effect and reliable correlations

with arousal were demonstrated, and no evidence of an anticholinergic effect of

chlordiazepoxide was found within 90 min with the drug dosage used. Conditions

are specified for the appropriate use of the FSP as a measure of the anti-anxiety

effects of chlordiazepoxide.

20
DYKSTRA, L. and McMILLAN, D.E. Shock-intensity adjustment by squirrel monkeys

under a titration procedure following administration of morphine, nalorphine,

pentazocine, propoxyphene, delta-8-tetrahydrocannabinol (delta-8-THC) or

chlorpromazine. Federation Proceedings 33: 516 (1974)

A titration procedure was used to determine the level at which squirrel

monkeys would maintain an A.C. electric current applied continuously to their

tails. Under the titration procedure the intensity of the electric shock increased

by 0.25 milliamperes (mA) every 2 seconds to a maximum level of 8.00 mA.

Each response on a lever by the monkeys reduced the shock intensity by 0.25

mA. Under control conditions the monkeys responded at a rate which maintained

the shock intensity between 0 and 0.75 mA. Injections of morphine (1-4 mg/kg),

nalorphine (5-30 mg/kg), pentazocine (3-17. 5 mg/kg), propoxyphene (3-100 mg/

kg) delta-8-THC (5.6-15 mg/kg or chlorpromazine (0.3-3 mg/kg were given 30

minutes before some sessions. The monkeys adjusted the shock intensity to

higher levels after morphine (2, 3 and 4 mg/kg), pentazocine (10 mg/kg), propoxyphene (56 mg/kg) and delta-8-THC (15 mg/kg). Increases in the shock intensity

after morphine were much larger than increases obtained after administration of

the other drugs. After nalorphene, the shock intensity was not adjusted to higher

levels, although vomiting was observed after the higher doses. Chloropromazine

either completely eliminated responding for long periods of time or had no effect.

EBBIGHAUSEN, W.O.R., MOWAT. J.H., STERNS, H. and VESTERGAARD, P. Mass

fragmentography of morphine and 6-monoacetylmorphine in blood with a stable

isotope internal standard. Biomedical Mass Spectrometry 345-354 (1974)

A mass fragmentographic method for the estimation of free and bound

morphine and free 6-monoacetylmorphine in blood has been developed. It

uses stable isotope internal standards and has a sensitivity of about 1 ng per ml

or about 100 times better than ordinary gas chromatography. The focusing on

specific high molecular fragments of the molecules gives high specificity to

the assay and the stable isotope internal standards allow correction for losses

occurring in the preparative steps of the analysis. A sensitive, specific method

for monoacetylmorphine is particularly valuable since this compound seems to

be a specific metabolite of heroin.

EBBIGHAUSEN, W.O.R., MOWAT. J.H., VESTERGAARD, P. and KLINE, N.S. Stable

isotope method for the assay of codeine and morphine by gas chromatographymass spectometry. A feasibility study. Advances in Biochemical Psychopharmacology, Vol. 7. New York: Raven Press, 1973. Pp. 135-146.

EICHBERG, R.H. and BENTLER, P.M. Current issues in the epidemiology of drug

abuse as related to psychosocial studies of adolescent drug use. Presented at

the National Institute on Drug Abuse Drug Lifestyles Conference, St. Simons,

Georgia, January, 1975.

Developing a set of potentially heuristic items to predict drug use is

discussed in terms of current issues in the epidemiology of drug abuse. The

utility of predictive research is questioned in view of multi-dimensional complexities in the drug field. The problem areas of defining terms, deciding

the type of predictions desired, selecting relevant target populations, being

cognizant of fads, and keeping in mind a variety of data sources which might be

necessary to complete a prediction equation are focused on. Demographic

variables which are relevant to predicting drug use are briefly reviewed. Additionally, the nature of a possible collaborative research effort is evaluated in

relation to the importance of interpreting data regarding trends and dynamics of

the populations being studied.

21
ELLINWOOD, E.H., ASNIS, S.F., HAMMOND, W.E. and LLOYD, S.C. Drug abuse

record keeping system with an interactive computer. I: Application. Presented

at the 34th conference on Problems of Drug Dependence, Ann Arbor, Michigan,

1972.

ELLINWOOD, E. H., JR. and BALSTER, R. L. Rating the behavioral effects of amphetamine.

European Journal of Pharmacology 28: 35-41 (1974)

A nine point rating scale with a highly standardized protocol for assessing

the continuum behavioral effects of amphetamine (e.g. hyperactivity, stereotypy,

dyskinetic-reactive effects) in rats is described. Dose-response curves for

d- and l-amphetamine were obtained demonstrating a 4 : 1 potency ratio of d- to l-.

The capability of the rating scale to assess antagonism of d-amphetamine by pimozide

suggested that this scale may be a useful quantitative measure of neuroleptic

activity of drugs.

FELDMAN. H. W. Street Status and the Drug Researcher: Issues in ParticipantObservation. Washington, D.C.: The Drug Abuse Council, Inc., 1974.

FENIMORE, D.C. and DAVIS, C.M., JR. Rapid screening of urine for detection of

narcotic drugs. Advances in Mental Science: Drug Dependence. Austin,

Texas: University of Texas Press, 1970. Pp. 242-250.

FENIMORE, D.C., FREEMAN, R.R. and LOY, P.R. Determination of delta-gtetrahydrocannabinol in blood by electron capture gas chromatography.

Analytical Chemistry 45(14): 2331-2335 (December. 1973)

Electron capture gas chromatographic determination of delta-9-

tetrahydrocannabinol (delta-9-THC) in blood serum is described. The compound

is detected as the heptafluorobutyrate on a dual column-dual oven gas chromatograph utilizing a capillary column as the final resolving component. The limit of

detection is below 100 pg per ml with excellent reproducibility using hexahydocannabinol as an internal standard. Blood serum concentrations in experimental

animals injected with 0.1 mg/kg delta-9-THC were determined with levels

below 1 ng/ml four hours after administration.

FENTIMAN, A.F., JR., FOLTZ, R.L. and KINZER, G.W. Identification of noncannabinoid phenols in marihuana smoke condensate using chemical ionization

mass spectrometry. Analytical Chemistry 45: 580 (March. 1973)

FETTERMAN, P.S., DOORENBOS, N.J., KEITH, E.S. and QUIMBY, M.W. A simple

gas liquid chromatography procedure for determination of cannabinoidic acids

in Cannabis sativa L. Experientia 27: 988-990 (1971)

FINK, M. Drugs, EEG and behavior. Chapter X of Drugs and the Brain. Edited by

P. Black. Baltimore, Maryland: Johns Hopkins Press, 1969. Pp. 149-160.

22
FINK. M. EEG classification of psychoactive compounds in man: Review and theory of

behavioral associations. Psychopharmacology: A Review of Progress, 1957-

1967. Edited by D. Efron, J. Cole, J. Levine and J.R. Wilttenborn. Washington,

D.C.: U.S. Government Printing Office, 1968. Pp. 497-507.

This review summarizes studies of the changes in the scalp recorded

EEG in alert man following the administration of psychoactive drugs. Psychoactive

drugs can be classified into four classes and five subclasses according to the

associated EEG changes, despite problems of quantification of the EEG changes

and of behavior and variations in dose of drugs, populations and recording methods.

The BEG classification shows interesting relations to the clinical

applications of the drugs, and leads to the expression of a theory of the association

of EEG changes and behavior.

Applications of this association in man is seen in the identification and

classification of novel psychoactive compounds in the treatment of depression and

psychosis and in the classification of hallucinogenic drugs.

FINK, M. Electroencephalograms, the mental state and psychoactive drugs. Pharmacology

for Physicians 3(5): 1-5 (May, 1969)

FINK, M. The human electroencephalogram: Index of clinical activity of new psychoactive

agents. Modern Problems of Pharmacopsychiatry 2: 106-110 (1969)

The EEG changes with thiothixene in man are increased theta activity

(4. 0-7. 5 cps.), decreased variability of frequencies, and a decrease in fast activity

(13. 5-27. 5 cps.). Of the psychoactive drugs, this pattern is most similar to the

phenothiazine anti-psychotic drugs, and classifies thiothixene as an anti-psychotic

agent.

The classification of psychoactive agents by EEG criteria depends upon

EEG quantification by analog or digital computer methods, especially those that

provide concurrent measurement of changes in frequencies, amplitude, variability

and pattern.

Classification of psychoactive agents by EEG pattern changes in man

provides a method for the identification of new psychoactive drugs in clinical

psychopharmacology.

FINK, M. Quantitative EEG classification of psychoactive drugs in man. The Nature of

Sleep: Proceedings. Edited by U.J. Jovanovic. New York: International

Publications Service, 1973. Pp. 76-78.

23
FINK, M. and ITIL, T. M. EEG and human psychopharmacology. IV: Clinical antidepressants. Psychopharmacology: A Review of Progress, 1957-1967.

Edited by D. Efron, J. Cole, J. Levine and J.R. Wittenborn. Washington, D.C.:

U.S. Government Printing Office, 1968. Pp. 671-682.

Recent studies define direct associations between the clinical activity

and the EEG signatures of psychoactive compounds in man. Among the defined

patterns, the induction of beta and theta activities increased variability of frequencies and reduction in alpha activity characterize two active tricyclic antidepressants, imipramine and amitriptyline, and some anticholinergic drugs, as

Ditran and atropine.

The EEG patterns of the benzomorphan analgesic and narcotic anatagonist

cyclazocine, are similar to those of imipramine.

Two open clinical studies of cyclazocine in depressed psychotic subjects

demonstrate clinical anti-depressant activity similar in degree to imipramine.

The use of EEG in the identification and classification of clinically active

anti-depressants is suggested.

FINK, M., ITIL, T. and SHAPIRO, D. Digital computer analysis of the human EEG in

psychiatric research. Comprehensive Psychiatry 8: 521-538 (1967)

FINK, M. and SHAPIRO, D.M. EEG indices of CNS bioavailability of psychoactive drugs.

Electroencephalography and Clinical Neurophysiology 33: 246-247 (1972)

Previously, we examined the EEG literature and defined the types of

EEG changes with known psychoactive drugs. These profiles have been used to

classify new experimental drugs, and to develop time and dose response curves.

In earlier studies we defined the antidepressant qualities of cyclazocine. the

mixed antidepressant antianxiety qualities of doxepin, and the sedative qualities

of fenfluramine, demonstrating a utility of the EEG classification for new drug

identification (Ann. Rev. Pharmacol., 1969, 9:241)

In defining time and dose relationships, these methods were first used

to distinguish two oral doses of amobarbital. 50 and 100 mg, from a 300 mg

sustained release formulation: and again to distinguish oral amobarbital, 50 and

100 mg from dextroamphetamine (10 mg) and fenfluramine (40 mg). We have also

applied the technique to two formulation questions as measures of bioavailability in

the CNS: a comparison of oral thiothixene in concentrate and capsule forms; and

two formulations of doxepin from different manufacturers.

These studies are done in male volunteers, using digital period analysis,

320 sps. 20 sec epochs, and a continuous alerting task. The effects of each drug

dose and formulation are compared to placebo for each of 20 measured variables,

using linear regression data reduction.

The data of two studies, thiothixene and doxepin, will be used to exemplify

the present state of this method as an index of drug bioavailability.

FINK, M. and SHAPIRO, D.M. EEG patterns as an index of clinical activity of psychoactive

drugs. Electroencephalography and Clinical Neurophysiology 27: 710 (1969)

The human scalp record of cerebral electrical activity is easily recorded,

sensitive to drug effects and related to clinical behavior. Frequency analysis,

amplitude integration, averaged evoked response, activated EEG to barbiturates

and chloralose, and changes during all night sleep recording are among the many

methods of analysis that have been investigated.

24
Fink, M. and Shapiro, D. M. EEG patterns . . . continued

In a review of the effects of psychoactive drugs in man a classification

of drugs emerges which is related to the clinical efficacy of the compounds. This

classification is being applied to the identification of the clinical effects of new,

potentially psychoactive compounds.

1. The EEG pattern of cyclazocine is similar to that of imipramine, and

in clinical trials it was found to be an active antidepressant.

2. The EEG patterns of thiothixene and trifluperidol are similar to

chlorpromazine. The psychoactive range is in the same class.

3. The EEG patterns of fenfluramine. an anorexigenic compound, are most

like 50 mg amobarbital and differ from dextroamphetamine. In clinical trials,

the principal secondary effects have been sedation and drowsiness.

4. Time-dose studies of 50 mg and 100 mg amobarbital and 300 mg sustained

release amobarbital showed different patterns for the different drug forms.

5. The separation of sympathomimetic and anticholinergic hallucinogens

by EEG criteria provides a basis for the selection of appropriate antagonists.

Quantitative EEG provides a useful means of identifying and classifying

psychoactive drugs in man for therapeutic purposes.

FINK, M. and SHAPIRO, D.M. EEG-profile for psychopharmacology: A progress report.

Electroencephalography and Clinical Neurophysiology 31: 103-106 (1971)

Since the mid-1950’s. quantitative studies of EEG changes with psychoactive drugs demonstrate intimate relationship between changes in the human scalp

EEG and the behavioral effects of psychoactive drugs. A review of the literature

of drug effects on EEG in alert man yielded a useful classification of psychoactive

drugs (Ann. Rev. Pharmacol. 1969, 9: 241). This scheme classifies known psychoactive drugs into clinically similar clusters.

Using period analysis, digital processing (320 sps, 20-60 sec epochs)

with an IBM 1800 process control system, we have defined EEG profiles of new

compounds, fenfluramine and doxepin, and compared these to the EEG profiles of

amobarbital, dextroamphetamine, diazepam and imipramine, used as standards.

Fenfluramine exhibited a profile highly correlated with that of amobarbital

and doxepin exhibited an EEG profile most like imipramine (1 1 measures) with some

similarities to diazepam (4 measures) - both EEG classifications closely related

with their clinical activity.

Bioavailability studies demonstrated equivalent EEG profiles for two

formulations of doxepin; and for two formulations of thiothixene, one capsule and one

liquid concentrate. In the thiothixene study the profiles were identical, but the

onset was 12-15 min earlier for the concentrate.

Profile studies have also been done with new compounds before clinical

trial, and the EEG profiles utilized in identification of target populations and

symptoms.

These data extend the classification model and support a theory of association

of EEG and behavior with psychoactive drugs.

FISHMAN. J., COTTER, M.L. and NORTON, B.I. Narcotic antagonists. 2. Preparation

and biological stability of naxolone-7, 8-3H. Journal of Medicinal Chemistry 16:

556-557 (1973)

FISHMAN, J. NORTON, B.I., COTTER, M.L. and HAHN, E.F. Preparation of morphine6-3H and its isotopic stability in man and in rat. Journal of Medicinal Chemistry 17(7):

778-781 (1974)

25
FISHMAN, J., NORTON, B.I. and HAHN, E. Differential distribution of opiate agonists

and antagonists in the rat brain as determined by double isotope techniques.

Presented at Meeting of the American Society of Biological Chemists, 1974.

The simultaneous or sequential administration of an opiate agonist and

antagonist labelled with different isotopes allows for the precise determination of

their relative concentrations in specific areas of the CNS. Disproportionately

greater antagonist to agonist concentration ratios in specific CNS sites could be

indicative of opiate receptor presence and allow its localization under physiological conditions. Male rats were injected with morphine-N-14CH3

 and simultaneously or 15 and 25 minutes later with naloxone-7, 8

3H. All animals were

sacrificed 30 minutes after the morphine injection and the 3H and 14C content of

various tissues was obtained after combustion in a tissue oxidizer. The 3H to

14C ratio in the brain was 7 times greater than in the blood. Within the brain the

medial thalamus exhibited significantly greater 3H to 14C ratios than other CNS

sites reflecting relatively greater naloxone and diminished morphine uptake.

Reversal of isotopic markers by using morphine-63H and naloxone-N-14C-allyl

did not alter these results indicating that N-demethylation was not responsible for

the observed disproportionation. The foregoing data is consistent with the localization of opiate receptors in the medial thalamus of the rat brain.

FISHMAN, J., NORTON, B.I. and HEMBREE, W. Preparation of morphine-3H by microwave discharge activation of tritium gas. Journal of Labelled Compounds 9(3):

563-565 (July-September, 1973)

FISHMAN, J., ROFFWARG, H. and HELLMAN, L. Disposition of naloxone-7, 8-3H

in normal and narcotic-dependent men. The Journal of Pharmacology and

Experimental Therapeutics 187(3): 575-580 (1973)

Naloxone-7, 8-3H was administered intravenously and orally on separate

occasions to the same normal male subject and its disposition was examined.

The fate of intravenous naloxone-7, 8-3H was also studied in an opiate-dependent

subject both while on heroin maintenance and after withdrawal. In all cases the

urinary excretion was rapid but incomplete, never exceeding 70% of the dose over

72 hours. Initial plasma concentrations of naloxone were low with a rapid rate of

disappearance. Oral naloxone entered plasma quickly but in a metabolized form.

The volume of distribution, plasma half-life and metabolic clearance rate of

naloxone as calculated from the intravenous studies were about 200 liters, 90

minutes and 2500 liters/day, respectively.

FORREST, F.M. and FORREST, I.S. Piperacetazine in chronic mental patients: Clinical

observations and new urine color test. Current Therapeutic Research 14(11):

689-695 (November, 1972)

Piperacetazine in daily doses of 25 to 150 mg. was administered to 22

male patients with chronic mental illness for periods of six weeks to 15 months.

Maximum improvement occurred in the dosage range of 30 to 75 mg. per day.

Infrequent side effects (insomnia and akathisia) were dose-related. Three

patients (14%) improved beyond the level reached by previous chemotherapy and

were discharged from the hospital. Seven patients (32%) showed marked or

moderate improvement. Six patients (27%) were unchanged, while six patients

(27%) were rated worse.

A rapid urine color test for direct semi-quantitative determinations of

excreted piperacetazine was developed for three dosage levels.

26
FORREST, I.S., BROOKES, L.G. and BARTH, R. Use of hepatic microsomes in the

preparation of model drug metabolites. Proceedings of the Western Pharmacological Society 13: 1-4 (1970)

FORREST, I.S., FORREST, F.M., BOLT, A.G. and SERRA, M.T. An attempt to

correlate urinary chlorpromazine excretion with clinical response to drug

therapy. Proceedings of the 5th International Congress on Neuro-PsychoPharmacology. Amsterdam, the Netherlands: Excerpta Medica Foundation,

1967. P. 1186.

FORREST, I.S., GREEN, D.E. and SERRA, M.T. The use of XAD-2 nonionic polymeric

adsorbent in the analysis of chlorpromazine and its metabolites. Psychopharmacology Bulletin 9(2): 20-21 (1973)

FORREST, I.S., GREEN, D.E. and WURSCH. 3H-delta-9-tetrahydrocannabinol (THC)

metabolites in rhesus monkey urine: Efficient new extraction procedures and

implications for metabolite structures. Abstracts of Volunteer Papers. Fifth

International Congress on Pharmacology, San Francisco, California, July, 1972.

FORREST, I.S., ROSE, S.D., BROOKES, L.G., HALPERN, B., BACON, V.A. and

SILBERG, I.A. Fluorescent labeling of psychoactive drugs. Agressologie 11:

127-133 (1970)

Fluorescent derivatives of demethylated or hydroxylated metabolites

of the psychoactive drugs chlorpromazine, imipramine and amitlptyline have been

prepared by “dansylation”. These compounds have been characterized by thin

layer chromatograph spectro photofluorometry and mass spectrometry. They

will serve as reference compounds for identification and assay of biotransformation products of these drugs in biological material from patients and experimental

animals.

FRACCHIA. J. F., FIORENTINO. D., SHEPPARD, C. and MERLIS, S. A comparison of

techniques for the scoring of avoidable errors on the Raven Progressive Matrices.

Journal of Psychology 72: 93-98 (1969)

The Raven Progressive Matrices of 88 narcotic users, divided into four

MMPI profile pattern groups, were scored for avoidable errors with the use of

three scoring methods. Two of the methods defining avoidable errors in terms

of empirically determined item-difficulty levels indicated significantly more

reasoning errors were made by patients with paranoid profiles than by

patients with either primary or secondary sociopathic patterns. The third

method, based upon expected set scores, did not score significantly different

numbers of avoidable errors in the four groups. The data were interpreted as

indicating that the manner of defining and that of scoring RPM avoidable errors

are important factors in determining sensitivity to reasoning errors related to

pathological ideation. It was suggested that where mental illness affects

consistency of performance, appropriately defined and objectively scored avoidable

error measures can be used to assess the impairment of intellectual functioning.

27
FRACCHIA, J., FIORENTINO, D., SHEPPARD, C. and MERLIS, S. Raven Progressive

Matrices avoidable errors as a measure of psychopathological ideational

influences upon reasoning ability. Psychological Reports 26: 359-362 (1970)

The Raven Progressive Matrices protocols of 88 narcotic addicts, divided

into four MMPI profile pattern groups, were scored for avoidable errors. Ss having

psychotic-like profiles (428’ and 987’) made significantly more avoidable reasoning

errors than Ss with sociopathic patterns (42’ and 49’). These data were interpreted

as evidence of the sensitivity of avoidable error measures to disturbances in

consistency and accuracy of comparative and analogical reasoning performance.

It was suggested that avoidable error indices might be used to (a) judge the effects

of pathological ideation upon complex reasoning, (b) estimate potential level of

intellectual functioning in clinical populations, and (c) serve as a criterion for

treatment efficacies.

FRIEDHOFF. A.J. Co-crystallization analysis: A short method for identification and

quantitative determination of DMPEA and other biological compounds.

Biological Psychiatry 5(2): 199-206 (1972)

A rapid quantitative method was developed for the determination and

identification of dimethoxyphenethylamine (DMPEA) or any compound, which

can be acetylated, or otherwise coupled with a radioactive compound to form

a crystalline labelled derivative. Material in extracts of biological tissues or

fluids is subjected to acetylation with 14-C-acetic anhydride. The unlabelled

acetyl derivative of the compound to be assayed is added to the mixture of

acetylated material as a carrier, and repeated fast “forced out” coprecipitations are carried out followed by several normal crystallizations. A

weighed portion of the crystals are then subjected to two-dimensional chromatography and radioactivity on one appropriate area of the chromatogram is

determined. From the specific activity of the final carrier crystals, the quantity of the compound being assayed can be determined. This method should

make it possible to obtain proof of identity and carry out quantitative analysis

of many compounds that were difficult or impossible to assay by previous

methods.

FRIEDHOFF, A.J., SCHWEITZER, J.W. and MILLER, J. Biosynthesis of mescaline

and N-acetylmescaline by mammalian liver. Nature 237: 454-455 (June, 1972)

28
GARRETT, E.R., BRES, J., SCHNELLE, K. and ROLF, L.L., JR. Pharmacokinetics

of saturably metabolized amobarbital. Journal of Pharmacokinetics and

Biopharmaceutics 2(1): 43-103 (1974)

The pharmacokinetics of intravenously administered amobarbital

(5-40 mg/kg) and its major metabolite, hydroxyamobarbital, were evaluated by

GLC monitoring in the blood and urine of dogs. The induction of alkalosis and

acidosis by adjustment cf respiration rates and by modification of blood pH

showed relatively instantaneous and significant changes in apparent blood levels

of the amobarbital that could be assigned to variable ratios of ionized to unionized drug, with the latter showing greater partition into peripheral tissues,

i.e., an effective change in apparent volumes of distribution. It was demonstrated

that metabolism of amobarbital was a saturable process and largely zero order

over the entire dose ranges studied. The rate of appearance of hydroxyamobarbital was of the same magnitude for the various doses. Enzymic induction by

prior chronic administration of phenobarbital dramatically increased the rate of

metabolism, and the operational pharmacokinetic model was consistent with the

two-compartment open body model with first-order transferences. This model

also held at all times for intravenously administered hydroxyamobarbital. The

administration of SKF 525 greatly inhibited the rate of amobarbital metabolism

in the dog.

GARRETT, E.R. and HUNT, C.A. Physicochemical properties, solubility, and protein

binding of delta-9-tetrahydrocannabinol. Journal of Pharmaceutical Sciences

63(7): 1056 -1064 (July, 1974)

The rate and extent of glass binding of delta-9-tetrahydrocannabinol

in aqueous solution depend on the surface area and pretreatment of glass and the

concentration of the drug. A total of 20 and 40% at 0.1 and 0. 05 mu-g/ml, respectively,

was bound to 50-ml volumetric flasks but could be minimized by silyl pretreatment of the glass. The drug rapidly diffused into plastics, and 70-97% was taken up

by the rubber closures used for plasma vials. These bindings precluded classical

methods of solubility determination, so spectral and particle-size counting determinations, which observed those concentrations at which true solution was terminated,

were used. The aqueous solubility was a linear function of both the ethanol concentration (increasing) at constant ionic strength and the square root of the ionic

strength (decreasing) at constant ethanol concentration. The salting-out coefficient was of high magnitude and typical solubilities were 2.8 mg/liter in water

and 0.77 mg/liter in 0.15 M NaCl at 23°. The bindings also precluded the use of the

classical methods of equilibrium dialysis and ultrafiltration to determine the protein

binding of tetrahydrocannabinol. A method of variable plasma concentrations was

devised, so protein binding was determined from the pseudoplasma concentrations

of the drug after the separation of the pseudoplasma from the red blood cells added

to form pseudoblood with known concentrations of delta-9-tetrahydrocannabinol.

This use of the competition between the high partitioning of drug

between red blood cells with plasma water (H)= 12. 5) and the binding to plasma

protein permitted an estimate of 97% binding which was not drug concentration

dependent. The spectrophotometric pKa of delta-9-tetrahydrocannabinol was

10. 6.

29
Garrett, E.R. and Hunt, C.A. Physicochemical properties . . . continued

Delta-9-tetrahydrocannabinol degraded readily in acid solutions. Subsequent to a

rapid loss, the kinetics appeared to be first-order and specific hydrogen-ion

catalyzed. Concomitantly, small amounts of delta-8-tetrahydrocannabinol were

were produced, as were two GLC observable products, P2 and P3, and the rate

of their appearance appeared to parallel the rate of delta-9-tetrahydrocannabinol

degradation. A peak, P1, also appeared almost instantaneously but did not

parallel drug degradation.

GARRETT, E.R. and HUNT, C.A. Picogram analysis of tetrahydrocannabinol and application to biological fluids. Journal of Pharmaceutical Sciences 62(7): 1211-1214

(July, 1973)

GARRETT, E.R. and TSAU, J. Stability of tetrahydrocannabinols I. Journal of

Pharmaceutical Sciences 63(10): 1563-1574 (October, 1974)

Delta-9-tetrahydrocannabinol, as monitored by flame-ionization GLC

at various temperatures, degrades by a biphasic semi-logarithmic curve with

time in acidic aqueous solution (less than 1 mg/liter) below pH 4 to GLC-observable

products with separate retention times and the degradations are specific hydrogenion catalyzed. The products are considered as delta-8-tetrahydrocannabinol,

P1, P2 and P3 and can be observed and isolated by TLC. These products do not

appear above pH4 in the neutral region, and these degradations are primarily

first order, are not biphasic, and are pH independent. The half-life of delta-gtetrahydrocannabinol is about 15 min at 37° and pH 1, typical stomach conditions.

The product P1 may give rise to cannabinol by the GLC and TLC procedures since

the IR, UV, TLC, NMR, and GLC of thin-layer chromatographed P1 and cannabinol

are coincident, but chloroform extracts do not show the higher absorbances

expected if the product that forms in solution to give P1 is cannabinol. The

products P2 and P3, isolated by TLC, are consistent with the expected properties

of delta-9-hydroxycannabidiol and 9-hydroxycannabinol, respectively, by IR, UV,

NMR, and mass spectroscopy. The final amounts of delta-8-tetrahydrocannabinol,

P1, P2 and P3 are in a constant ratio independent of pH below pH 4. Delta-9-

tetrahydrocannabinol, as monitored by flame-ionization GLC, degrades solely by a

first-order process to an equilibrium with P2 and P3 at acidic pH values and the

process is specific hydrogen-ion catalyzed. The equilibrium appears to be independent of pH below pH 4 and is the same when TLC-isolated P2

 or P3 is used as

the starting material. It follows that the acidcatalyzed isolated double-bond

migration favors delta-8-tetrahydrocannabinol over the delta-9 compound, and it

is most probable that the equilibrating P2 and P3 are results of water addition to

the isolated double bond and ether solvolysis. The product that gives rise to the

P1 retention time that ultimately gives cannabinol is structurally indeterminate at

present.

GAZTANAGA, P., ABRAMS, R., SIMEON, J., JONES, T. and FINK, M. Clinical

evaluation of GP-41299: An antianxiety agent of the doxepin type. ArzneimittelForschung 22: 1903-1905 (1972)

GERSHMAN, H., POWERS, E., LEVINE, L. and VANVUNAKIS, H. Radioimmunoassay

of prostaglandins, angiotensin, digoxin, morphine and adenosine-3-5-monophosphare with nitrocellulose membranes. Prostaglandins (in press)

30
GESSNER, P. K. The isobolographic method applied to drug interactions. Drug Interactions.

Edited by P.L. Morselli and S.N. Cohen. New York: Raven Press, 1974.

Pp. 349-362.

GOLDSTEIN, A. Accurate measurement of urinary morphine. New England Journal of

Medicine 286: 1417 (1972)

GOLDSTEIN, A. Partial purification of an opiate receptor from mouse brain. Science

183: 749-753 (1974)

GOLDSTEIN, A., LOWNEY, L.I. and PAL, B.K. Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse

brain. Proceedings of the National Academy of Sciences 68(8): 1742-1747

(August, 1971)

A method is described for analyzing the association of the opiate narcotic

levorphanol with brain tissue into three components: nonsaturable, saturable

nonspecific, and saturable stereospecific. The method may be of general

applicability for the study of the interaction of drugs with body tissues. In

mouse brain the stereospecific binding of levorphanol represents only 2% of the

total association of drug with tissue, and it was found only in certain membrane

fractions. The material responsible for the stereospecific binding might be the

opiate receptor.

GOLDSTEIN, J.W. Assessing the interpersonal determinants of adolescent drug use.

Presented at the National Institute on Drug Abuse Conference on Drug Lifestyles,

St. Simons, Georgia, January, 1975.

The nature of items on model surveys of adolescent drug usage is discussed in the framework of a person-situation interactionist view of use causation.

If drug effects are dependent upon the setting of use, then an assessment of the

social norms of the respondent’s salient reference groups should be valuable.

Usage conceptualized as a dynamic pattern of a range of drugs and viewed according to the role which it plays in the life of the user will be most meaningful. A

changing world means that assessments of usage must be periodically reconceptualized.

CORODETZKY, C.W. Efficiency and sensitivity of two common screening methods for

detecting morphine in urine. Clinical Chemistry 19(7): 753-755 (1973)

Modified procedures are described for extracting morphine from urine

with organic solvents and with paper impregnated with ion-exchange resin, followed

by detection by thin-layer chromatography. I propose that efficiency of extraction

(percent recovery) be defined in terms of the amount of drug reaching the detection

system vs. the amount in the total urine sample analyzed. Percent recoveries

were determined experimentally with 95% confidence limits and 95%, P = .05

tolerance limits, and were 60.6% for the organic solvent procedure and 48.2% for

the ion-exchange paper procedure. Sensitivity of the overall detection method

can be defined as the concentration of drug in the urine detectable at least 99%

of the time. Values (95% confidence limits) determined experimentally were 0.19

(0.14-0.25) mu-g/ml for the organic solvent procedure and 0.16 (0.07-0.35)

mu-g/ml for the ion-exchange paper procedure.

31
GORODETZKY, C.W. Sensitivity of thin-layer chromatography for detection of 16

opioids, cocaine and quinine. Toxicology and Applied Pharmacology 23:

511-518 (1972)

A method has been developed to evaluate quantitatively the sensitivity

of thin-layer chromatography (TLC). For each drug studied, seven different

amounts of the drug and a solvent control are randomly spotted across a 20 x 20

cm thin-layer plate. Ten to 30 such plates are made with the technician blind

to the order of spotting. For each amount of drug, the ratio of (number of spots

detected)/(number of spots plated) is determined, converted to percentage and

plotted on log probability paper. The method of Litchfield and Wilcoxon is used

to determine the amount which can be identified any given percentage of the time

(termed the “identifiable amount” or IA) and its 95% confidence limits. Sensitivity data for 16 opioids, cocaine and quinine, using iodoplatinate alone and

followed by ammoniacal AgNO3 and KMnO4 for spot detection show that TLC

is not uniformly sensitive for the detection of all opioids. Adding AgNO3 and

KMnO4 after iodoplatinate produced an increase in sensitivity, with the exception

of the arylpiperidines studied, levallorphan, propoxyphene, cocaine and

quinine. A relative detection index for each drug, taking into account sensitivity

for detection by TLC, euphorogenic dose and 24 hr urinary excretion relative

to morphine showed that all opioids would not be predicted to be equally detectable

in the urine following administration of equieuphorogenic doses. Rf data show

widely overlapping tolerance limits between drugs, indicating that the Rf of a

single unknown spot would be expected to be a poor measure of specificity

under these TLC conditions.

GORODETZKY, C.W., ANGEL, C.R., BEACH, D.J., CATLIN, D.H. and YEH, S.Y.

Validity of screening methods for drugs of abuse in biological fluids. I. Heroin.

Clinical Pharmacology and Therapeutics 15(5): 461-471 (May, 1974)

In evaluating methods of detecting drugs of abuse in biological fluids it is

of special importance to determine the ability of detecting a drug or its metabolites

in biological fluids. To evaluate several methods of detecting heroin use by urine

analysis for morphine and its metabolites, single intravenous doses of 2. 5 and 5

mg/70 kg heroin were administered a week apart in random order to 10 nontolerant

subjects and their urine was collected for the week following. Along with pre-drug

control urines, each sample was coded, randomized, and analyzed under blind

conditions by the following methods: (1) thin-layer chromatography (TLC) with

iodoplatinate preceded by each of 4 extraction procedures, organic solvent and ion

exchange resin impregnated paper extraction both without and with prior acid

hydrolysis; (2) the free radical assay technique (FRAT); (3) radioimmunoassay

(RIA); and (4) the Technicon Autoanalyzer. There was a high probability of

detection for the first 8 hours by all methods except the Technicon Autoanalyzer

(which gave a low proportion of positives 8 hours after the 2.5 mg per 70 kg

heroin dose); up to 16 hours with TLC procedures with hydrolysis and FRAT; and

up to 32 to 48 hours with RIA.

32
GORODETZKY, C.W. and KULLBERG, M.P. Validity of screening methods for drugs

of abuse in biological fluids. II. Heroin in plasma and saliva. Clinical

Pharmacology and Therapeutics 15(6): 579-587 (June, 1974)

Five subjects received 3 single intravenous doses of heroin, 2.5, 5,

and 10 mg per 70 kg and 1 oral dose of dextromethorphan, 60 mg per 70 kg;

another 4 subjects received morphine, 30 mg, subcutaneously, 4 times per day

for 3 months. Saliva and plasma samples were collected at intervals for 48

hours following each single drug dose and hourly for 6 hours between chronic

doses. Plasma samples were analyzed for opiate by RIA, and saliva samples

by RIA, a modified FRAT, and the EMIT. The low dose of heroin was not

consistently detectable at any sampling time in either the plasma or the saliva.

The medium and high doses were detectable with high probability for 2 to 4

hours in plasma and 1 to 2 hours in saliva. Dextromethorphan was not detectable

in plasma but was detected with high probability in saliva for 30 minutes by

EMIT and 2 hours by FRAT. During chronic administration there were high

probabilities of detection of morphine in plasma for at least 6 hours and in

saliva for 3 to 4 hours after the last morphine dose. While these fluids do not

appear to be as useful as urine in routine screening for heroin, they may be

useful in the detection of high-dose chronic abuse.

GREEN, D.E. Automated detection of abused drugs by direct mass fragmentography.

Proceedings of the Western Pharmacological Society 15: 74-77 (1972)

GREEN, D.E. Direct, multiple ion detection of chlorpromazine by mass fragmentography. The Phenothiazines and Structurally Related Drugs. Edited by I.S.

Forrest, C. J. Carr and E. Usdin. New York: Raven Press, 1974.

Automated specific molecule detection by means of multiple-ion detection mass fragmentography using a specifically designed dedicated microcomputer

to control the operation of, and to retrieve and analyze the data from, a unique

mass-analyzer system is described. Utilization of this powerful new tool for

the study of drug disposition in a somewhat conventional manner in conjunction

with a gas chromatograph is described.

Examples of direct mass fragmentography (i.e., without the use of a

gas chromatograph) demonstrate the ability of this novel system to detect and

quantitate chlorpromazine and its metabolites at levels from 10 ng to 10 mu-g

in a few seconds in complex biological specimens.

GREEN, D.E. and FORREST, I.S. Fully automated detection and assay of drugs by

“direct multiple-mass fragmentography,” a new, ultra-sensitive analytical

technique. Abstracts of Volunteer Papers. Fifth International Congress on

Pharmacology, San Francisco, California, July, 1972. P. 88.

GREEN, D.E. and LITTLEJOHN, D.P. Automated analysis of biological specimens

using a compound-specific detector. Proceedings of the Western Pharmacological

Society 16: 226-230 (1973)

GREEN, D.E., ROSE, S.L. and FORREST, I.S. New Methodology for the detection and

characterization of drugs and drug metabolites. Proceedings of the Western

Pharmacological Society 14: 187-189 (1971)

33
GROSS, S.J., SOARES, J.R., WONG, S-L.R. and SCHUSTER, R.E. Marihuana

metabolites measured by a radioimmune technique. Nature (in press)

HAMILTON, H.E., WALLACE, J.E. and BLUM, K. Improved methods for quantitative

determination of methadone. Journal of Pharmaceutical Sciences 63(5): 741-745

(May, 1974)

A spectrophotometric method is described that permits the rapid analysis

of methadone in urine or tissues at concentrations corresponding to therapeutic,

maintenance, or toxic doses of that drug. As little as 5 mu-g may be detected

in a biological specimen. The procedure involves an alkaline extraction into

n-hexane and subsequent back-extraction into a ceric sulfate-sulfuric acid

solution. The acid extract is refluxed with n-heptane for 30 min. oxidizing

methadone to benzophenone which, in contrast to the unchanged drug, has a

high molar absorptivity in the UV region. A GLC method is also described.

Both procedures require fewer manipulations and less analysis time than previously reported methods for determining methadone.

HARRISON, S.D., JR., CHIU, P. and MAICKEL, R.P. Polyamide thin-layer chromatographic separation of DOPA metabolites and related compounds. Journal of

Chromatography 85: 151-153 (1973)

The use of L-DOPA in therapy of Parkinsonism has stimulated interest

in the metabolism of this compound in normal and pathologic states. Goodall and

Alton separated 35 DOPA metabolites from the urine of healthy subjects by GLC.

Seventeen of these metabolites, including 11 acidic compounds, were unidentified.

Recently, 3-hydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenyllactic acid,

and 4-hydroxyphenyllactic acid were identified in the urine of patients receiving

large oral doses of L-DOPA. More recently, 3-hydroxyphenylacetic acid has

been shown to be produced from DOPA by the intestinal microflora. The substituted phenyllactic acids are products of a transamination pathway of metabolism

enhanced by large doses of L-DOPA. This pathway, a major route for the

metabolism of L-3-O-methylDOPA, as well as other possible pathways, may have

significance in Parkinson patients, The production of 3-methoxy-4-hydroxyphenyllactic acid by such patients receiving L-DOPA confirms earlier observations of

this metabolite in the urine of patients with DOPA-secreting tumors. The present

study was prompted by the possibility that important DOPA metabolites may not

yet have been identified and by the lack of a simple, readily-available method for

the separation of potential DOPA metabolites differing only slightly in structure.

The advantages of polyamide thin layers for the separation of phenolic

compounds has been recognized. This report includes TLC data obtained with

authentic samples of compounds not previously available for study.

HARVEY, J.A. Physiological and pharmacological analysis of behavior. Advances in

Behavioral Biology. Edited by R. Whalen. New York: Plenum Press, 1974.

Pp. 125-147.

Recent developments in neuropharmacology, neurochemistry and

neuroanatomy provide the contemporary student of brain function with a variety

of techniques and thus the ability to perform manipulations and measurements not

previously possible. In addition, we now know that brain lesions, stimulation or

drugs produce effects on behavior that are mediated via changes in the functional

amounts of putative synaptic transmitters that are localized within defined

anatomical systems. It is no longer desirable, therefore, to employ a single

technique in the biological analysis of behavior. Rather, we have the possibility

of a unitary view concerning the mechanism by which a variety of methods

affect behavior and an ability to relate behavior to anatomy, neurochemistry,

and physiology.

34
HO, I.K., SUTHERLAND, V.C. and LOH, H.H. A model for the rapid development of

tolerance to barbiturates. Research Communications in Chemical Pathology

and Pharmacology 6(1): 33-46 (July, 1973)

The subcutaneous implantation of pellets of sodium pentobarbital

(5.4 mg) in the back of a conscious mouse results in a measurable tolerance

within 24 to 48 hours. The development and the degree of tolerance induced

by pellet implantation were compared with mice receiving daily intraperitoneal injections of anesthetic doses of 75 mg or 100 mg/kg of sodium pentobarbital. An increasing number of mice failed to lose their righting reflex

following each daily implantation and the reduction in sleep time in those that

did was 58 percent following the second pellet at 48 hours and 73 percent following the third pellet at 72 hours. The percent reduction of sleeping time or

degrees of tolerance in response to single challenge doses of either 75 mg or

100 mg/kg, i.p., of sodium pentobarbital in implanted mice were 65 percent

(75 mg) or 68 percent (100 mg) by 24 hours (first pellet), 72 percent for both

doses after 48 hours (second pellet), and 76 percent (75 mg) or 73 percent

(100 mg) after 72 hours (third pellet). These percentages represent a significantly greater reduction in sleep time than the maximum 41 percent reduction

produced on the fourth day of daily injections for 10 days of 75 mg/kg or the

40 percent reduction of sleep time in mice on the third day of five daily doses

of 200 mg/kg of sodium pentobarbital. In addition, there was a reduced mortality rate in repeated pellet implantation as compared to daily injections of

100 mg/kg.

HO, I.K., YAMA MOTO, I. and LOH, H.H. A model for the rapid development of

dispositional and functional tolerance to barbiturates. European Journal of

Pharmacology (in press)

The subcutaneous implantation of a 75 mg pentobarbital pellet in the

back of a conscious mouse resulted in a much more rapid development of tolerance

to barbiturates than that produced in mice receiving daily intraperitoneal injections of 75 mg/kg sodium pentobarbital. Acceleration in tolerance development

by pentobarbital pellet implantation was evidenced by a decrease in sleeping

time after the challenge with either sodium pentobarbital or sodium barbital.

The degree of hepatic microsomal drug enzyme induction after pentobarbital

pellet implantation also was found to be significantly higher than that produced

by the injection technique. Further studies demonstrated that the threshold for

pentylenetetrazol-induced seizures was significantly reduced compared to that

of the sodium pentobarbital daily-injected and control groups. These studies

provide an animal model for studying the mechanism of barbiturate tolerance

and dependence.

HOLDEN, J.M., ITIL, T., SIMEON, J. and FINK, M. Clinical laboratory test standards

in new drug trials. Journal of Clinical Pharmacology and New Drugs 7: 1-8

(1967)

HOLLANDER, C. editor. Collection of Background Papers on Student Drug Involvement.

Washington, D.C.: United States National Student Association, 1967.

35
HOLTZMAN, S.G. and JEWETT. R.E. Shock intensity as a determinant of the

behavioral effects of morphine in the rat. Life Sciences 11 (Part I): 1085-

1091 (September, 1972)

When a relatively high shock intensity is the reinforcer, morphine

produces a well-defined dose-related increase in the rate of avoidance responding in the rat. This is in contrast to the usual depression of behavior associated

with morphine administration. Thus, the qualitative nature of morphine’s

effects on behavior can be a function of environmental determinants. This type

of procedure may be of value for studying certain aspects of the stimulant

component of morphine’s action.

HUANG, J.C-Y. and BADEN, M.M. Rapid methods of screening micro-quantities of

abuse drugs from urine samples for microcrystal tests. Clinical Toxicology

6(3): 325-350 (1973)

A simple, comprehensive and economic system for detection of narcotic

drugs is described. It provides a rapid method for screening microquantities

of abused drugs from urine samples for microcrystal tests. The procedures

and methods are presented.

HUGHES, J., KOSTERLITZ, H.W. and LESLIE, F.M. Assessment of the agonist and

antagonist activities of narcotic analgesic activities of narcotic analgesic drugs

by means of the mouse vas deferens. British Journal of Pharmacology 51:

139-140 (1974)

HUNT, H.F. Unconditioned stimulus functions of drugs: Interpretations, I. Chapter 5

of Stimulus Properties of Drugs. Edited by T. Thompson and R. Pickens. New

York: Appleton-Century-Crofts, 1971.

ITIL, T., SHAPIRO, D. and FINK, M. Differentiation of psychotropic drugs by

quantitative EEG analysis. Agressologie 9: 267-280 (1968)

ITIL, T. M., SHAPIRO, D.M., FINK, M. and KASSEBAUM, B.A. Digital computer

classifications of EEG sleep stages. Electroencephalography and Clinical

Neurophysiology 27: 76-83 (1969)

Various electronic analysis techniques have been used for quantitative

analysis of the EEG during sleep, but due to the lack of reliability and the

expense such procedures entail, they have not achieved general use (Knott et al.

1942; Kaiser et al. 1964; Hord et al. 1965; Maulsby et al. 1966; Agnew et al.

1967). The application of digital computer procedures the analysis of the

sleep EEG, including power spectrum analysis, baseline cross analysis, phase

detection, and averaging techniques, shows promise of greater reliability

(Bickford 1959; Brazier 1961, 1965: Adey and Walter 1963; Burch et al. 1964;

Fink and Shapiro 1965; Johnson et al. 1967; Walter et al. 1967).

We have successfully used on-line digital computer analyses for the

identification and classification of EEG changes induced by psychotropic drugs

(Fink et al. 1967, 1968; Itil 1968a; Itil et al. 1968a,b). Of the methods employed,

analysis of the baseline cross of the primary EEG wave and its first derivative

proved to be the most useful (Burch 1959; Burch and Fink 1964; Shapiro and

Fink 1966); consequently, this technique has been used to objectively classify the

EEG stages in all-night sleep recordings. This report summarizes our recent

investigations and suggests pragmatic solutions to the problem of rapid and

consistent analysis of EEG sleep stages.

36
ITIL, T., SHAPIRO. D., HICKMAN, C., FINK. M. and KIREMITCI, N. The differentiation of tranquilizers by quantitative EEG. Electrocncephalography and

Clinical Neurophysiology 24: 288 (1968)

The majority of EEG studies in recent years have shown that tranquillizers induce various kinds of EEG changes. Investigations of more than

25 tranquillizers have demonstrated in the past that drug induced changes are

related to the type of drug, dosage, method and speed of administration (Itil

1961, 1964). Compounds with different clinical effects produce EEG changes of

different type and quantity.

In the present study using quantitative EEG analyses (power spectral

density analysis with electronic frequency analyzer and period analysis with

computer programs, IBM-1710), 3 tranquillizers with different chemical

structures. pharmacologic. profiles and clinical effects were studied in normal

volunteers and psychotic populations. Our investigations have shown that fixed

body weight dosages of 3 tranquillizers (chlorpromazine, imipramine and

chlordiazepoxide) given i.v. in a fixed amount of time produced signficant changes

in the various EEG frequency patterns of a group of patients and volunteers in

contrast to pre-drug records. Saline did not produce any significant EEG alterations in the same group. Statistical evaluation of the power spectral density

analysis data demonstrated that chlorpromazine, imipramine and chlordiazepoxide

induce significantly different EEG alterations than saline in the total group.

Furthermore, each drug could be significantly discriminated from each other

based on the various quantitative EEG changes. In addition to the power spectral

analysis, period analysis results were obtained using the IBM-1710 and supplied

additional information concerning the characteristic EEG effects and their time

courses.

JACQUET, Y. Intracerebral administration of opiates. Methods of Narcotic Research.

Edited by S. Ehrenpries and A. Neidle. New York: Marcel Dekker, Inc., 1974.

JACQUET, Y.F. and LAJTHA, A. CNS sites of morphine action: Hypo- or hyperalgesia depending on injection site and dose. Proceedings of the 3rd Annual

Meeting of the Society for Neuroscience, Wards Island, New York,

November 7-10, 1973.

Morphine is used therapeutically as an analgesic; yet very little is known

about its CNS sites of action. Assays of different CNS regions following systemic

administrations of morphine have failed to reveal any marked differential distribution of the drug. This may be due to the action of the “blood-brain” barrier,

since it has been estimated that less than 0.1% of the administered dose reaches

the CNS. By using fine-gauge cannula permanently implanted in various subcortical

sites to inject morphine, we were able to deliver precise quantities of the drug to

the intended sites. Morphine (10 mu-g) injected into the posterior hypothalamus

(PH) and the 3rd ventricle resulted in significant hypo-algesia, while the same dose

injected into the caudate, the medial septal nucleus, and the periaqueductal gray

matter (PGM) in the mesencephalon yielded hyper-algesia. Of the latter three,

the last resulted in the most marked hyper-algesia, with rats unable to tolerate

a low level of foot shock which normal rats tolerate without even flinching. This

same area has been reported to give rise to profound analgesia when electrically

stimulated. Morphine has been shown to block the release of acetylcholine in

peripheral and central tissues: thus its action here may be the opposite of

electrical stimulation and may block cholinergic neural transmission in what has

been suggested to be pain-inhibitory pathways.

37
Jacquet, Y.F. and Lajtha. A. continued

These results show that intracerebral injections of morphine differ

in a significant manner from systemic injections of morphine, and result in

either hypo- or hyper-algesia, depending on site and dose. These sites show

specificity in that dextrorphan, the inactive isomer, had no effect at either

the hypo-(PH) or hyper-(PGM) algesia sites.

JAFFE, J., DAHLBERG. C.C. and FELDSTEIN, S. Practical aspects of systematic

research in psychoanalytic office settings: Report of to Committee on Research.

Part IV: Research. Edited by J.H. Masserman. Science and Psychoanalysis,

Vol. XI. New York: Grune and Stratton. 1967. Pp. 202-226.

JAMES, J. Female addictive research. Addictive Diseases: An International Journal

(in press)

JATLOW, P.I. Analysis of drugs and toxicological agents. Gas Chromatography

in Clinical Microbiology and Medicine. Edited by B. Mitruka and

R. Kundargi. New York: John Wiley and Sons, 1975. Pp. 396-416.

The title “toxicological agents” has been interpreted in a narrow

sense in preparing this chapter, which has been restricted to a discussion of

drug analysis. Gas chromatography has been applied to the analyses of other

categories of toxic compounds including carbon monoxide, pesticides, and

organic mercury compounds. Gas chromatography with electron capture

detection is. for example, the method of choice for identification and

measurement of nanogram concentrations of chlorinated hydrocarbon

pesticides.

Gas chromatography has or can be applied to almost every drug in

use today. Although this chapter discusses relatively few of then. it touches

on those drugs or drug categories that are in most common therapeutic use and

which are most often of toxicologic interest. The analysis of these drugs is based

on concepts which are readily applicable to the measurement of those agents

that have been omitted.

JATLOW, P. Chlordiazepoxide analysis. Selected Standard Methods of Clinical Chemistry,

Vol. 8. New York: Academic Press (in press)

JATLOW. P. A rapid ultraviolet spectrophotometric procedure for the analysis of drugs

frequently involved in overdose emergencies. Manual of Analytic Toxicology,

Vol. 2. Edited by I. Sunshine. Cleveland, Ohio: Chemical Rubber Company

Press, Inc., 1971.

JATLOW, P. Toxicology. Gradwohl’s Clinical Laboratory Methods and Diagnoses.

Edited by A. Sonnenwirth and L. Jarett. St. Louis, Missouri: C. V. Mosby

Company (in press)

38
JATLOW, P. Ultraviolet spectrophotometric analysis of barbiturates: Evaluation of

potential interferences. American Journal of Clinical Pathology 59: 167-173

(1973)

Twenty drugs, including salicylic acid and sulfonamides, were studied to

determine whether they interfered with the ultraviolet spectrophotometric

analysis of barbiturates. These were drugs which have been cited as possibly

or probahly interfering with this type of analysis. Only p-aminophenol, which

would not be expected in blood in the free form, interfered. Ultraviolet

spectrophotometry is suitable for the. emergency analysis of barbiturates in

the hospital laboratory. It is recommended that the method selected utilize

extraction at neutral pH, and differential spectrophotometry in which

equal concentrations of drugs at pH 13 and pH 10 are compared directly with a

single scan. The net difference between the absorbances measured at wavelengths of 260 nm. and 240 nm. is least subject to interference and can be used for

quantification. At these wavelengths interference from other drugs is rare.

JATLOW, P. Ultraviolet spectrophotometric analysis of drugs in biological fluids.

American Journal of Medical Technology 39(6): 231-236 (June, 1973)

The application of ultraviolet absorption spectrophotometry to the

analysis of drugs in body fluids is reviewed. Its special suitability for

hospital toxicology is emphasized. Rapid procedures which are suitable for

the emergency analysis of barbiturates, chlordiazepoxide, glutethimide, and

methaqualone in serum are described.

JATLOW, P. Ultraviolet spectrophotometric measurement of chlordiazepoxide in

plasma. Clinical Chemistry 18: 516-518 (1972)

A simple ultraviolet spectrophotometric method is described for measurement of chlordiazepoxide in blood. The drug is extracted into chloroform at pH 7.4

and, after a NaOH wash, extracted back into HCI. The drug is identified by its

characteristic ultraviolet spectra at acidic and basic pH’s, and quantified from the

absorbance value measured at the major acid peak of 247 nm. Although certain

weekly basic drugs theoretically could interfere if present concurrently with

chlordiazepoxide, we have not seen this during three years of experience. This

procedure is easily combined with established methods for barbiturates and

glutethimide. Specimens from more than 60 cases of documented chlordiazepoxide

ingestion have had concentrations ranging from 0.2 to 6.6 mg/100 ml by this

procedure.

39
JATLOW, P. I. and BAILEY, D. N. Gas chromatographic measurement of cocaine in plasma

using a nitrogen detector. Clinical Chemistry (in press)

Cocaine, like most alkaloids, achieves relatively low plasma concentrations

after its use. A nitrogen detector was employed because of its greater sensitivity

and selectivity relative to flame ionization.

The internal standard (IS) was the propyl ester of benzoylecgonine, a homologue

of cocaine. It was prepared in our laboratory by refluxing benzoylecgonine in n-propanol

containing 0.3N HCl, with subsequent purification by preparative thin-layer

chromatography. Four ml of plasma was extracted with heptane containing 2%

isoamyl alcohol and IS. This was followed by back extraction into 0.1 N H2SO4,

alkalinization with solid Na2C03 - NaHCO3 to pH 9.7, and re-extraction into solvent.

The latter was evaporated at room temperature under air, and the residue, dissolved

in methanol, was chromatographed at 255°C on a 3% OV-17 column. Cocaine

standards in plasma were carried through the entire procedure. A model 3920 gas

chromatograph (Perkin-Elmer Corp.) containing a nitrogen detector was used.

The precision (RSD) was 5.3% at an 0.05 ug/ml concentration. Although

as little as 200 pg could be detected, negative sera showed a background equivalent

to 0-.002 ug/ml cocaine.

The method was validated using plasma obtained from patients receiving

mucosal applications of cocaine for local anesthesia. A level of 0.23 ug/ml was

found 15 minutes after topical application of 100 mg.

JATLOW. P., MCKAY. D. and SELIGSON, D. Computer assisted emergency analysis of

drugs. Clinical Chemistry 18: 712 (1972)

A systematic approach to the emergency analysis of drugs in body fluids

has been developed. The total procedure which is designed for emergency

toxicology minimizes manipulations, provides qualitative and quantitative data,

and uses a digital computer for interpretation, computation and reporting of data.

Data is entered by the technologist at a keyboard in response to computer

instructions which relate to each analytic step. Location of major and minor

absorption peaks (at two pH’s in some cases), ratios of major to minor peak absorbances

and peak absorbance values are used in the program for analysis of spectrophotometric

data. Results are printed by the console printer or teletype at each stage of the

analysis. A final lineprinter summary indicates drugs present (with concentration), drugs

absent, and those not tested.

Following a single chloroform extraction at pH 7.4, drugs are partitioned into

the following four groups for spectrophotometric analysis: barbiturates; other weak

acids; bases; other benzodiazepines. Neutral drugs remaining in the solvent are

analyzed by semiquantitative thin-layer chromatography. Alcohol and ethchlorvynol

are determined in a single steam distillate by visible and ultraviolet spectrophotometry

respectively. Drugs not easily detected in blood are identified in urine by

calorimetric tests.

Choice of body fluids for analysis of each drug is consistent with its biological

disposition. The chemistry and data processing are modular, and so can be

abbreviated to meet the special needs of a specific case. The program has been

applied on an in-laboratory computer, and modified for use on a terminal to a

remote computer.

40
JATLOW, P. and SELIGSON, D. Application of a digital computer to emergency toxicology.

Clinica Chimica Acta 50: 19-39 (1974)

A digital computer has been applied to the laboratory diagnosis of drug

overdose. Analytic data is entered by the technologist at a keyboard in response to,

computer instructions. Major and minor ultraviolet absorption peaks, pH dependent spectral shifts, and peak absorbance ratios are used for decision making.

Data derived from thin-layer chromatography and calorimetric tests are used

for drugs without sufficiently strong spectra. The program can be interrupted and

re-entered at any point if additional analyses are required. Results are printed out at

the terminal after each step. Upon completion of the screen a summary report

lists drugs present (with concentration), absent, and not tested. This system has

been developed primarily for application in the general hospital laboratory. The

drugs or drug groups included in the program comprise well over 90% of those

Involved in acute overdose.

JOE, G. W. Patient background indices for a drug-abusing population - development and

distribution characteristics of a set of patient background index measures, based

on the DARP population admitted to treatment between June 1969 and June 1971.

Research on Patients, Treatments, and Outcomes. Edited by S. B. Sells.

Studies on the Effectiveness of Treatments for Drug Abuse, Vol. 2. Cambridge,

Massachusetts: Ballinger, 1974.

JOHNSON, J.C., GOLD, G.J. and CLOUET, D.H. An improved method for the assay

of DOPA. Analytical Biochemistry 54: 129-136 (1973)

A modified dopa assay is described which increases sensitivity 100-fold

over existing methods, so that as little as 1 ng of dopa/ml can be measured.

The method involves KI-I2 oxidation and catalysis of the fluorophore rearrangement by uv irradiation. The method is sufficiently sensitive to measure

endogenous brain dopa levels.

KAIKO, R.F. and INTURRISI, C.E. Human biotransformation and excretion of orally

administered cyclazocine: A method and its application. The Pharmacologist

15(2) (Fall, 1973)

Cyclazocine (C) is a narcotic antagonist currently under evaluation

for the treatment of opiate dependence. A method employing solvent extraction

and gas-liquid chromatography of trifluoroacetyl (TFA) derivatives has been

developed for the quantitative determination of C and its biotransformation

products. The separation of the TFA derivatives of C and norcyclazocine (NC)

was achieved using 3% SE-30 as the stationary phase. As little as 40 ng can be

recovered and quantitated by this method. Acid hydrolysis of the conjugated biotransformation products was carried out at 121° under pressure in an autoclave.

Urine and plasma samples were collected from two patients receiving 1.9 mg

of C every 12 hours. An average of 60% of the administered dose appeared in

the total 12 hour urine as C and biotransformation products. This included an

average of 21% of the dose as unchanged C, 24% as conjugated C, 4% as NC and

11% as conjugated NC. The applicability of this method to plasma samples was

also demonstrated. These results indicate that both N-dealkylation and conjugation are routes of biotransformation for C in man.

41
KAIKO, R.F. and INTURRISI, C.E. The quantitation of cyclazocine and its metabolites

in human urine by use of gas-liquid chromatography. Journal of Chromatography

100: 63-72 (1974)

A method is described for the quantitative determination of cyclazocine

and its N-dealkylated biotransformation product, norcyclazocine, in human urine.

The method can also be used to estimate the levels of conjugated cyclazocine and

norcyclazocine by measurement of the amount of these compounds released by

acid hydrolysis. The compounds are recovered from urine by the use of solvent

extraction and separated as their trifluoroacetyl derivatives by the use of gasliquid chromatography.

The levels of cyclazocine and metabolites were determined in the urine

collected from two patients receiving 1.9 mg of cyclazocine every 12 h for the

treatment of opiate dependence. Approximately 60% of the administered dose

was recovered in patient urine as cydlazocine and metabolites. An average of

21% of the administered dose appeared in the urine as cyclazocine, 24% as conjugated cyclazocine, 4% as norcyclazocine and 11% as conjugated norcyclazocine.

KANANEN, G., OSIEWICZ, R. and SUNSHINE, I. Barbiturate analysis -- A current

assessment. Journal of Chromatographic Science 10: 283-287 (May, 1972)

GC and UV/TLC procedures for barbiturate determinations yield

clinically comparable analyses. Depending on the available personnel and equipment, one or the other may be used satisfactorily. When a large number of

samples (20 or more) of barbiturate analyses are required, the described GC

procedure is as reliable, but faster and more sensitive than the UV procedure.

It involves extracting 1 ml of blood or urine with 5 ml of toluene containing

aprobarbital as an internal standard. Any barbiturate in the toluene extract is

then concentrated in 25 mu-l of 40% TMAH, an aliquot of which is injected into

the gas chromatograph. The methylated barbiturates thus formed require 20

minutes for quantitative analysis.

KANDEL, D. Reaching the hard-to-reach: Illicit drug use among high school absentees.

Addictive Diseases (in press)

While school surveys are based on students present on the days the surveys are conducted, resulting findings are interpreted as representative for

youths enrolled in school in the particular ages sampled. As part of a large

scale survey of adolescent drug use in the State of New York, two absentee

studies were carried out to estimate levels of drug use among school absentees.

Students interviewed in households reported very little drug use. By contrast,

absentees self-selecting themselves to participate in a group administered

questionnaire, reported much higher illicit drug use than regular students from

the same schools. However, comparison of students in the absentee sample with

the total target absentee population and the reverse association between drug use

and selected background factors among absentees, suggests that most chronic

absentees and heavy users, especially blacks and males, did not participate in

the self-selected absentee sample. Attempts to identify factors related to higher

drug use among absentees were unsuccessful. While poor school performance

brings levels of illicit drug use among regular students to levels comparable

to those of the absentees, poor school performance per se does not explain the

higher rates of illicit drug use among absentees. It is clear that school absentees

who are generally excluded from school surveys are extremely hard to reach

for research pruposes.

42
KANDEL, D. Some comments on the relationship of selected criteria variables to

adolescent drug use. Presented at the National Institute on Drug Abuse Drug

Lifestyles Conference, St. Simons, Georgia, January, 1975.

KANTER. S.L., HOLLISTER, L.E., MOORE, F. and GREEN, D.E. Marihuana

metabolites in urine of man. IV. Extraction procedures using diethyl

ether. Research Communications in Chemical Pathology and Pharmacology

9(2): 205-213 (October, 1974)

A new extraction scheme has been described which separated urine

samples into neutral, weak and strong acids fractions for studying marihuana

metabolites by thin-layer chromatography. The weak acids fraction, previously ignored, has provided the cleanest separation of drug-related

metabolites and in the greatest abundance.

KAUFMAN, J.J. Quantum chemical and theoretical techniques for the understanding

of psychoactive drugs and narcotic agents. Proceedings of the International

Conference on Computers in Chemical Research and Education. Ljublajana,

Yugoslavia (in press)

KAUFMAN, J.J. and KERMAN, E. Quantum-chemical and theoretical techniques for

the understanding of the action of drugs which affect the central nervous

system. Jerusalem Symposia on Quantum Chemistry and Biochemistry 6:

524-547 (1974)

KAUFMAN, J.J. and KOSKI. W.S. Physicochemical, quantum chemical and other

theoretical techniques for the understanding of the mechanism of action of

CNS agents: Psychoactive drugs, narcotics and narcotic antagonists and

anesthetics. Drug Design, Vol. V. Edited by E.J. Ariens. New York:

Academic Press, 1971.

KENNEDY, J.S. and WADDELL, W.J. Whole-body autoradiography of the pregnant mouse

after administration of 14C-delta-9-THC. Toxicology and Applied Pharmacology 22: 252-258 (1972)

The distribution of 14C-delta-9-tetrahydrocannabinol in pregnant

A/JAX mice at 12 days of gestation was studied by whole-body autoradiography

0.33, 1, 3 or 24 hr after iv or 3 hr after sc administration, High concentrations of radioactivity were found after either iv or sc administration in liver,

intestinal contents, Harder’s gland, fat, corpora lutea, and adrenal cortex.

The concentration was low in maternal brain and in the fetuses at all time

intervals after injection. The fetal central nervous system had the highest

concentration of all fetal tissues. The concentration was high in maternal lung

and spleen after iv but not after sc administration.

43
KHAZAN, N. EEG correlates of morphine dependence and withdrawal in the rat.

Drug Addiction: Experimental Pharmacology, Vol 1. Edited by J.M. Singh,

L.H. Miller and H. Lal. Mount Kisco, New York: Futura Publishing

Company, Inc., 1972. Pp. 159-172.

A morphine addiction cycle in rats prepared with chronically implanted

cortical electrodes and i.v. cannulae has been described. Electroencephalographic (EEG), electromyographic (EMG) and behavioral monitoring revealed

that, after the initiation of hourly automatic injections of morphine, sleep was

greatly reduced and REM sleep virtually eliminated. During this period high

voltage slow bursts of 4 to 7 Hz appeared in the EEG of the awake state. In the

next stage, i.e., morphine dependence, when the rats self-injected the drug by

pressing a lever, a state of behavioral wakefulness with EEG slow bursts prevailed immediately following an injection, while prolonged episodes of sleep and

REM sleep predominated in the period preceding the next injection. During the

ensuing stage of morphine withdrawal or abstinence, the amount of sleep decreased and became progressively superseded by a state of wakefulness and

hyperirritability. The primary EEG manifestation accompanying the abstinence

syndrome was a decline in the voltage output of the sleep-awake cycle, a

phenomenon which correlated with the behavioral hyperirritability of the

abstinent rats. Reduction in the voltage output of the sleep state was more pronounced and of longer duration than that of the awake or REM sleep states.

After these initial changes peaked at the height of abstinence, a marked rebound

in REM time developed, was accompanied by a rebound in the REM EEG voltage

output, and remained evident throughout the 12 days of the study. Apart from the

above, post-addict rats were found to display EEG and behavioral responses to

morphine injection in a way markedly different from those of naive rats. Instead

of the biphasic response of the naives, wherein initial stuporous behavior associated with high voltage EEG slow bursts was later followed by EEG and behavioral arousal, post-addict rats of 1 month exhibited a single phase of almost continuous and prolonged arousal. Although post-addict rats of 6 months tended

to approach the biphasic pattern, these rats were still readily readily distinguishable from the naives simultaneously challenged. In contrast with the latter group

receiving the first morphine challenge, post-addict rats which were given

repeated challenges within periods up to one year following morphine withdrawal

showed a more persistent arousal phase.

KHAZAN, N., COLASANTI, B. and KIRCHMAN, A. REM sleep during morphine

dependence and abstinence in the rat: Pellet implantation versus i.v. administration. The Pharmacologist 13: 314 (1971)

Previous studies of morphine addiction in the rat utilizing the i.v.

route (Khazan et al., J. Pharmacol. Exp. Ther. 155: 521, 1967) have demonstrated alterations both the amount and distribution of REM sleep. The

present study was undertaken to determine the time course of such changes in

rats implanted s.c. with morphine pellets and in i.v. rats. EEG and EMG

recordings collected continuously revealed total suppression of REM sleep for

up to 16-20 hours after pellet implantation. By the third day REM time had

not only returned to normal but showed a tendency toward rebound as well.

Upon withdrawal of the pellet 72 hours after implantation, the reduction in

REM time within the first day, although not as pronounced, was comparable

to that seen in rats addicted by the i.v. method. In contrast with i.v. rats,

however, in which a rebound in REM sleep remained evident throughout the

12-day withdrawal period studied, REM rebound in post-pellet rats was maximal on the third day, with normal REM time reached by the fourth day. Thus,

although the changes in REM sleep following both procedures are analogous,

their time courses during dependence and abstinence suggest that the consequences in rats addicted to morphine by the i.v. method are more severe.

44
KIMIZUKA, H. and ABOOD, L.G. Interfacial adsorption of a psychotomimetic drug

using liquid scintillation. Journal of Pharmaceutical Sciences 62(5): 740-745

(May. 1973)

A study was conducted on the oil-water partitioning and interfacial

adsorption of 3H-2-pyrrolidylmethyl N-methyl cyclopentylphenylglycolate (I),

an anticholinergic psychotom metic agent. A new technique for radiotracer

adsorption was developed involving the use of liquid scintillation counting.

Among the physical parameters examined were partition coefficient, permeation

constant, stability constant, and rate constant, of I in a two-phase

system of water and a lipid, didodecyl phosphate (II). II greatly accelerated

the rate of oil-water partitioning of I and exhibited interfacial

absorption with I. The presence of polyanions, such as hyaluronic

acid in the aqueous phase, promotes the transfer of drug from the oil to water

phase. Equations found applicable to permeation of ions across membranes

have been used to describe drug transfer through an oil-water interface.

KLEMM, W.R. A new, chronic experimental procedure for electrographic study of

neuropharmacological mechanisms. Presented at Society for Neuroscience

4th Annual Meeting, St. Louis, Missouri, October 20-24, 1974.

A stable baseline of electrographic activity for studying drug mechanisms and actions is difficult, if not impossible, to achieve in the common

methods that use animals which are either freely behaving, immobilized with

muscle relaxant or surgically deafferented. A new experimental procedure

for drug studies has been developed in which the EEG, multiple-unit activity, and

averaged evoked responses seem to be unusually stable and free of artifacts.

This procedure involves inducing a state of Immobility Reflex (IR) (also known as

“animal hypnosis”). The IR is a reversible, involuntary, and an unconditioned

reflex response in certain species to sudden change in afferent stimulation that

results from the common method of simultaneous inversion and manual restraint. Because intact, chronically prepared animals are used, the same

brain areas can be tested repeatedly with vehicle or different drug doses,

administered either systemically or topically. The IR offers the unique combination of simplicity, of being non-surgical and non-traumatic, of reproducibility,

and of relative freedom from behavioral variables.

KOKOSKI. R.J., SANDS, F.L. and KURLAND, A.A. Morphine detection by thin-layer

chromatography in a urine-screening program. A comparison of ion-exchangeresin loaded paper extraction with direct solvent extraction. Committee on

Problems of Drug Dependence. Washington, D.C.: National Academy of Sciences,

1969.

KOSERSKY, D.S. and HARRIS, L.S. Chronic intravenous drug administration in the

pigeon. European Journal of Pharmacology (in press)

45
KOSTERLITZ, H.W., LESLIE, F.M. and WATERFIELD, A.A. Narcotic agonist and

antagonist potencies of a homologous series of N-alkyl-norketobemidones

measured by the guinea pig ileum and mouse vas deferens methods. Journal

of Pharmacology 27: 73-78 (1975)

The narcotic agonist and antagonist potencies of the series of Nalkyl-norketobemidones from norketobemidone to decylnorketobemidone have

been determined. The values obtained in the electrically stimulated preparations

of the guinea-pig ileum and the mouse vas deferens are closely correlated.

The agonist potencies observed in the guinea-pig ileum agree well with those

found in the mouse hot-plate test (Oh-ishi & May) and those obtained by determining the inhibition of naloxone binding in brain homogenates (Wilson, Rogers,

Pert & Snyder). The antagonist potencies in the guinea-pig ileum and, to a

lesser extent, those in the mouse vas deferens agree with the values obtained

in the morphine-dependent monkey.

KULLBERG, M.P. and GORODETZKY, C.W. Studies on the use of XAD-2 resin for

detection of abused drugs in urine. Clinical Chemistry 20(2): 177-183 (1974)

We describe a procedure for extracting weakly acidic, neutral, and

basic drugs from urine by using a column of XAD-2 resin. Adsorption of drugs

from 20 ml of urine buffered at pH 8.5 ± 0.5 at a controlled flow rate of 2.5 ml/

min was greater than 89% for all drugs tested except aspirin. On eluting the

drugs tested with acetone and methanol/chloroform, recoveries ranged from 75

to 93%. Overall recoveries of drugs from urine to a thin-layer chromatography

plate were between 63 and 78%. The concentration of morphine added to normal

urine that can be detected 99% of the time (95% confidence limits) by this method

was 80 (65-100) mu-g/liter. We evaluated three methods for recovering morphine

from morphine glucuronide added to urine, by using appropriate modifications of

the XAD-2 resin extraction method. Hydrolysis of urine, hydrolysis of urine

extracts adsorbed on XAD-2 resin, and hydrolysis of urine extracts from the

XAD-2 resin followed by a solvent extraction gave 75%, 40%, and 10% recoveries

of morphine, respectively.

LATHES, V.G. On the use of reference substances in behavioral toxicology. Adverse

Effects of Environmental Chemicals and Psychotropic Drugs: Quantitative

Interpretation of Functional Tests. Edited by E. Frantik. Proceedings of the

I.A.O.H. Study Groups on Functional Toxicity, Vol. I. New York: Elsevier,

1973. Pp. 83-88.

LAW, N.C. A modern approach for drug identification. American Journal of Medical

Technology 39(6): 237-243 (June, 1973)

The experience that has been gained by using GC/MS system convinces

us that for this type of analysis it cannot, at present, be challenged by any other

method at least for identification in drug overdose cases.

The disadvantage, of course, is the cost of the instrument and its upkeep,

making it impractical for a single hospital to undertake. However, as the number

of acute overdoses increases, so do the number of types ingested, thus making

treatment and analysis more difficult for the physician and analyst. There is no

way to predict the physiological reaction to mixtures of newer and older drugs.

A C.I. mode is now under investigation and preliminary results are

not yet conclusive.

46
LAW, N.C. and CEHRS, F.D. Four years of drug identification by gas chromatography mass spectrometry. Clinical Chemistry 20: 902 (1974)

LAWRENCE, R.H., JR. and WALLER. G.R. GC-MS/Probe-MS analysis of cannabinoids in resin glands of Cannabis sativa L. Proceedings of 13th Annual

Meeting of the Phytochemical Society of North America, Pacific Grove,

California, 1973. P. 24.

Glandular cells, stalked and sessile, are present on both vegetative

and reproductive parts of Cannabis sativa L. plants. These glandular cells

secrete a resin which we have found to consist mainly of cannabinoids, with

minor amounts of monoterpenes and sesquiterpenes. Our interest in

cannabinoid biosynthesis in Cannabis has stimulated us to study the cannabinoid

content of these glandular cells. Resin gland cells from stems, leaves, female

flower bracts and male flower sepals and anthers of C. sativa L. plants were

collected by microdissection. The gland cells were placed in hollow glass

beads for solid injection for GC-MS analysis (3% OV-17 Chrom W(HP),

5. 5’ x 1⁄4”; LKB-9000) or in glass sample holders for direct probe-MS analysis.

Two C. sativa L. variants, Mexican (M-A2, drug phenotype) and Turkish (TA2, non-drug phenotype), were studied. Major differences in cannabinoid

content of anther glands in comparison to leaf, stem, and bract glands were

observed in relation to delta1-THC/CBD ratio in the Turkish variant, and to

a major heterogeneous GC peak with molecular ions of m/e 310, 314, 316) in

the Mexican variant. A detailed analysis of major and minor cannabinoids in

resin glands will be presented.

LAWRENCE, R.H., JR. and WALLER, G.R. Glandular structures of Cannabis sativa L.

and cannabinoid production. Presented at the 50th Annual Meeting of the

American Society of Plant Physiologists, Cornell University, Ithica, New York.

Plant Physiology 53: 5-13 (1974)

Two types of glandular structures develop on the epidermis of Cannabis

sativa L., elongated unicellular hairs (UH) and multicellular capitate glands

(MG). Both types occur on the epidermis of stems, leaves, braces of female

flowers and sepals of male flowers. Hypocotyl epidermis develops only UH and

cotyledons show no glandular development. Direct analysis by GC-MS of cap

cells dissected from MG reveals that these cells accumulate cannabinoids (as

carboxylic acids), monoterpenes, and sesquiterpenes in high concentration.

Cannabinoids appear to be associated with only the MG and are not present in

UH nor in tissues devoid of MG (hypocotyls, cotyledons, roots, pith, and

xylem). Our results lead to the tentative hypothesis that cahnabinoid biosynthesis occurs in the stalk or basal cells of the MG resulting in accumulation

in the cap cells. A possible exception to the above appears to be in tissue

cultures of Cannabis recently established in our lab. These cultures contain

cannabinoids but do not develop glands.

47
LAWRENCE, R.H., JR. and WALLER, G.R. The role of specialized epidermal glands

in the production of cannabinoids in Cannabis sativa L. Proceedings of the 9th

IUPAC International Symposium on Chemistry of Natural Products, Ottawa,

Canada, Abstract 24c, 1974.

The occurrence of natural products in specialized epidermal cells of

plants is a common phenomenon. In Cannabis sativa L. two types of epidermal

glandular structures develop, elongated unicellular hairs and multicellular

capitate glands. Data is presented which indicates that cannabinoids are

associated with the multicellular capitate glands and that tissues devoid of these

glands appear to lack cannabinoids. Additional data is presented which suggest

that cannabinoid biosynthesis may occur in the stalk and/or basal cells of the

multicellular glands resulting in accumulation in the cap cells. Gas chromatography-mass spectrometry (GC-MS) analysis of compounds (associated

with specific cell types) utilizes a recently developed all glass, solid injection

system which permits direct analysis of cells without solvent extraction. Cells

for analysis are collected from the plant by microdissection and placed in

hollow glass beads for injection into the GC-MS. To detect cannabinoids present as carboxylic acids their trimethylsilyl derivatives are formed by exposing injector beads containing glandular cells to N,O-bis-(trimethylsilyl)-

acetamide vapor at 40°C for 5 minutes prior to injection. Recent experiments

with Cannabis cell cultures are also discussed.

LAWRENCE, R.H., JR., WALLER, G.R. and KINNEBERG, K.F. An improved method

of sample introduction in gas chromatography-mass spectrometry of biological

materials. Analytical Biochemistry 62(1): 102-107 (November, 1974)

In the GC-MS analysis of biological materials the method of sample

introduction is an important factor affecting the value of the information

obtained. A method has been developed which utilizes small glass beads as

sample holders which are introduced into the GC column by way of a gas-tight,

Teflon stopcock. This glass sample holder introduction system is very simple

to construct and, in GC-MS analysis, offers advantages over other methods of

sample introduction.

LEAFE, T.D., SARNER, S.F., WOODLAND, J.H.R., YOLLES, S., BLAKE, D.A.

and MEYER, F.J. Injection method for delivery of long-acting narcotic

antagonists. Narcotic Antagonists. Edited by M.C. Braude, L.S. Harris,

E.L. May, J.P. Smith and J.E. Villarreal. Advances in Biochemical

Psychopharmacology, Vol. 8. New York: Raven Press, 1973.

Cyclazocine-poly(lactic acid) composites in small particle form were

implanted as well as injected into rats and the amounts of cyclazocine released

were determined at various intervals of time. The results obtained by the

injection method are comparable to those given by implantation. The former

method is preferable because it makes surgical incision unnecessary. Particle size, within the dimensions investigated, appears to show small differences

on the release rate of cyclazocine.

48
LEANDER, J.D. and McMILLAN, D.E. Substantial oral morphine intake by the rat

using schedule-induced polydipsia. Federation Proceedings 32: 726 (1973)

Rats were trained to lever press under a fixed-interval 90-sec schedule

of food pellet presentation. A water bottle was freely available, and all animals

developed the typical pattern of excessive post-pellet drinking (consuming approximately 30 ml/hr). Initial exposure to various morphine solutions decreased

drinking but increased lever pressing. The average dose of morphine consumed

using concentrations of 0.3, 0.56, and 1.0 mg/ml was 10 mg/kg during a one hr

session. After 2 weeks of exposure during daily 4 hr sessions to morphine solutions of 0.25 and 0. 5 mg/ml, there was little change (as compared to the water

solution) in average lever-pressing rate; a slight dose-dependent decrease in

drinking rate; and an appreciable dose-depepdent increase in total dose consumed.

During the last 3 days of exposure to 0.25 mg/ml, the average dose consumed

was approximately 75 mg/kg/4 hr session. After working up to a solution of 1.0

mg/ml, the average dose consumed was 200 mg/kg/4 hr session. The stable

pattern of drinking exhibited by rats chronically maintained on a 0.5 mg/ml solution was a tendency for drinking to no longer reliably be a post-pellet phenomenon, but to be long drinks spaced throughout the 4 hr session. Thus, scheduleinduced polydipsia can be used to induce rats to chronically consume large doses

of morphine orally.

LENTZ, P.L., TURNER, C.E., ROBERTSON, L.W. and GENTNER, W.A. First North

American record for Cercospora Cannabina, with notes on the identification of

C. Cannabina and C. Cannabis. Plant Disease Reporter 58(2): 165-168

(February, 1974)

Late in August 1972, a fungal disease appeared in an experimental

planting of Cannabis sativa in Oxford, Mississippi. The causal organism was

Cercospora cannabina, which was previously unrecorded from North America.

The only other known Cercospora on Cannabis is C. cannabis, recorded in the

United States in Wisconsin and Missouri. Comparison of the Mississippi fungus

with the American collections of C. cannabis showed significant dissimilarities

in growth habit and in characteristics of conidiophores and conidia.

LIN, C.H., BRAVERMAN, S., KEINATH, S., TRESK, R. and ADLER, M.W.

Anticonvulsant action of acute morphine administration in rats. Federation

Proceedings (in press)

49
LINDER. C. and FISHMAN, J. Narcotic antagonists. 1. Isomeric sulfate and acetate

esters of naloxone (N-allylnoroxymorphone). Journal of Medicinal Chemistry

16(5): 553-556 (1973)

The synthesis of the two isomeric monosulfates lb, c and the disulfate

ld esters of naloxone is described. These and the corresponding acetates le-g

were prepared as potentially longer acting narcotic antagonists than naloxone

itself. The sulfation and acylation reactions appeared to reflect group interactions within the naloxone molecule. Intravenous administration to rats showed

the acetates to have the same range of antagonistic potency as naloxone, with

respect to the reversal of morphine-induced respiratory depression. By oral

administration the acetates appeared to be several-fold more potent as well as

longer acting than naloxone in preventing respiratory depression induced by

morphine. In both intravenous and oral administration to rats, the sulfate

esters proved inferior to naloxone in both potency and duration of action. Neither

the acetates nor sulfates had any agonistic properties at relatively high iv

dosages.

LIU, C-T. and ADLER, F.L. Immunological studies on drug addiction. I. Antibodies

reactive with methadone and their use for detection of the drug. Journal of

Immunology 111: 472 (1973)

LLOYD, S.C., ASNIS. S.F., HAMMOND, W.E. and ELLINWOOD, E.J., JR.

Drug abuse record keeping system with an interactive computer, II: The

GEMISCH method. Committee on the Problems of Drug Dependence.

Washington, D.C.: National Academy of Sciences, National Research Council,

1972.

LOEFFLER, K.O., GREEN, D.E., CHAO, F-C. and FORREST, I.S. New approaches

to assay of cannabinoids in biological extracts. Proceedings of the Western

Pharmacological Society (in press)

LOEW. G.H., BERKOWITZ, D., WEINSTEIN, H. and SREBRENICK. S. Quantum

chemical studies of morphine-like opiate narcotics: Effect of polar group

variations. Molecular and Quantum Pharmacology. Edited by E. Bergmann

and B. Pullman. Dordrecht, the Netherlands: D. Reidel Publishing Company,

1974.

LOH, H.H., CHO, T.M. and LIPSCOMB, W. Estimation of morphine by polyamide

mini thin-layer chromatography. Journal of Chromatography 76: 505-508

(1973)

50
LOWY, K., WEISS, B. and ABOOD, L.G. Influence of an anticholinergic psychotomimetic agent on behaviour in cats controlled by an auditory stimulus.

Neuropharmacology 13: 707-718 (1974)

An anticholinergic psychotomimetic agent was examined for its

behavioural effects on cats trained to press a lever, the location of which

corresponded to one of two sound sources. The cats were trained to lick

a protruding sponge in dim light which then caused the main light to turn

on, and an auditory signal to be emitted from either side of a panel in the

chamber. Any lever response terminated the trial. A food reward was

given only if the cat pressed a lever on the same side as the sound signal.

A new trial cycle began when the cat licked the sponge. A computer programme controlled the experiment, stored we experimental data, and

permitted an analysis of various psychophysical parameters, such as ability

to localize an auditory cue, threshold of sound intensity, rate of trial onset,

and lateral tendency. Doses of 10-20 mu-g/kg, N-methyl 4-piperidylcyclobutylphenyl glycolate (CBG) reduced the number of responses, and tended

to lower the relative time spent in the light period. However, at lower doses

CBG produced a marked increase in some cats in total number of trials.

Higher doses of scopolamine also reduced total trials, but less consistently.

An increase of the number of responses was not observed. A number of

animals exhibited a lateral preference for either the right or left lever.

CBG, but not scopolamine, markedly shifted this lateral tendency in some

cats. The results are discussed in relation to the central effects of the

glycolate esters in man.

LYNN, R.K., SMITH, R., OLSEN, G.D., LEGER, R.M. and GERBER, N.

Studies of the metabolism of methadone (M) and methodology for isolation

and quantification of the drug and its primary metabolite, 2-ethylidene-1,

5-dimethyl-3, 3-diphenylpyrrolidine (P) using gas chromatography (GC)

and mass spectrometry (MS). Federation Proceedings (in press)

A specific GC assay has been developed for the quantification of M

and P. The method involves extraction of M and P with 1-chlorobutane from

tissue (human plasma, mouse homogenate, perfusate) at pH 9.8, re-extraction

of an aliquot of solvent with 0.1 N HCl, alkalinization and final extraction into

chloroform. The partition coefficient of M determined by 4 tube counter

current distribution between 1-chlorobutane and pH 9.8 buffer (volume ratio

1:3) is greater than 70. Mice pretreated with phenobarbital showed a twofold

increase in the rate of metabolism of M at 15 min. In the perfusate of the

isolated perfused rat liver there was an initial rapid decline of M followed by

a slower decline (t/2 114 min) after 30 min. Small quantities of M and P were

eliminated in the bile. Concentration of P in the mouse and the perfusate increases with time. GC-MS of the methylated (CH3I, DMSO ̄) glucuronic acid

conjugates from bile gave molecular ions at m/e 525 and 555 indicating the

presence of mono- and di-hydroxylated P glucuronides. GC-MS demonstrated

the presence of other hydroxylated metabolites. M was quantitated in the

plasma of M tolerant subjects.

51
MCAULIFFE, W.E. and GORDON, R.A. A test of Lindesmith’s theory of addiction:

The frequency of euphoria among long-term addicts. American Journal of

Sociology 79(4): 795-840 (January, 1974)

Lindesmith and others claim that once physical dependence is

established addicts do not experience euphoria. Consequently, euphoria

cannot explain chronic addiction. Data are presented to show that, contrary to this view, long-term addicts experience euphoria frequently,

crave it, and act to obtain it. “Lack of money” is the most important reason

addicts give for not experiencing euphoria more often. Based on success in

achieving euphoria, two classes of addicts are identified. The sources of

income of addicts who experience euphoria most often correspond to those of

types described by others as highest in prestige. Analysis suggests an addict

stratification system founded on the two major psychopharmacological

phenomena of opiates: withdrawal and euphoria. Addicts who barely succeed

at tending to their daily need to avoid withdrawal are lowest in prestige. In

the higher prestige ranges, addicts are stratified by their success in achieving euphoria. Thus, the social as well as the value system of addicts owes

much to success at achieving what are universally considered, at the individual

level, to be the most fundamental reinforcers. Since these reinforcers

operate at the individual level, our analysis reveals the addict social system

as a microcosm of broader theoretical interest, with transitions between

physiological, psychological, cultural, economic, and sociological phenomena in plain view.

McCLUNG, R., DAFNY, N. and BURKS, T.F. Effects of morphine and naloxone on

CNS field in unanesthetized rats. Federation Proceedings (in press)

Evoked field potentials in response to acoustic stimulation were

recorded from freely behaving animals before and after intraperitoneal injections of morphine (10 mg/kg, 30 mg/kg or 50 mg/kg). Sites of recording

were: cochlear nucleus, septum, substantia nigra, raphe nucleus, pineal

body, caudate nucleus and ventromedial hypothalamus. The most consistent

effects of morphine occurred in the pineal body and caudate nucleus. The

amplitude of the field potentials in response to acoustic stimulation were consistently increased in the pineal body at all dose levels of morphine. This

effect of morphine was reversed upon administration of naloxone (1 mg/kg).

Responses in the caudate nucleus to acoustic stimulation were related to the

dose of morphine administered. Smaller doses of morphine (10 and 30 mg/kg)

decreased the amplitude of field potentials, while 50 mg/kg of morphine

resulted in an increase in the amplitude of the response, Subsequent naloxone

administration resulted in response amplitudes similar to controls. Effects

of morphine on field potential responses to acoustic stimulation in the other

recording sites were more variable. Effects of morphine on responses of the

pineal body and caudate nucleus to acoustic stimuli were attenuated by prior

administration of naloxone. These results indicate that morphine can act

selectively to produce changes in evoked field potentials in specific brain

structures.

52
McISAAC, W.M., HARRIS, R.T. and HO, B.T. The indole hallucinogens.

Advances in Mental Science, Drug Dependence, Vol. 2. Austin, Texas:

University of Texas Press, 1969. Pp. 41-54.

McMILLAN, D.E. Physical dependence in rats after drinking narcotic analgesics.

Federation Proceedings (in press)

Narcotics were placed in the drinking water of rats during a 12-day

period. The average daily intake was 34 and 100 mg/kg of morphine (0.3 and

1.0 mg/ml), 11 and 41 mg/kg of levorphanol (0.1 and 0.3 mg/ml), 28 and 72

mg/kg of meperidine (0.3 and 1.0 mg/ml), 38 and 62 mg/kg of methadone (0.3

and 1.0 mg/ml), and 0.5 and 1.4 mg/kg of etonitazene (3 and 10 mu-g/ml). When

1 mg/kg of naloxone was administered after 12 days of drug drinking, the rats

drinking morphine, etonitazene and 1.0 mg/ml of meperidine lost almost 40

gms in weight during the first 6 hours, while rats drinking levorphanol lost

about 20 gms and rats drinking methadone, or 0. 3 mg/ml of meperidine lost

about 10 gms. Rats drinking morphine, etonitazene or levorphanol increased

drug intake during the 24 hours after naloxone, while rats drinking meperidine

or methadone did not. After 15-17 days of drug drinking the rats were switched

to water. The body weights of the ex-drinkers of morphine, etonitazene, or

levorphanol decreased about 40 gms in two days, with gradual recovery in about

a week, but ex-drinkers of methadone or meperidine only gained weight. During

the 24 hours after the switch to water, the fluid intake of ex-drinkers of morphine

or etonitazene decreased, that of ex-methadone drinkers increased and that of

ex-drinkers of levorphanol or meperidine did not change.

McMILLAN. D.E., WADDELL, F.B. and CATHCART, C.F. Establishment of physical

dependence in mice by oral ingestion of morphine. The Journal of Pharmacology

and Experimental Therapeutics 190(2): 416-419 (1974)

Morphine solutions were the only drinking solutions available to mice for

13 days. During the last 9 days of drinking a 1.0 mg/ml of morphine solution, the

mice averaged a daily morphine intake of approximately 150 mg/kg. When injected

with naloxone, the mice showed characteristic abstinence jumping, diarrhea, weight

loss and abnormal posturing, suggesting that physical dependence had been produced by the morphine ingestion.

McRAE, D.J. Development of a patient topology. Research on Patients, Treatments, and

Outcomes. Edited by S. B. Sells. Studies of the Effectiveness of Treatments for

Drug Abuse, Vol. 2. Cambridge, Massachusetts: Ballinger, 1974.

MAICKEL, R.P., BRAUNSTEIN, M.C., McGLYNN, M., SNODGRASS, W.R. and

WEBB, R.W. Behavioral, biochemical, and pharmacological effects of

chronic dosage of phenothiazine tranquilizers in rats. The Phenothiazines and

Structurally Related Drugs. Edited by I.S. Forrest, C.J. Carr and E. Usdin.

New York: Raven Press, 1974.

The data presented herein indicate that a variety of biochemical, behavioral and pharmacological effects are seen when rats are chronically dosed

with phenothiazine tranquilizers. The drugs accumulate in plasma and tissues.

Concomitant with this accumulation are moderate elevations in liver glycogen

and triglycerides, extrapyramidal symptoms, and various types of behavioral

adaptations. Since many of these effects cannot be correlated with brain levels

of drugs themselves, further study of the possible role of active metabolites

appears to be a necessity.

53
MAICKEL. R.P., FEDYNSKYJ, N.M., POTTER, W.Z. and MANIAN, A.A. Tissue

localization of 7- and 8-hydroxychlorpromazines. Toxicology and Applied

Pharmacology 28: 8-17 (1974)

The time course of physiological disposition of 3H-labeled 7-

hydroxychlorpromazine and 8-hydroxychlorpromazine has been examined

in rats after a single dosage, and the accumulation of each compound has

been studied after 6, 14 and 28 doses on a bid schedule. The 8-hydroxycompound decays at a slower rate and shows a greater degree of accumulation on

repeated dosage than does the 7-hydroxychlorpromazine. Both compounds

enter the brain (the 7-hydroxy to a greater extent) and distribute uniformly,

with no significant overt behavioral effects. Both compounds caused significant liver and kidney damage as demonstrated by histological evaluation.

MAICKEL, R.P., LEVINE, R.M. and QUIRCE, C.M. Differential effects of d- and

l-amphetamine on spontaneous motor activity in mice. Research Communications in Chemical Pathology and Pharmacology 8(4): 711-714 (August, 1974)

The effects of single doses of d- and l-amphetamine on motor activity

in mice differed both in quantitative and qualitative aspects. At low doses

(0. 5 mg/kg, i.p.) and at high does (8.0 mg/kg, i.p.), both isomers were

stimulants of SMA, differing only in potency. However, at intermediate doses

(2.0, 4.0 mg/kg. i.p.) the l-isomer caused a significant depression of SMA

while the d-isomer was stimulatory.

MAICKEL, R.P., ROMPALO, A.M. and COX. R.H., JR. Differential effects of

monoamine oxidase inhibitors. Research Communications in Chemical

Pathology and Pharmacology 8(4): 727-730 (August, 1974)

Chronic dosage of rats for 20 days with non-toxic doses of different

monoamine oxidase inhibitors had clearly differential effects on brain

biogenic amines and spontaneous motor activity. No correlation could be

seen between behavioral and biochemical effects of the drugs.

54
MANDELL, A.J. Frontiers in the neurobiology of euphoria. American Handbook of

Psychiatry, Vol. VI. Edited by S. Arieti, D.A. Hamburg and H.K.H. Brodie.

New York: Basic Books, 1972.

In summary, the current social recognition and acknowledgement of

euphoria as a desired and sought after affect state in man has been discussed.

A group of drugs has been described which appear to produce this sort of state

in man and which bear an interesting resemblance to two major naturally

occurring neurotransmitter families. In addition, we have reported the possibility that at least one of these compounds can be synthesized in brain via a

newly described N-methylation pathway. It appears there is a major obstacle

to the use of euphorogens as a chronic management technique which relates to

the multifaceted nature of the brain’s metabolic adaptational processes. These

adaptational processes are currently being looked at in two ways: (1) The

possibility of purposely inducing these adaptational processes with the behavioral

and subjective concomitants of these adaptations being the end product of the

chemical maneuver; (2) The possibility of chemically and hormonally altering

or inhibiting the rate of adaptation the brain makes to these new treatments.

It appears that the age of euphorogens is upon us and we are coming to

it with a far greater understanding of brain biology than in eras involving other

drug families and other affect states. It will be exciting times indeed for those

in the brain sciences. It wouldn’t be a surprise if over the next few years a

wide variety of drugs that produce euphoria will be available for use. The

question about who will be in charge of them when they will be used and how they

will be used I think probably reaches beyond the area that is legitimately the

purview of a brain scientist or psychiatrist. Whether they can ever be used

effectively except on a periodic basis will await further research. It’s perhaps

philosophically important that drug-induced pleasure habituates so quickly. It

calls to mind a recent statement Heinz Lehman made after hearing about some

of this work: “It seems to me that puritanical attitudes toward pleasure must

have as part of their bases these neurobiological mechanisms of adaptation.”

55
MANNO, B.R. and MANNO, J.E. 11-hydroxy-delta-9-tetrahydrocannabinol induced

changes in the perfused rat heart. Presented at the Meeting of the Society of

Toxicology, Williamsburg, Virginia, Spring, 1975.

The effects of 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-delta-9-

THC) on the myocardium and the coronary vasculature have been evaluated using

the isolated perfused rat heart. The 11-OH-delta-9-THC was suspended in a

vehicle of 1.5% Tween 80, 5% ethanol and water and doses ranging from 0.1 to 28

micrograms were infused over a 3 minute period. Hearts were monitored for

changes in rate, force of contraction and perfusion pressure continuously during

the infusion period and for 20 minutes after the infusion of 11-OH-delta-9-THC

ceased. Heart rate fluctuations ranging from 3 to 5% of control occurred but

were not considered to be significant. With low concentrations of 11-OH-delta-9-

THC, an initial slight increase in the inotropic response (less than 5% of control)

occurred followed by a negative inotropic response (less than -6% of control).

Only a negative inotropic response occurred at high concentrations of 11-OH-delta9-THC (up to 20% of control). Perfusion pressure, an index of coronary vasculature resistance, increased slightly with most doses of the drug (up to 10% of

control). With doses of 25.5 and 28 micrograms of 11-OH-delta-9-THC, a

biphasic response occurred. Initially, a decrease (vasodilation) was observed

(-15 and -9% of control) followed by an increase in perfusion pressure (vasoconstriction) not exceeding 10% of control. The data indicate that 11-OH-delta9-THC has little direct effect on heart rate, however, it does produce a negative

inotropic response on the myocardium with a subsequent decreased coronary

vasculature resistance followed by increased vasculature resistance.

MANNO, B.R. and MANNO, J.E. The marihuana dilemma: Has it been resolved?

Toxicology Annual. Edited by C.L. Winek. New York: Marcel Dekker, Inc.

(in press)

MANNO, B.R. and MANNO. J.E. Some cardiovascular actions of delta-9-tetrahydrocannabinol in the rat. Toxicology and Applied Pharmacology 25: 451 (1973)

The mechanism of the highly reproducible, delta-9-tetrahydrocannabinol

(delta-9-THC) dose-related tachycardia in humans who have smoked marihuana

remains obscure. This work was initiated as one phase of a study to differentiate

the centrally mediated versus direct myocardial and vascular effect of delta-9-

THC. Hearts from decapitated rats were perfused by a modified Langendorf

technique with a modified Krebs-Henseleit bicarbonate medium, pH 7.4. A10-g

diastolic tension was maintained on the spontaneously beating heart for the

duration of the experiment. Force of contraction and coronary perfusion

pressure changes were also monitored. Twelve doses of delta-9-THC(1.04

x 10-5M) were infused into the hearts for 3-min intervals. No chronotropic

change was observed at any dose of delta-9-THC used. Alterations in both

inotropic response and coronary vasculature resistance were observed. As

the concentration of delta-9-THC increased, a negative inotropic effect of as

much as -26% of control was observed. The vasculature resistance denoted by

changes in perfusion pressure produced a biphasic response. Concentration

of delta-9-THC from 1.04 x 10-9 to 2. 91 x 10-6M were vasoconstrictive with increases in pressure as much as +33% of control. Delta-9-THC concentrations

of 2.65 x 10-6 to 1.04 x 10-5M produced a decrease in pressure of as much as

34% of control indicating vasodilation. These studies using varied concentrations

of delta-9-THC in isolated perfused hearts indicate that (1) the delta-9-THC doserelated tachycardia is not a direct effect on the myocardium; (2) a direct myocardial inotropic effect was induced by low concentrations of delta-9-THC and

(3) a direct coronary vasculature effect was produced by delta-9-THC and (4) a

direct coronary vasculature effect was produced by delta-9-THC.

56
MANNO, J.E. and FORNEY, R.B. Drug effects on motor performance. Principles and

Techniques of Human Experimentation. Edited by E.G. McMahon. Mount Kisco,

New York: Futura Publishing Company (in press)

MANNO, J.E., KIPLINGER, G.F., RODDA, B.E., FORNEY, R.B. and MANNO, B.R.

Dose-dependent alterations in human motor and mental performance after smoking marijuana cigarettes. Chapter 1 of Drug Addiction: Clinical and Socio-legal

Aspects, Vol. II. Edited by J. Singh. Mount Kisco, New York: Futura Publishing

Company, 1972. Pp. 3-11.

MANNO, J.E. and MANNO, B.R. The interaction of delta-9-tetrahydrocannabinol (THC),

pentobarbital and SKF-525A with the cardiovascular system of the rat. Federation

Proceedings 32: 755 (1973)

Aqueous suspensions of THC were administered intravenously to male rats

in doses of 0.05 mg/kg and 0.5 mg/kg. Direct arterial blood pressure and heart

rate were continuously monitored from indwelling carotid catheters in pentobarbital

anesthetized and unanesthetized. non-restrained animals. Control rats were administered saline and monitored in the same manner as the experimental animals.

A similar series of experiments investigated the effect of pretreatment with the

metabolic inhibitor SKF-525A (beta-diethylaminoethyl diphenyl propylacetate). A

maximal bradycardia was produced in all conditions at 10 minutes after THC administration. The bradycardia reverted to a tachycardia at 60 minutes in unanesthetized rats. The initial bradycardia was greater in anesthetized animals than in

unanesthetized rats. Pretreatment with SKF-525A potentiated the initial negative

chronotropic action of THC, particularly in unanesthetized rats. The tachycardia

at 60 minutes was also potentiated by SKF-525A. The implications of the pretreatment of SKF-525A will be discussed with reference to alerations in THC and 11-

hydroxy THC concentrations as described by Gill and Jones (Biochem. Pharm.

21: 2237, 1972).

MANNO. J., MANNO, B., WALSWORTH, D. and HERD. R. Analysis and interpretation

of the cannabinolic content of confiscated marihuana samples. Journal of

Forensic Sciences 19(4): 884-890 (1974)

Confiscated marihuana samples from a three-year period were assayed

quantitatively for their concentrations of delta-9-tetrahydrocannabinol (THC),

cannabidiol (CBD), and cannabinol (CBN) by gas chromatography. A wide variability in the concentrations of the cannabinols was observed and a steady increase

in potency of the samples was evident in the more recently confiscated specimens.

The concentration of THC, CBN, and CBD and their ratios can be used to relate

the approximate age of the sample (time from harvest), the potential source of

the marihuana, and its potency. The relationships and their significance are

discussed.

MELIKLAN. A.P., GREEN, D.E., SKINNER, J.L. and FORREST, I.S. Isolation of

in vivo delta-9-tetrahydrocannabinol metabolites from primate urine. Proceedings

of the Western Pharmacological Society 16: 234-239 (1973)

MELLET, L.B. and STROBEL, J. An electrophoretic study of acute and chronic drug

effects. Bulletin, Problems of Drug Dependence 30: 5376-5391 (1968)

57
MERLIS, S. Problems and experiences with drug trials outside the United States. Diseases

of the Nervous System 35(7): 5-7 (1974)

MILLER, L.L., editor. Marijuana. Effects on Human Behavior. New York: Academic

Press, 1974.

This book summarizes recent scientific evidence concerning the effects

of marijuana on human behavior. It not only reviews acute and chronic laboratory

effects of cannabinoids on cognition and psychomotor performance, but covers

more controversial topics: the relationship of marijuana use to aggressive behavior, progression to more dangerous drugs of abuse, the development of

psychiatric illness, and effects on driving.

The book places emphasis on the unbiased summary and interpretation of

relevant data on a given topic. Many of its fourteen chapters cover new and original material not previously published. It will be of interest to clinical investigators and researchers in pharmacology, as well as psychologists, psychiatrists,

sociologists, lawyers and legislators.

MISRA, A.L., VADLAMANI, N.L. and MULE, S.J. Chromatographic separation of

methadone, some of its metabolites and congeners. Journal of Chromatography

67: 379-381 (1972)

MOLE, M.L., BUELKE, J. and TURNER, C.E. Preliminary observations on cardiac

activities of Cannabis sativa L. root extracts. Journal of Pharmaceutical

Sciences 63(7): 1169-1170 (July, 1974)

MOLE, M.L., JR. and TURNER, C.E. Phytochemical screening of Cannabis sativa L.

II. Choline and neurine in the roots of a Mexican variant. Acta Pharmaceutica

Jugoslavica 23(4): 203-205 (1973)

The presence of nitrogen containing components in Cannabis sativa L.

has been reported by various workers. Jahns isolated choline, Schulze and

Frankfurt and Merz and Bergner isolated choline and trigonelline, Kwasniewski

suggested the presence of muscarine and Obata, et.al. identified piperidine.

Lousberg and Salemink have reported the isolation of a compound containing a

betain type moiety; however, full structural details have yet to be reported. Also,

Rapoport, et.al. isolated small amounts of four alkaloids which were subjected to

high resolution mass spectrometry; but no conclusions about the total structures

could be drawn from the limited data. In recent communications from these

laboratories, Slatkin confirmed the presence of N-(p-hydroxy-beta-phenylethyl)-

p-hydroxy-trans-cinnamamide and Turner and Mole reported the isolation of

L.-proline. We wish now to report the isolation and characterization of the

quaternary alkaloid neurine. The presence of choline has also been confirmed.

58
MOLE, M.L., JR. and TURNER, C.E. Phytochemical screening of Cannabis sativa L.

I: Constituents of an Indian variant. Journal of Pharmaceutical Sciences 63(1):

154 -156 (January, 1974)

Delta-9-trans-tetrahydrocannabivarin, a mixture of sterols (campesterol,

stigmasterol, and beta-sitosterol), and the amino acid. L-proline were isolated

from an Indian variant of Cannabis sativa L. Characterizations were accomplished

by the usual spectral methods, except for the sterols which were subjected to GLCmass spectral analysis.

MOON, J.H., STARK, J.D., SUN, C.D. and WOODS, J.H. Computer controlled drug

self-administration facility. Committee on the Problems of Drug Dependence.

Washington, D.C.: National Academy of Sciences, National Research Council,

1973. P. 788.

This paper describes the development of a computer controlled drug

self-administration facility for rhesus monkeys.

MORETON, J.E. and DAVIS, W. M. A simple method for the preparation of injectables

of tetrahydrocannabinols and cannabis extracts. Journal of Pharmacy and

Pharmacology 24: 176 (1972)

MULE, S.J. and MISRA, A.L. Disposition and metabolism of levo-metadone-1-methyl3H in the rat. Federation Proceedings 31: 528 (1972)

MULE, S.J., SUNSHINE, I., BRAUDE, M. and WILLETTE, R.E., editors. Immunoassays

for Drugs Subject to Abuse. Cleveland, Ohio: Chemical Rubber Company Press, Inc.,

1974.

This monograph consists of the proceedings of a meeting on Immunoassays

for Drugs Subject to Abuse held under the sponsorship of the Center for Studies of

Narcotic and Drug Abuse, National Institute on Drug Abuse, Rockville, Maryland.

The meeting brought together a select group of outstanding people actively engaged

in the development or the evaluation of immunoassay techniques for the detection

of drugs of abuse. The presentations are limited to general methodologies and

essentially omit technical details as applied specifically to each drug of abuse, as

these have already been published.

NYBACK, H., SCHUBERT, J. and SEDVALL, G. Effect of apomorphine and pimozide on

synthesis and turnover of labelled catecholamines in mouse brain. Journal of

Pharmacy and Pharmacology 22: 622-624 (1970)

59
OLTMANS, G.A. and HARVEY, J.A. “LH syndrome” and brain catecholamine levels

after lesions of the nigrostriatal bundle. Physiology and Behavior 8: 69-78 (1972)

Lesions of the nigrostriatal bundle (NSB), whose fibers pass through the

medial portions of the internal capsule and the immediately adjacent lateral

hypothalamus (LH), produced a more severe aphagia, adipsia and disturbance

of water regulation than did lesions of the medial forebrain bundle (MFB). When

deprived of food, animals with NSB lesions drank significantly less than controls and

animals with MFB lesions. NSB lesions also produced greater decreases in

telenlephalic content of the catecholamines than MFB lesions, while the reverse was

true for serotonin. Water intake during food deprivation was highly correlated

with telencephalic catecholamine levels in animals with NSB lesions. Thus, the

inability to regulate water intake in the absence of food, one of the characteristics

and long lasting effects of the LH syndrome appears to be due to destruction of the

NSB and the consequent decline in telencephalic content of catecholamines.

PAPESCHI, R. and RANDRUP, A. Catalepsy, sedation and hypothermia induced by alphamethyl-p-tyrosine in the rat. An ideal tool for screening of drugs active on central

catecholaminergic receptors. Pharmakosychiatrie Neuro-Psychopharmakologie

6: 137-156 (1973)

AMT (alpha-methyl-p-tyrosine), injected at 250 mg/kg, ip, at 0 and 3 h in

rats, induced a state of reduced exploratory activity and catalepsy, which appeared

first at 5-6 h, reached its peak at 10-12 h and was gradually obscured by supervening

signs of toxicity of the drug. Aphagia, adipsia and hypothermia accompanied

sedation and catalepsy. The behavioral phenomena followed the same temporal pattern

as the decrease of concentration of both dopamine and noradrenaline in the whole

brain.

Catalepsy and decreased exploratory activity were not consequence of the

toxicity of AMT; catalepsy was due to the block of synthesis of dopamine in the

CNS, whereas reduced exploratory activity was correlated with that of both

central CAs. Adipsia and aphagia could also be related to the central effects of

AMT on catecholaminergic neurons.

In contrast, hypothermia appeared to depend mainly on the inhibition of

synthesis of both catecholamines in the periphery and of dopamine centrally.

Postural tremor or rigidity were never seen after either AMT or FLA-63.

The fact that catalepsy and sedation appeared only 5-6 h after AMT indicates

that spontaneous behavior is not dependent on “newly synthesized” catecholamines,

but rather on the total concentration of these compounds in the brain; this concentration must be decreased below a certain critical level before changes of spontaneous

behavior set in.

PAUL, S.M., HSU, L.L. and MANDELL, A.J. Extrapineal N - acetyltransferase

activity in rat brain. Life Sciences 15(12): 2135-2143 ( 1973 )

An extrapineal enzyme that N-acetylates a variety of indole and catechol

alkylamines. including the psychoactive drugs mescaline and d-amphetamine,

has been partially purified from rat brain. This enzymatic activity has a

distinct pH optimum, is linear with incubation time and protein concentration,

and is abolished by heating. Purification is approximately ten fold with

ammonium sulfate precipitation and column chromatography, yielding a

specific activity of 7936 pmoles of product per mg of protein per hour with

tryptamine as substrate.

60
PIRAINO, A.J. and DiGREGORIO, G.J. Quantitation of barbituates in the induced

parotid saliva of rats. The Pharmacologist 16: 217 (19741

QUIMBY, M.W., DOORENBOS, N. J., TURNER, C.E. and MASOUD, A. Mississippigrown marihuana - Cannabis sativa cultivation and observed morphological

variations. Economic Botany 27(1): 117-127 (January-March, 1973)

RANDRUP, A., MUNKVAD, I. and SCHEEL-KRÜGER, J. Mechanisms by which

amphetamines produce stereotypy, aggression and other behavioural effects,

Proceedings of the Symposia held at the VIII Congress of the Collegium

Internationale Neuro-Psychopharmacologicum, Copenhagen, Denmark,

August 14-17, 1972. Edited by T. A. Ban, J. R. Boissier, G. J. Gessa,

H. Heimann, L. Hollister, H. E. Lehmann. I. Munkvad, H. Steinberg, F. Sulser,

A. Sundwall and O. Vinar. Amsterdam, the Netherlands: North-Holland

Publishing Company, 1973.

The dopaminergic systems in the forebrain (nucleus caudatus, putamen

and some adjacent areas) appear to have effects, in mammals, on many perhaps

all types of behaviour, and these effects tend in the extreme to change the

whole pattern of behaviour into a stereotyped, apparently aimless one.

At the same time each type of behaviour e.g. locomotion, aggressive

and other social activities, drinking etc. appear to be influenced also by other

brain systems. The behavioural effects of a drug, which like amphetamines

acts on several brain systems (dopaminergic, noradrenergic, serotonergic

and possibly others) are therefore bound to be complicated. For example: smaller

doses of d-amphetamine cause increase in locomotion of rats while larger doses

cause inhibition. The increased locomotion can be stereotyped, consisting in

repetition of a fixed route in a restricted part of the cage. Brain dopamine plays

a role in these locomotor effects, but locomotion is also influenced by brain

noradrenaline.

Recent findings about the mechanisms by which amphetamines produce

their behavioural effects are reviewed. Real and apparent contradictions in the

most recent publications about experiments with brain lesions are discussed; the

extent of lesions in the striatum and the slow recovery of behaviour after such

lesions seem to be important items in this context. Clinical implications of the

animal experiments are suggested.

RENAULT, P.F., SCHUSTER, C.R., HEINRICH, R. and FREEMAN, D.X.

Marihuana: Standardized smoke administration and dose effect curves on

heart rate in humans. Science 174: 589-591 (November, 1971)

A spirometer was used to deliver marihuana and placebo smoke to

human subjects. This procedure produced linear dose-effect curves on heart

rate and replicable dose effects in individual subjects. No differences were

observed between experienced and inexperienced smokers in responsiveness

to heart rate increases produced by marihuana.

Report of the Panel on the Impact of Information on Drug Use and Misuse.

Phase II: Evaluating Drug Information Programs. Washington, D.C.:

National Academy of Sciences,. National Research Council, 1973.

61
ROBINS, L.N. The Vietnam Drug User Returns. Final report submitted to the

Special Action Office for Drug Abuse Prevention. Special Action Office

Monograph, Series A, Number 2. May 1974. Washington, D.C.: U.S.

Government Printing Office, 1974.

Definitive study of the extent and consequences of drug use by Americans

in Vietnam. The report also serves as a contribution to the understanding of the

natural history of drug abuse.

ROSENBERG, H.C. and OKAMOTO, M. A method for producing maximal pentobarbital

dependence in cats: Dependency characteristics. Drug Addiction: Neurobiology

and Influences on Behavior, Vol. 3. Edited by J.M. Singh and H. Lal. New

York: Stratton Intercontinental Medical Book Company, 1974.

A study is described of a reliable laboratory method for producing

pentobarbital physical dependence in the cat. Sodium pentobarbital was administered

via a chronically implanted intragastric cannula. Cats were treated 22-40 days,

twice a day, with a predetermined dose to produce the maximally tolerable depression

of the CNS. Subjective neurological observations were recorded throughout the

chronic treatment period. Quantitation of these observations provided a check on

our method and showed that the cats were indeed maintained at maximally tolerable

doses and that the dose was increased in parallel with the development of tolerance.

By 18 hours after abrupt termination of the treatment, signs of withdrawal

hyperexcitability appeared. By 24 hours, these signs included tremors, twitching

of facial muscles, increased startle response, myoclonic jerking, anorexia, piloerection, delirium and grand mal type convulsions. The appearance of these signs

was compared to the decline in blood pentobarbital levels. Frequency of grand mal

type convulsions was found to be a good Indicator of the degree of dependence. The

single most important factor determining the seizure frequency in cats treated by

this method was the rate of pentobarbital elimination. The half-life was well

correlated with seizure frequency; this indicates that the ability to maintain high

levels of pentobarbital between doses, by virtue of differences in elimination rate,

played a key role in the determination of the severity of physical dependence.

ROTH, L.J., DIAB, I.M., WATANABE, M. and DINERSTEIN, R.J. A correlative

radioautographic, fluorescent, and histochemical technique for cytopharmacology.

Molecular Pharmacology 10: 986-998 (1974)

Using mouse intestine, a model system has been developed in which two

target cell loci, biogenic amine-containing enterochromaffin cells and regenerating

crypt cells, are used for correlation of drug localization with fluorescence and

microscope structure. The combined procedure described for the cellular

localization of drug and fluorophore is based on the use of frozen freeze-dried

sections, dry-mounted on dried photographic emulsion, and has general applicability.

Tissues need not be subjected to contact with any solvents until after radioautography,

cellular fluorescence, and microspectrophotofluorometry have been completed. The

use of freeze-dried frozen sections provides the possibility for localization by

immunofluorescence labeling and thus offers the opportunity, by combining radioautographic and fluorescence labeling to investigate competitive inhibition at the

cellular level. Because this technique provides for reversible separation of the

tissue from the emulsion for independent treatment, histochemical methods that

are potentially destructive for the radioautogram can also be used. The correlative

technique described here is rigorously controlled and. systematic, and the results

are unambiguous.

62
SALZMAN, C., VAN DER KOLK, B.A. and SHADER, R.I. Marijuana and hostility

in a small group setting. Presented at the American Psychiatric Association

Meeting, May, 1975.

SCHMIDT, M.J., ROBISON, G.A. and SCHMIDT, D.E. Cyclic AMP in the rat brain:

Microwave irradiation as a means of tissue fixation. Advances in Cyclic Nucleotide

Research. New York: Raven Press, 1972. Pp. 425-435.

SCHUBERT, J., NYBACK, H. and SEDVALL, G. Accumulation and disappearance

of 3H-tryptophan in mouse brain; effect of LSD-25. European Journal of Pharmacology

10: 215-224 (1970)

3H-Tryptophan was administered intravenously to conscious mice by injection

or constant rate infusion. Endogenous tryptophan and 5-hydroxytryptamine levels

were not significantly altered by this treatment. 3H-5-HT formed in vivo from

the labelled precursor was identified by paper chromatography. Following a pulseinjection of 3H-tryptophan the level of 3H-5-HT in brain rapidly increased reaching

a peak within 30 min. Pretreatment of the animals with the tryptophan hydroxylase

inhibitor, p-chlorophenylalanine or reserpine, markedly reduced the accumulation

of 3H-5-HT.

Following the initial peak, the content of 3H-5-HT declined over several

hours at a rate that seemed to be exponential between 30 and 180 min after precursor

administration with a half-life of about 60 min. Treatment with p-chloro-phenylalanine

60 min after precursor administration did not accelerate the rate of disappearance of

3H-5-HT indicating that the decline of 3H-5-HT content is predominantly

determined by turnover of the amine.

The procedures were used to study the effect of LSD-25 on mouse brain

serotonin metabolism. Following LSD-25 treatment the rates of accumulation

and disappearance of 3H-5-HT after 3H-tryptophan administration were markedly

reduced. The contents of labelled tryptophan and endogenous tryptophan and

5-HT levels were not altered by drug treatment. The results indicate that LSD-25

reduces both synthesis and turnover of 5-HT in brain. The LSD-25 analogue

BOL 148 showed no effect on brain 5-HT metabolism. Possible mechanisms of

action of LSD-25 are discussed.

SCHUBERT, J., NYBACK. H. and SEDVALL, G. Regional differences in synthesis

and turnover of 5-hydroxy-tryptamine formed in vivo from 3H-tryptophan in

rat brain. Prag, Czechoslovakia: College of International Neuropsychopharmacology,

1970. P. 391.

3H-Tryptophan was administered i.v. to conscious rats. Rates of accumulation

and disappearance of 3H-5-hydroxytryptamine in seven regions of the central nervous

system were determined. During infusion of the precursor, 3-H-5-HT accumulated

at the highest rate in brain stem, followed by diencephalon, spinal cord, corpus

striatum, hippocampus, cerebral cortex and cerebellum. Rates of accumulation of

labelled 5-HT were correlated to the regional, distribution of endogenous 5-HT. The

disappearance rates of 3H-5-HT from the various brain regions were determined

between 60 and 180 min after precursor injection. Treatment with the tryptophan

hydroxylase inhibitor, H 22/54, did not alter the rate of 3H-5-HT disappearance. The

rate constant for 3H-5-HT disappearance varied about two-fold between regions, and was

highest in the brain stem. Assuming that 5-HT in each region is stored in a single

compartment the synthesis rate was calculated from the product of the rate constant

for 3H-5-HT disappearance and the steady-state level of 5-HT. Rates of 5-HT synthesis

were significantly higher in brain stem and diencephalon than in other regions. In

corpus striatum, hippocampus and spinal cord synthesis rates were about half that of

brain stem. Cerebral cortex and cerebellum synthesized 5-HT at rates that were only

20% and 10% respectively of that in brain stem.

63
SCHUSTER, C.R. Variables affecting the self-administration of drugs by rhesus monkeys.

Use of Nonhuman Primates in Drug Evaluation. Edited by II. Vagtborg. Austin, Texas:

University of Texas Press, 1968. Pp. 283-299.

SCHUSTER, C.R. and VILLARREAL, J.E. The experimental analysis of opioid dependence.

Psychopharmacology: A Review of Progress, 1957-1967. Edited by D. Efron, J. Cole,

J. Levine and J.R. Wittenborn. Washington, D.C.: U.S. Government Printing Office,

1968. Pp. 811-828.

SCHWEITZER, J.W., FRIEDHOFF, A.J., ANGRIST, B.M. and GERSHON, S. Excretion

of p-methoxyamphetamine administered to humans. Nature 229: 133-134 (January, 1971)

SEGELMAN, A.B. Cannabis sativa L. (Marijuana). III. The RIM test: A reliable and

useful procedure for the detection and identification of marijuana utilizing combined

microscopy and thin-layer chromatography. Journal of Chromatography 82: 151-157 (1973)

A simple, reliable and easily performed method for detecting and identifying

marijuana in suspect material is presented. The method, designated as the RIM test

(Rutgers Identification for Marijuana test), utilizes combined histochemical and thinlayer chromatography techniques and thus eliminates the need for a separate extraction step to obtain a suitable sample for thin-layer chromatographic study.

SELLS, S.B. Evaluation of treatment for drug abuse - A discussion of research

problems and approaches from the perspective of the DARP. Report to the Joint

NIMH-TCU drug abuse reporting program. The Effectiveness of Drug Abuse Treatment.

Edited by S.B. Sells. Evaluation of Treatments, Vol. 1. Washington, D.C.:

National Institute of Mental Health, IBR Report 73-14, 1973. Pp. 3-9.

SHEPPARD, C., FIORENTINO, D., COLLINS, L. and MERLIS, S. Performance

errors on Ravens Progressive Matrices (1938) by sociopathic and schizotypic

personality types. Psychological Reports 23: 1043-1046 (1968)

In an attempt to identify the existence of reasoning errors in psychiatric

patients, the performance of male narcotic users defined as sociopathic (N = 36)

and schizotypic (N = 34) by MMPI profile patterns was analyzed for avoidable

errors on the Ravens Progressive Matrices (RPM). An avoidable error was

defined as a failure to solve an item whose difficulty level was within the testee's

range of ability as measured by his performance. Construct validity was defined

in terms of the intercorrelations of Ravens centile and item difficulty levels.

Parametric and non-parametric tests of significance indicated that the schizotypic

group commit significantly more identifiable reasoning errors than the sociopathic

group.

64
SHEPPARD, C., RICCA, E., FRACCHIA, J., ROSENBERG, N. and MERLIS, S. Crossvalidation of a heroin addiction scale from the Minnesota Multiphasic Personality

Inventory. Journal of Psychology 81: 263-268 (1972)

A heroin addiction scale (He) gleaned from MMPI self-report was developed on

a sample of 63 prisoner addicts. It was later cross-validated on a sample of 160

prisoner addicts. One purpose of this study was to cross-validate the He scale on

a larger sample of male narcotic addicts (N = 274) while extending the use of the

scale to this sample drawn from a psychiatric installation. Additionally, attempts

were made to evaluate responses of narcotic addicts and two samples of male

alcoholic patients (N = 117 and N = 111) on the He scale.

On the basis of the data reported, the following conclusions seem justified.

The He scale discriminates heroin addicts from alcoholics in samples treated at

psychiatric installations. Whatever the attribute or attributes underlying the He

scale, alcoholics and heroin addicts differ in intensity. Heroin addicts score

significantly higher. There appears to be possible racial and ethnic response

differences on the He scale which indicate the need for further item analyses and

refinement of items. But, in view of the incidence and prevalence of drug abuse

and addiction in the society, continued reporting of these data seems warranted.

SILVERMAN, I. On the methodology of student drug use surveys: From an epidemiologic

to a cybernetic model. Proceedings of the First International Conference on Student

Drug Surveys, September 12-15. 1971, Newark, New Jersey. Edited by S. Einstein and

S. Allen. Farmingdale, New York: Baywood Publishing Company, 1972. Pp. 195-198.

SILVERMAN, I., BROTMAN, R., SUFFET, F. and ORDES. D. Reaching for accountability

in community practice. Public Health Reports 85(3): 251-260 (March, 1970)

SIMON, E.J. Methods used in the study of opiate receptors. Methods in Narcotic Research.

Edited by S. Ehrenpreis and A. Neidle. New York: Marcel Dekker, Inc., 1974.

SIMON, E.J. Opiate receptors (methods). Methods in Receptor Research. Edited by

M. Blecher. New York: Marcel Dekker, Inc. (in press)

SIMON, E.J., DOLE, W.P. and HILLER. J.M. Coupling of a new, active morphine

derivative to sepharose for affinity chromatography. Proceedings of the National

Academy of Sciences 69(7): 1835-1837 (July, 1972)

A new, pharmacologically active morphine derivative, 6-succinylmorphine,

was synthesized. The properties of this compound and evidence for its structure are

presented. Succinylmorphine was covalently coupled to ethylamino-Sepharose.

Morphine-Sepharose containing up to 40 mu-g of morphine did not block the electrically

stimulated contraction of isolated guinea pig ileum, but after alkaline hydrolysis of

beads containing 2 mu-g of morphine the supernatant completely blocked contraction.

This block was reversed by the specific morphine antagonist naloxone. Antibodies to

morphine were removed from serum by morphine-Sepharose, but not by ethylaminoSepharose, providing evidence of the efficacy of the beads for affinity chromatography.

65
SIMPSON, D.D. and SELLS, S.B. Patterns of multiple drug abuse: 1969-1971.

International Journal of the Addictions 9(2): 301-314 (1974)

Information concerning types and frequencies of pretreatment drug abuse, obtained

by interview from 11,380 patients included in the first two years (June 1969-June 1971) of the

NIMH-TCU Drug Abuse Reporting Program, were examined with respect to patterns of

usage. Twenty-eight patterns were defined, involving various combinations of drugs used and

frequencies of use. The results indicated that the most frequent drug-abuse pattern in

this patient sample, accounting for 28% of the entire sample, was the daily or weekly use

of heroin with no other drugs. The daily or weekly use of heroin with cocaine, with

marihuana, and with both cocaine and marihuana were also frequently observed patterns,

and combined with the heroin-only pattern, they characterized the majority of all the

patients. The most common patterns reported by the remainder of the patients were of

poly-drug use, typically involving marihuana, amphetamines, and barbiturates, as well

as heroin and cocaine.

SINGLE, E., KANDEL, D. and JOHNSON, B. The internal validity and reliability of

drug use responses in a large scale survey. Journal of Drug Issues (in press)

The problem of developing valid and reliable measures is potentially

greater for drug use than for other behaviors because the use of many of the drugs

is illegal and disapproved of by society. In the absence of independent criteria,

responses to drug use questions may be tested for internal consistency and

reliability. In a survey based on a representative, sample of 8. 206 New York State

public secondary school students, we find that self-reported illicit drug use is

consistent both at one point in time and over time. Further, it is strongly related

with adolescents’ attributes as well as with data independently obtained from best

school friends. Only a very small proportion of respondents report the use of a

fictitious drug. Self-reported use of alcohol appears to be less reliable, indicating

that for the more socially accepted drugs a higher level of use is necessary to

insure accurate recall. Self-reports obtained in large scale surveys appear to provide

valid and reliable measures of adolescent illicit drug use.

SMITH, S.G. and DAVIS, W.M. Haloperidol effects on morphine self-administration:

Testing for pharmacological modification of the primary reinforcement mechanism.

The Psychological Record 23: 215-221 (1973)

Rats were allowed to acquire morphine self-administration behavior and then

were extinguished. Following extinction, pre-treatment with saline and saline and

various doses of haloperidol were given before a reacquisition test. Reacquisition data

indicated that a low dose of haloperidol increased self-administration, while higher

doses reduced responding. Data from a second experiment using conditioned reinforcement demonstrated that haloperidol did not block the reinforcing action of morphine. Results

are discussed in terms of a need to differentiate between reinforcement antagonism and

motor impairment.

66
SONG, C.H., KANTER, S.L., and HOLLISTER, L.E. Extraction and gas chromatographic

quantification of tetrahydrocannabinol from marihuana. Research Communications in

Chemical Pathology and Pharmacology 1(3): 375-382 (May, 1970)

Assay of tetrahydronannabinol (THC) and related compounds by gas-liquid

chromatography (GLC) has been described by Lerner and Heaysman, et. al. The

former prepared methylated derivatives with diazomethane to assure detecting

cannabidiolic acid as well as the other common plant cannabinoids. The latter

prepared trimethyl silylether (TMSE) derivatives and used a more polar column to

effect their separation. Quantitative evaluation could not be made reliably because

pure standard was not available. Recently the synthesis of delta-1-trans-THC has been

accomplished. This material has been supplied to investigators by the National

Institute of Mental Health. A description will be given of simple procedures for

extracting THC and related compounds from marihuana plant materials and for

quantitative assay of the THC content of such extracts. An evaluation of the

stability of extracted THC in ethanol has also been done.

STERNBACH. D.D., ABOOD. L.G. and HOSS, W. A benzilate ester of pyrrolizidine

and its stereochemical relationship to other psychotomimetic glycolates.

Life Sciences 14: 1847-1856 (1974)

In an effort to further test the hypothesis that psychotomimetic

potency is related to the availability of the nonbonding electrons on the N

of a series of heterocyclic amino glycolate esters, the 1-benzilate ester

of pyrrolizidine was synthesized. The compound was found to have about

1/10 the anticholinergic and central nervous system potency of N-methyl4-piperidylbenzilate, which was among the most potent centrally active

glyc olates. The final product was a racemic mixture and, as determined

by nmr, consisted of one diasteroisomer, with the acid moiety trans to the

heterocyclic N. By the use of Dreiding models and measurement of the

relative rate of quaternization by CH3I, it was inferred that 1,2-syn

interference, by the H’s on the adjacent C’s, with the nonbonding electrons

on N was a factor in the’ diminished pharmacological potency of the pyrrolizidine ester.

Student Association for the Study of Hallucinogens, Inc. STASH fact sheet on the British

Narcotic System. Grassroots (October, 1972 Supplement)

TAKEMORI, A.E. Determination of pharmacological constants: Use of narcotic

antagonists to characterize analgesic receptors. Narcotic Antagonists.

Edited by M. Braude, L.S. Harris, E.L. May, J.P. Smith and J.E.

Villarreal. Advances in Biochemical Psychopharmacology Vol. 8.

New York: Raven Press, 1973.

The concept of pAx (17) has been used mostly with isolated tissue

preparations to identify agonists which act on similar receptors. In

recent years our group has applied the concept of pAx to data obtained in

intact animals for the characterization of analgesic receptors. The

definition of the apparent pA2in vivo then becomes the negative logarithm

01’ the molar dose of the injected antagonist which reduces the effect of a

double dose of an agonist to that of a single dose. The concentration of

the antagonist at the receptor site is unknown but it is assumed to be

proportional to the dose. Although pA2 is regarded as equal to the log of

the affinity constant (Kb) of the antagonist for the receptor, this is not

entirely true in vivo. However, the “Kb

” in vivo should be proportional

to the real Kb if the above assumption about the antagonist concentration

67
Takemori, A.E. continued

is correct. Aside from the theoretical implications of “pA2” in vivo,

the procedure offers a means to summarize a large amount of

quantitative data on competitive drug antagonism as well as a standard

method to compare antagonists. Our group has used this procedure for the

characertization of receptors interacting with narcotic and narcoticantagonist analgesics, for the comparison of the type of narcotic-receptor

interaction involved in various analgesic assays, and for the comparison

of the potencies of certain narcotic antagonists, The concept of pAx has

also been used to gather evidence that morphine causes a structural change

in analgesic receptors.

TAKEMORI, A.E., STESIN, A.J. and TULUNAY, F.C. A single-dose suppression

test in morphine-dependent mice. Proceedings of the Society for

Experimental Biology and Medicine 145: 1232-1235 (1974)

A simple single-dose suppression test based on a quantitative

method for assessing withdrawal jumping in morphine-dependent mice

has been established for the prediction of dependence liability. When

various narcotic, non-narcotic and narcotic antagonist agents were

coded and tested blindly, the experimenter was able to identify all the

drugs correctly.

TART, C.T. On Being Stoned: A Psychological Study of Marijuana Intoxication.

Palo Alto, California: Science and Behavior Books, 1971.

TAYLOR, J.F. Methods of chemical analysis. Narcotic Drugs: Biochemical

Pharmacology. Edited by D. Clouet New York: Plenum Press,

1971.

TULUNAY, F.C. and TAKEMORI, A.E. Further studies on the alteration of

analgesic receptor-antagonist interaction induced by morphine.

The Journal of Pharmacology and Experimental Therapeutics

190(3): 401-407 (1974)

In previous studies, we observed that pretreatment of mice with

narcotic analgesics induced a substantial increase in the efficacy of

narcotic antagonists whereas pretreatment with non-narcotic drugs or

antagonists did not. In the present study, experiments were designed to

see whether or not there was a relationship between the development of

narcotic tolerance and the induction of increased narcotic antagonism.

The increase in the efficacy of naloxone due to treatment of animals with

morphine is observed before analgesic tolerance can be detected and the

efficacy of the antagonist rises much faster than the development of

tolerance. The increased efficacy of naloxone reaches a maximum in

highly tolerant animals, i.e., those that received a morphine pellet

implant for 3 days In the tolerant state, the apparent pA2 value of

morphine-naloxone was 7.82 compared with 6.90 control animals. This

represented a greater than 8-fold increase in the apparent affinity

constant of the analgesic receptors for the antagonist and indicated that

a qualitative rather than a quantitative change in receptors took place

with the development of narcotic tolerance. Acute injections of

cycloheximide did not alter the ED50 of morphine or the increased

potency of naloxone. However, daily injections of cycloheximide for

7 days (4 days prior to morphine pellet implantation and 3 days during

the implant) inhibited the development of tolerance by 84% and the

increased efficacy of naloxone by 64%. The increased efficacy of

naloxone due to treatment with morphine appears to be a sensitive

indicator of the development of tolerance.

68
TULUNAY, F.C. and TAKEMORI, A.E. The increased efficacy of narcotic

antagonists induced by various narcotic analgesics. The Journal

of Pharmacology and Experimental Therapeutics 190(3): 395-400

(1974)

In a previous study using Nihon Clea (Japan) mice and the

abdominal stretching assay, we showed that pretreatment of mice with

a single dose of morphine hydrochloride caused a marked increase in

the antagonistic effect of naloxone without any apparent change in the

analgesic activity of morphine. These results were confirmed using

Sasco mice, the tail-flick assay and morphine sulfate. The

duration of the increased efficacy of naloxone was greater than 12 and

less than 24 hours. Morphine pretreatment induced the antagonistic

potency of other antagonists besides naloxone such as nalorphine and

diprenorphine. Pretreatment of mice with other narcotic analgesics

such as levorphanol and methadone also induced an increased

potency of naloxone. On the other hand, pretreatment with the

inactive optical isomer of levorphanol, dextrorphan or naloxone itself

did not cause this type of change. It is suggested that this increased

efficacy of narcotic antagonist due to narcotic pretreatment might be

a sensitive indicator of the initiation and development of tolerance to

narcotic analgesics.

TURANO, P., CANTON, C., TURNER, W.J. and MERLIS. S. Chromatographic

evidence for the existence of 8-hydroxy-chlorpromazine in urine.

Agressologie 9(2): 192-194 (March-April, 1968)

TURANO, P., TURNER, W.J. and MANIAN, A.A. Thin-layer chromatography of

chlorpromazine metabolites. Attempt to identify each of the metabolites

appearing in blood, urine and feces of chronically medicated schizophrenics.

Journal of Chromatography 75: 277-293 (1973)

Data are presented for thin-layer chromatographic behavior of

chlorpromazine and thirty-five of its metabolites, as well as for the thinlayer chromatographic behavior of forty-two still unidentified metabolites

found free or as glucuronides in plasma, erythrocytes, urine or feces.

Tables are given on the frequency of occurrence of each compound in each

source. The presence and identification of several new phenothiazine

metabolites and their methoxylated analogs are reported.

TURNER, C.E. Chemical analysis of cannabis using gas liquid chromatography and

thin layer chromatography. Presented at the First South African

International Conference on Alcoholism and Drug Dependence, Cape Town,

South Africa, November 4-8. 1974.

TURNER, C.E. and HADLEY, K. Preservation of cannabis. Journal of the American

Medical Association 223(9): 1043 (1973)

TURNER, C.E. and HADLEY, K. The relationship of chemical analysis to conflicting

pharmacological reports on Cannabis sativa L. Committee on Problems of

Drug Dependence, Washington, D.C.: National Academy of Sciences.

National Research Council, Division of Medical Sciences, 1974.

69
TURNER, C.E., HADLEY, K.W. and DAVIS, K.H., JR. Constituents of Cannabis

sativa L. V. Stability of an analytical sample extracted with chloroform.

Acta Pharmaceutics Jugoslavica 23(2): 89-94 (1973)

Chloroform extracts of Cannabis sativa L. are stable under ambient

temperature for at least a period of 144 hours. When compared to seven

other solvents, chloroform was the solvent of choice for extracting delta-gtetrahydrocannabinol from plant material. Additionally, chloroform extracts

can be used to analyze for other neutral cannabinoids or for their carboxylate

acid derivatives.

TURNER, C.E. and MOLE, M.L. Chemical components of Cannabis sativa. Journal

of the American Medical Association 225(6): 639 (August, 1973)

TURNER, W.J. and MERLIS. S. Vicissitudes in research: The twenty-four hour urine

collection. Clinical Pharmacology and Therapeutics 12(2. Part I): 163-166

(March-April, 1971)

Often much depends in metabolic studies upon the accuracy of 24 hour

urine collections. In the belief that many common sources of error occur and

lead to faulty conclusions, this report of some experiences in a psychiatric

hospital is presented as a cautionary tale. Difficulties described are due to

inadequate communication, patient resistance, personnel variables, and

medication errors.

TURNER, W.J., TURANO. P.A. and MARCH, J.E. Quantitative determination of

chlorpromazine metabolites in urine. Clinical Chemistry 16(11): 916-921

(1970)

A simple, rapid, precise, and accurate method is described for the

simultaneous and quantitative determination of conjugated and unconjugated

chlorpromazine metabolites in urine. It depends on reduction of sulfoxides

to sulfides, and oxidation of sulfides to ion radicals in a solution of

Fe+3(10)-3N) in 18N H2S04. Absorbance is measured at 422, 530, 565, and

700 nm, and concentration of metabolites in calculated by substituting values

obtained in appropriate equations. Our data for urines (from schizophrenic

men chronically medicated with chlorpromazine) generally agree with those

of other workers.

UYENO, E.T. Lysergic acid diethylamide, chlorpromazine and maze performance.

Archives internationes de Pharmacodynamie et de There 184(2):

389-394 (April, 1970)

The effects of LSD-25 and CPZ on the learned performance of

eighteen-day old rat weanlings, were evaluated in the two-channel Lashley

maze. The time of peak disrupting effect. of LSD-25 was 10 min after the

intraperitoneal injection and that of CPZ was 45 min. Dose response

experiments, conducted at the time of peak effect, showed that the impairing

effects of the compounds were dose-dependent. The median effective dose

(ED50) of LSD-25 was 0. 27 mu-mole/kg and that of CPZ was 12.5 mu-moles/

kg. The percentage of LSD-25 treated animals (33.3%) that took more than

50 sec to reach their home cages, was not significantly different from that

of CPZ treated animals (21.1%). However, a significantly greater number

of LSD-25 treated animals than CPZ treated animals made two or more

errors.

70
VILLARREAL, J.E. A suggested procedure for evaluating the dependence liability of

morphine-like compounds with mixed agonist-antagonist properties. Committee

on Problems of Drug Dependence. Washington, D.C: National Academy of

Sciences, National Research Council, 1969. Pp. 6015-6028.

WAINER, B.H., FITCH. F.W., FRIED, J. and ROTHBERG, R. M. Immunological studies

of opioids: Specificities of antibodies against codeine and hydromorphone. Clinical

Immunology and Immunopathology 3(2): 155-170 (1974)

Two new immunogenic opioid-protein conjugates were prepared. Codeine6-hemisuccinate was synthesized from the reaction of codeine with succinic

anhydride and hydromorphone-6-carboxymethyloxime was synthesized from the

reaction of hydromorphone with alpha-aminoxyacetic acid. Both opioids were

attached covalently to bovine serum albumin using the mixed anhydride procedure

and employed as immunogens in rabbits. Antibody measured by the ammonium

sulfate method showed increases in titer and avidity following subsequent immunizations. The specificities of both antisera were studied by competitively

inhibiting the binding of labeled opioid to antibody by the prior addition of

increasing concentrations of various unlabeled opioids. The ranges of immunoreactivity

of both antisera were different and corresponded closely to the structures of the

respective immunizing haptens. These observations suggest that antibodies prepared

against codeine, hydromorphonc, and morphine may be used multiply for qualitative

as well as quantitative determinations of opioids in biologic fluids.

WAINER, B.H., FITCH, F.W., FRIED, J. and ROTHBERG, R.M. A measurement of

the specificities of antibodies to morphine-6-succinyl-BSA by competitive

inhibition of 14C-morphine binding. Journal of Immunology 110(3): 667-673

(March, 1973)

Antisera reacting with morphine were produced in rabbits by

immunization with morphine-6-succinyl-bovine serum albumin. The antibody

assay employed ammonium sulfate precipitation of antibody-14C-morphine

complexes. The specificities of the sera were measured by prior incubation

of appropriate serum dilutions with increasing concentrations of various

unlabeled opioids before the addition of 14C-morphine. Opioids differed in

their ability to inhibit interaction of 14C-morphine and antibody; concentrations

inhibiting binding of 88 pmol/ml of 14C-morphine by 50% were: morphine-6-

hemisuccinate, 0.052 nmol/ml; heroin, 0.10 nmol/ml; morphine, 0.11 nmol/

ml; codeine, 0.16 nmol/ml; hydromorphone, 0.50 nmol/ml; nalorphine, 2.1

nmol /ml; meperidine 80.0 nmol/ml; naloxone, 30% inhibition at 1.0 X 103

nmol/ml. Variations in the ability to inhibit 14C-morphine binding were

related to the nature of the structural dissimilarities between the competing

compound and the homologous hapten. Differences in I5o values for the opioids

studied were reflections of inhibition curves with differing slopes. Such

observations allow the possibility of both qualitative and quantitative analyses

in assay systems.

71
WAINER, B.H., FITCH, F.W., ROTHBERG, R.M. and FRIED, J. Morphine-3-

succinyl-bovine serum albumin: An immunogenic hapten-protein

conjugate. Science 176: 1143-1145 (June, 1972)

Morphine-3-hemisuccinate was synthesized by reaction of morphine

with succinic anhydride. This compound was conjugated to bovine serum

albumin by the mixed anhydride method, and the degree of conjugation was

determined by base hydrolysis of the conjugate, extraction, and measurement

of free morphine. An average of 6.5 molecules of morphine were conjugated

to each molecule of protein. Eleven rabbits immunized with varying doses of

the conjugate were producing antibody 8 weeks later, as determined by a

modification of the ammonium sulfate method, which measures primary

binding of antigen by antibody.

WAJDA, I.J., MANIGAULT, I., HUDICK. J.P. and LAJTHA, A. Regional and

subcrllular distribution of choline acetyltransferase in the brain of

normal and morphine treated rats. Federation Proceedings 32(3):

3057 (March, 1973)

Homogenates from the caudate nucleus (CN), cerebral cortex (Cx)

and hypothalamus (H) were fractionated, and the distribution of choline

acetyltransferase (ChAc) was compared to that of protein, monoamine

oxidose (MAO) and potassium. Synaptosomol and mitrochondrial fractions

were obtained from discontinuous Ficoll or sucrose gradients. Differences

in the distribution of ChAc in the three brain regions were found, and

confirmed using continuous sucrose gradients. ChAc was localized in

denser particles from CN than from Cx or H. The density of MAO

containing particles, however, was similar from all three brain regions.

K

+

 rich particles coincided with those containing ChAc in Cx and H, but

were located in less dense fractions in CN. Morphine treatment, did not

influence the distribution of ChAc, but a slight shift of MAO toward

lower density fractions was noticed in preparation from CN. Regional

differences in the density of cholinergic particles parallel those found

in uptake experiments (Green et. al. JPET, 168: 264, 1969). The

activation of ChAc by EDTA - butanol medium was also studied. The

latent form of ChAc was found to be associated with synaptosomal fractions.

WALLACE, J.E., FARQUHAR. J.K., HAMILTON, H.E. and EVERHART, B.A.

Comments on the determination of diphenylhydantoin. Clinical Chemistry

20(4): 515-516 (1974)

WALLACE, J.E., HAMILTON, H.E., BLUM. K. and PETTY, C. Determination

of morphine in biologic fluids by electron capture gas-liquid

chromatography. Analytical Chemistry 46(14): 2107-2111 (December, 1974)

A method that permits the quantitative determination of morphine

at therapeutic levels in 1-2 ml of serum of plasma is described. Morphine

levels at less than twenty-five nanograms per ml can be effectively assayed

providing an internal standard of nalorphine is employed. Both the opiates

are measured by electron capture detection (

63Ni) as their respective

trifluoroacetyl derivatives. Sensitivity of the technique is sufficient to

permit the forensic scientist to establish the cause of death in “opiate

sensitivity reactions” as well as those intoxications that involve high blood

levels of morphine. The procedure has sufficient reliability for utilization

in pharmacokinetic studies of morphine.

72
WEI, E. Assessment of precipitated abstinence in morphine-dependent rats.

Psychopharmacologia 28: 35-44 (1973)

An experimental model is described for quantifying the precipitated

abstinence syndrome in morphine-dependent rats. Male rats were made

dependent on morphine by subcutaneous implantation of a morphine pellet and

the abstinence syndrome precipitated by intraperitoneal injection of naloxone

hydrochloride. A ranking system, based on the median effective dose of

naloxone for abstinence signs, quantitatively related the incidence of certain

precipitated signs to the dose of naloxone. The time course for the

development of dependence was shown to be maximal 70–74 h after pellet

implantation. Food or water deprivation for 48 h dissociated the body

weight loss during abstinence from the behavioral signs of precipitated

withdrawal. Ganglionic blockade did not significantly modify abstinence

behavior. An evaluative procedure which ranks abstinence signs is proposed for quantifying physical dependence on morphine.

WEI, E. Morphine analgesia, tolerance and physical dependence in the adrenalectomized

rat. British Journal of Pharmacology 47(4): 693-699 (April, 1973)

1. Adrenalectomy reduced the median antinociceptive dose (AD50) of

morphine in male Sprague-Dawley rats. The antinociceptive effect was assessed

by the tail-flick method of D’Amour & Smith (1941).

2. Tolerance to the antinociceptive effect of morphine developed in

adrenalectomized and sham-operated rats after chronic exposure to morphine.

Development of tolerance did not significantly alter the increased sensitivity

of adrenalectomized rats to the antinociceptive effect of morphine.

3. Adrenal weights were not increased in rats rendered physically

dependent on morphine by subcutaneous implanation of a morphine pellet.

Withdrawal, induced by intraperitoneal injection of naloxone hydrochloride,

4 mg/kg. or by removal of the implanted pellet, resulted in a rapid increase

in adrenal weight.

4. In morphine-dependent animals, the incidence of abstinence signs

and body weight loss during precipitated withdrawal did not appear to be

significantly influenced by adrenalectomy or by corticosterone-pretreatment.

WEI, E., LOH, H.H. and WAY, E.L. Neuroanatomical correlates of morphine dependence.

Science 177: 616-617 (August, 1972)

Naloxone hydrochloride, an opioid antagonist, was applied to several

discrete brain regions of morphine-dependent rats to precipitate abstinence.

Severe withdrawal signs were elicited after administration in the thalamus

but not in neocortical, hippocampal, hypothalamic, or tegmental areas of the

brain.

73
WEI, E., LOH, H.H. and WAY, E.L. Neuroanatomical correlates of wet shake behavior

in the rat. Life Sciences, 12, Part II: 489-496 (1973)

Immersion of pentobarbital-anesthetized rats into water elicits

repetitive shaking movements. These wet shakes are similar to the shaking

behavior characteristic of the morphine abstinence syndrome in rats. Morphine

sulphate, 10 mg/kg i.p., completely inhibited the wet shake response of normal

rats to ice water (2 to 6° C). The inhibitory action of morphine on wet shakes

was diminished in rats rendered tolerant to morphine by subcutaneous

implantation of a morphine pellet for 3 days. Transverse brain lesions, made

bilaterally with an iridectomy knife in anesthetized, non-tolerant rats, completely

inhibited the wet shake response to ice water when the transection was made at the

mid-collicular level. Lesions at the mid-thalamic level did not significantly

affect the wet shake response. It is postulated that the shaking response of

morphine abstinence and the wet shake response of normal rats to ice water may

share common neural pathways.

WEI, E., LOH, H.H. and WAY, E.L. Quantitative aspects of precipitated abstinence in

morphine-dependent rate. The Journal of Pharmacology and Experimental

Therapeutics 184(2): 398-403 (1973)

The dose-response relationships of naloxone to selected signs of the

precipitated abstinence syndrome were studied in male rats rendered

physically dependent on morphine by subcutaneous implantation of two

morphine pellets. Abstinence behavior was precipitated by i.p. injection of

naloxone hydrochloride 72 hours after the first pellet implant. The median

effective dose of naloxone was determined for the quantal abstinence responses of

diarrhea, abnormal posturing, ear blanching. ptosis, teeth chattering,

swallowing movements, escape attempts and wet shakes. Other signs of

precipitated abstinence such as the incidence of seminal emissions and

chromodacryorrhea as well as the average number of wet shakes and escape

attempts per responding animal were found to exhibit a poor dose-response

relationship with increasing naloxone dosage in the tested range of 0.04 to

10 mg/kg. Loss of body weight, measured three hours after naloxone

administration, was correlated to the log dose of naloxone. The relative

merits of different criteria for quantifying the morphine abstinence

syndrome are discussed.

WEI, E. and WAY, E.L. Application of the pellet implantation technique for the

assessment of tolerance and physical dependence in the rodent. Methods

of Narcotic Research. Edited by S. Ehrenpreis and A. Neidle. New York:

Marcel Dekker, Inc., 1974.

WEISS, B. Digital computers in the behavior laboratory. Biomedical Symposium Proceedings.

Maynard, Massachusetts: Digital Equipment Corporation Users Society, 1967.

74
WERNER, I., PETERSON, G.R. and SHUSTER, L. Choline acetyltransferase and

acetylcholinesterase in cultured brain cells from chick embryos.

Journal of Neurochemistry 18: 141-151 (1971)

Dissociated cells from brains of 7-day chick embryos were grown in

primary culture for as long as 20 days. Many of the plated cells grew out

long processes. Others, which proliferated rapidly, formed a confluent layer

of flat cells after 4-6 days. Total DNA and protein increased five-fold, and

activity of choline acetyltransferase (EC2.3.1.6) increased about 40-fold in

20 days. Acetylcholinesterase (EC3.1.1.7) increased three-fold by the

fourth day of culture and then declined. The pattern of increase for choline

acetyltransferase was similar to that for the in vivo development of the

enzyme.

L-Thyroxine, cyclic AMP (adenosine-3’,5’-monophosphate) or

theophylline promoted increased levels of both enzymes by 30-200 per cent.

L-Thyroxine also increased the activity of acetylcholinesterase in vivo by

40 per cent. When overgrowth by flat cells was prevented by the addition of

10-3M-5-flourouracil, there was a decrease in the activity of choline

acetyltransferase and an increase in the activity of acetylcholinesterase in

comparison to control activities. The addition of 10-3M-morphine or

cocaine produced a 30 per cent elevation in the activity of choline

acetyltransferase, but this effect could be mimicked with equimolar

concentrations of ammonium ion.

WILK, S., GITLOW, S.E. and BERTANI. L.M. Gas liquid chromatographic methods

for assay of catecholamine metabolites. Chapter 6 of Methods of

Investigative and Diagnostic Endocrinology. Edited by J.E. Rall and I.J. Kopin.

New York: North-Holland Publishing Company, 1972.

Highly specific and sensitive techniques have been described for the

determination of vanillylmandelic acid, 3-methoxy-4-hydroxyphenylethylene

glycol normetanephrine, metanephrine and dopamine by gas-liquid

chromatography. With modifications, levels of these compounds may be

obtained in tissues, plasma and cerebrospinal fluid as has been accomplished

for MHPG. In particular, the utilization of electron capture detection has

proven useful in the study of urinary catecholamine metabolites in normal

human subjects as well as those with gross derangements in their metabolism

due to the presence of neural crest tumors. Moreover, levels of

catecholamine metabolites may be adequately evaluated in other states in

which only subtle aberrations in autonomic dysfunction are apparent. Future

work must be directed toward the development of procedures for

norepinephrine and epinephrine in urine and eventually in plasma. Although

the potential for sensitive and specific assays of these compounds has been

demonstrated technical difficulties arising from derivative instability and

sample preparation await solution. Gas-liquid chromatography offers the

promise of assay techniques whereby multiple substances perhaps present

in only picogram amounts may some day be measured accurately by a single

sample preparation from urine, plasma or tissue specimens.

75
WILSON, T.W., WALLACE, S.C. and McMILLAN, D.E. Morphine drinking as a

model of opiate dependence. Presented at the 52nd General Session of the

International Association for Dental Research and the Annual Session of

The North American Division of IADR. Dental Research (in press)

In an attempt to develop a model for the study of drug abuse patterns,

rats were given 0.3 and 1.0 mg/ml solutions of morphine as the only fluid

available for 12 days. Initially, both concentrations of morphine decreased

fluid intake and disrupted the usual diurnal drinking pattern. All rats

drinking the lower-concentration of morphine regained their pre-drug levels of

fluid intake in a few days, as did some of the rats drinking the higher

concentration. The daily morphine intake was about 50 mg/kg/day (0.3 mg/ml

solution) to 120 mg/kg/day (1.0 mg/ml solution). Physical dependence on

morphine was demonstrated in the morphine-drinking rats by observations of

a variety of abstinence signs following injections of naloxone, or following

replacement of the morphine solutions with water. Rats switched from

morphine solutions to water, or given naloxone and then switched to water,

decreased their fluid intake for 24 hours after morphine was withdrawn and

showed a marked decrease in body weight for a week or more. Rats injected

with naloxone, but permitted to continue drinking morphine solutions showed

a similar pattern of symptoms for a few hours, but then increased their

morphine solution intake to terminate the abstinence syndrome.

WINKELHAKE, J.L. and VOSS, E.W., JR. Synthesis, isolation and immunochemical

characterization of N-(carboxymethyl-3H)-D-lysergamide. Journal of

Labelled Compounds 10(3): 475-488 (July-September, 1974)

Covalent amide linkage of glycine-2-3H to the non-hallucinogenic derivative, d-lysergic acid (LSA). by carbodiimide activation

results in a lysergic acid analogue which has potential use in

biochemical studies of the mode of action, metabolism and immunology

of d-lysergic acid diethylamide (LSD). Optimal conditions for the

reaction and isolation of the product, N-(carboxy-methyl-3H)-d-lysergamide.

were determined. The product was analyzed by radioimmune assay and by

equilibrium dialysis with highly specific antibody to the lysergyl moiety.

WOODLAND, J.H.R., YOLLES, S., BLAKE, D.A., HELRICH. M. and MEYER, F.J.

Long-acting delivery systems for narcotic antagonists. Journal of Medicinal

Chemistry 16(8): 897-901 (1973)

The relationship between the release rate of cyclazocine from

composites with poly(lactic acid) and (a) the molecular weight of the polymer

and (b) the form of the composite, as a film sealed in an envelope or as

discrete small particles, has been investigated in vivo and in vitro. The

release rate is not very sensitive to variations in the molecular weight of

the polymer within the values investigated. As may be expected. the lower

molecular weight polymer is absorbed faster than the higher molecular

weight polymer. The use of the composite as a film sealed in an envelope

of pure polymer permits control of the release rate. Desirable delivery

rates have been obtained by injecting suspensions of small particles of the

composite thereby eliminating the necessity of surgery. In experiments

with films, the release rate of cyclazocine in vivo is faster than in vitro,

whereas in experiments with small particles a reverse effect is observed.

YANAGITA, T. Development of tolerance and physical dependence to barbiturates in

rhesus monkeys. Committee on Problems of Drug Dependence. Washington,

D.C.: National Academy of Sciences, National Research Council, 1968. P. 5618.

76
YANAGITA. T. A technique for self-administration of water insoluble drugs to monkeys

by means of chronically implanted stomach catheters. Committee on Problems

of Drug Dependence. Washington, D.C.: National Academy of Sciences,

National Research Council. 1968. P. 5631.

YANAGITA, T., ANDO, K. and TAKAHASHI, S. A testing method for psychological

dependence liability of drugs in monkeys. Committee on Problems of Drug

Dependence. Washington D.C.: National Academy of Sciences, National

Research Council, 1970. P. 6563.

YOLLES, S., ELDRIDGE. J., LEAFE, T., WOODLAND, J.H.R., BLAKE, D.R.

and MEYER. F. Long-acting delivery systems for narcotic antagonists.

Controlled Release of Biologically Active Agents. Edited by A.C. Tanquary

and R.E. Lacey. New York: Plenum Press, 1974. Pp. 177-193.

YOLLES, S., ELDRIDGE. J.E. and WOODLAND, J.H.R. Sustained delivery of

drugs from polymer/drug mixtures. Polymer News 1(4-5): 9-15 (1970)

Experimental measurements have generally confirmed the

theoretical predictions of the rate of release of the drug, at least during

the first unit of dimensionless time. As yet, our experimental data for

the period with theta greater than 1 are not sufficiently reliable to

determine whether classical diffusion theory or permeability theory

better describes the migration of the drug.

It appears that the method of administering a drug as here

proposed will not provide a constant dose rate unless the original concept

is modified. There may be many medical situations, of course, where a

continuously decreasing dose rate is actually desired. On the other hand,

if a nearly constant dose rate is needed, one could leach the impregnated

polymer for a brief period just before implantation in the patient. In

this way, the concentration of drug near the exposed surfaces of the

structure would be reduced. In effect, one would eliminate the early

part of the delivery rate curve, where (on a linear plot) the rate drops

sharply with increasing time. The rate falls much more gradually

Thereafter.

We expect to continue work on this method of administering drugs,

developing it to the point where clinical evaluation will be justified.

YUNGER, L. M., HARVEY, J. A. and LORENS, S. A. Dissociation of the analgesic and

rewarding effects of brain stimulation in the rat. Physiology and Behavior

10: 909-913 (1973)

Lateral hypothalamic stimulation in rats produces both rewarding and

analgesic effects. In comparison to the rewarding effect, significantly higher current intensities were required to produce analgesia as measured by the hot-plate

method. The analgesia did not outlast stimulation. Alpha-methyl-p-tyrosine

(250 kg/kg) decreased self-stimulation rates but had no effect on stimulationinduced analgesia. It was concluded that the rewarding and analgesic effects

of lateral hypothalamic stimulation involve separate neurochemical systems.

77
ZAKS, A.M., BRUNER, A., FINK, M. and FREEDMAN, A.M. Intravenous

diacetylmorphine (heroin) in studies of opiate dependence. Diseases

of the Nervous System 30 (Supplement): 89-92 (1969)

78
II

Drug Chemistry

and Metabolism

ABEL, E.L., editor. Behavioral and Social Effects of Marijuana. New York: MSS

Information Corporation, 1973.

Collection of approximately 32 papers published from 1970-1972

on various aspects of marijuana. Studies on the pharmacology, physiology

and pathology of marijuana usage are presented. Specifics discussed are

liver function, diabetic coma, growth inhibition, central nervous system

metabolism and the chemical identification and synthesis of cannabidiol

derivatives. These reports are intended to provide a basis for a chemical

understanding of the effects of this widely used drug.

ABRAMS, L.S. and ELLIOTT, H.W. Morphine metabolism in vivo and in vitro by

homozygous Gunn rats. The Journal of Pharmacology and Experimental

Therapeutics 189(1): 285-292 (1974)

Adult homozygous Gunn and Wistar rats were given daily injections

with subcutaneous doses of morphine sulfate starting at 20 mg/kg and gradually

increasing to 35 mg/kg over a 30-day treatment period. No differences were

found between Gunn and Wistar rats in the average urinary excretion of conjugated morphine during the treatment period. The reported existence of

codeine as a urinary morphine metabolite in rats was not confirmed. Incubation of the urine of morphine treated rats with beta-glucuronidase provided no

evidence to support the existence of any morphine conjugate other than glucuronide. The percentage of dose recovered as urinary conjugated morphine

was not decreased by chronic morphine treatment of either Gunn or Wistar

rats but the percentage recovered as free morphine was increased significantly

more in Gunn than in Wistar rats. No significant differences were observed

between Gunn and Wistar rat uridine diphosphate glucuronyltransferase activity

when hepatic microsomes from adult Gunn and Wistar rats were incubated with

morphine and uridine diphosphate glucuronic acid. Subsequent hydrolysis of

the product with beta-glucuronidase indicated that the morphine conjugate

formed was a glucuronide.

ADAMS, T.C., JR. and JONES, L.A. Long-chain hydrocarbons of Cannabis and its

smoke. Agricultural and Food Chemistry 21(6): 1129-1131 (NovemberDecember, 1973)

A series of long-chain paraffins has been identified in Cannabis and

its smoke by gas chromatography and mass spectrometry. The level of hydrocarbons was determined to be about half that found in tobacco and its smoke,

although the effect of smoking on the paraffins in the Cannabis plant material

was comparable to analogous studies of tobacco and its smoke.

79
ADAMS, T.C., JR. and JONES, L.A. Phytosterols of Cannabis smoke. Agricultural

and Food Chemistry (in press)

The 3-beta-hydroxysterols present in American-grown (MS-13)

Cannabis were identified and quantitated in its smoke. The free sterol fraction

of the smoke contained campesterol, stigmasterol, and beta-sitosterol in essentially the same ratio as that found in the plant material.

ADLER, F.L., LIU, C-T. AND CATLIN. D.H. Immunological studies on heroin addiction. I. Methodology and application of a hemagglutination inhibition test for

detection of morphine. Clinical Immunology and Immunopathology 1: 53-68

(1972)

For abstract, see Section I. Methodology of Drug Research.

ADLER, M.W., KOSTOWSKI, W., RECCHIA. V. and SAMANIN, R. Anatomical

specificity as the critical determinant of the effect of raphe lesions on morphine

analgesia. European Journal of Pharmacology (in press)

AGHAJANIAN, G.K. and FREEDMAN, D.X. Biochemical and morphological aspects of

LSD pharmacology. Psychopharmacology: A Review of Progress 1957-1967.

Edited by D. Efron, J. Cole, J. Levine and J.R.W. Henborn. Washington, D.C.:

U.S. Government Printing Office, 1968. Pp. 1185-1193.

A brief account is given of some reported effects of lysergic acid

diethylamide (LSD) on biochemical systems as well as an analysis of the possible significance of these effects within the context of histochemically defined

neuronal systems. The effects of LSD on serotonin metabolism and the binding

of serotonin were established and these changes were seen with the psychoactive

congeners of the drug. The data show a reduction in serotonin metabolism most

marked at the termination of acute behavioral and autonomic effects. The

mechanism of the LSD induced changes in the concentration of serotonin and

5-hydroxyindoleacetic acid (5-HIAA) cannot be understood in purely chemical

terms since the level of activity of serotoninergic neurons plays an important

role in indole metabolism. Whatever the initiating interactions at the biochemical level, the changes in serotonin and 5-HIAA seen after LSD could be secondary to a reduction in the firing rate of the serotoninergic neurons. A number of

neural systems related to habituation, to constancies and to maintenance of

perceptual and sensory boundaries will have to be identified and studied to elucidate the effects of this class of drugs.

ANGRIST, R., SHOPSIN, B. and GERSHON, S. Metabolites of monoamines in urine and

cerebrospinal fluid, after large dose amphetamine administration. Psychopharmacologia 26: 1-9 (1972)

Four physically healthy non-schizophrenic amphetamine abusers volunteered to ingest amphetamine in large doses and to cooperate with behavioral

assessments, urine collections and to undergo lumbar punctures before and

after doing so. The effects of administered amphetamine on behavior and on

urine and cerebrospinal fluid levels of homovanillic acid (HVA), 5-hydroxy

indoleacetic acid (5-HIAA), 3-methoxy-4-hydroxy-phenyl glycol (MHPG) and

vanillylmandelic acid (VMA) are presented and discussed with regard to the

findings of other investigators.

80
ARREGUI. A., LOGAN, W.J., BENNETT, J.P. and SNYDER, S.H. Specific glycineaccumulating synaptosomes in the spinal cord of rats. Proceedings of the

National Academy of Sciences 69(11): 3485-3489 (November, 1972)

Subcellular fractionation of rat spinal cord on continuous sucrose

density gradients provides evidence for the existence of a specific synaptosomal fraction (enriched in pinched-off nerve endings) that accumulates glycine

selectively by way of a high-affinity transport system. The particles in this

fraction sediment to a less-dense portion of sucrose gradients than do particles

that accumulate neutral, basic, aromatic, and acidic amino acids. Particles

accumulating gamma-aminobutyric acid are even less-dense than those storing

exogenous glycine. The glycine-specific synaptosomal fraction also exists in

the brain stem but not in the cerebral cortex. These findings provide neurochemical support for the suggestion that glycine has a specialized synaptic

function, perhaps as a neurotransmitter, in mammalian spinal cord.

AURORI, K.C. and VESELL, E.S. Comparative stimulatory effects of four phenothiazines on hepatic microsomal enzymes. Drug Metabolism and Disposition

2(6): 566-572 (1974)

Four phenothiazine derivatives were compared with respect to the

extent that they stimulated hepatic microsomal drug metabolism of mature

male rats. Daily oral administration of chlorpromazine (16 mg/kg) for 3 days

stimulated ethylmorphine N-dcmethylase activity to 135% of control values.

Three- and seven-day pretreatment with promazine, thioridazine, or triflupromazine, and 7-day pretreatment with chlorpromazine stimulated ethylmorphine

N-demethylase activity less than observed for 3-day chlorpromazine pretreatment. Administration of chlorpromazine (32 mg/kg) or of promazine (64 mg/kg)

for 3 days stimulated both aniline hydroxylase activity and cytochrome P-450

content to levels exceeding 150% of control values. After 7 days of chlorpromazine or promazine administration, aniline hydroxylase activity declined, whereas

cytochrome P-450 content was maintained or increased. After 7 days of pretreatment with thioridazine or triflupromazine, aniline hydroxylase activity and

cytochrome P-450 content were weakly stimulated.

BAILEY, D.N. and JATLOW, P.I. Chemical analysis of massive crystalluria following

primidone overdose. American Journal of Clinical Pathology 58(5): 583-589

(November, 1972)

A 43-year-old woman was hospitalized with a 36-hr. history of stupor

and massive crystalluria following an apparent suicide attempt. Toxicologic

studies revealed phenobarbital and primidone in both blood and urine. Collection,

purification, and chemical analysis of the urinary crystals are described.

Microscopic examination, melting-point studies, infrared and ultraviolet

spectroscopy, and thin-layer and gas-liquid chromatography identified the

crystals as primidone. The clinical utility of crystalluria in the diagnosis of

primidone over-dosage is emphasized.

81
BAILEY, D. N. and JATLOW, P. I. Methaqualone, a new drug of abuse: Studies of

analytical methodology and interpretation of serum drug levels in overdose.

Clinical Chemistry 19: 666 (1973)

For abstract, see Section I. Methodology of Drug Research.

BAILEY, D. N. and JATLOW, P. I. Methaqualone overdose: Analytical methodology, and

the significance of serum drug concentrations. Clinical Chemistry 19: 615-629

(1973)

For abstract, see Section I. Methodology of Drug Research.

BARTOLINI, A. and DOMINO, E.F. Cholinergic mechanisms in the cat visual system.

Federation Proceedings 30: 425 (1971)

The distribution of acetylcholine (ACh), cholineacetylase (ChA), acetylcholinesterase (AChE) and cholinesterase (ChE) were determined in pentobarbital anesthetized cats given 100 mg/kg i.p. physostigmine. The ACh content

of discrete brain areas was bioassayed and their enzymatic activity measured

using radiochemical techniques. The lateral geniculate and superior colliculus

contained high levels of these substances which were as great or greater than

those in the caudate nucleus. In contrast, the optic nerve and tract showed very

low activity in agreement with previous literature in other species. Five days

after bilateral removal of the eyes under pentobarbital anesthesia there was no

change in lateral geniculate levels of ACh, ChAc, AChE, and ChE even though

it is known that synaptic transmission fails 72-96 hrs after enucleation. This

would rule out ACh as the principal synaptic mediator from the retina to the

lateral geniculate. Photic stimulation (2.5 flashes/sec for 15 min) did not

affect ACh release from the visual cortex of pretrigeminal midpontine cat preparations. The content of ACh in various brain areas showed differential changes

following i.p. pentobarbital (40 mg/kg) or scopolamine (1.0 mg/kg). Pentobarbital increased ACh content in all brain areas studied while scopolamine caused

a significant decrease in the caudate nucleus and hippocampus but only a slight

decrease in the lateral geniculate, superior colliculus and visual cortex.

BASMADJIAN, G.P. and PAUL, A.G. The isolation of an O-methyltransferase from

peyote and its role in the biosynthesis of mescaline. Lloydia 34(1): 91-93

(March. 1971)

An O-methyltransferase has been partially purified from Lophophora

williamsii and shown to have a molecular weight of 410,000 ± 1000 by Sephadex

filtration. This enzyme will transfer the methyl group of S-adenosyl-L-methionine to the meta-hydroxyl group of dopamine and will O-methylate, at various

rates, other catecholic and monophenolic phenethylamines that have been

postulated as intermediates in the in vivo biosynthesis of mescaline. Naturally

occurring phenolic tetrahydroisoquinolines of peyote were not O-methylated.

82
BEN-ZVI. Z., BERGEN, J.R. and BURSTEIN, S. Cannabinol-7-oic acid: A metabolite

of delta-1-tetrahydrocannabinol in the rhesus monkey. Research Communications in Chemical Pathology and Pharmacology 9(1): 201-204 (September, 1974)

Injection of 14C-delta-1-tetrahydrocannabinol (THC) into male rhesus

monkeys gave rise to a complex mixture of urinary metabolites. One of these

has been isolated and identified as cannabinol-7-oic acid (I). This finding suggests a new metabolic pathway for delta-1-THC and raises the possibility that

other cannabinol derivatives may also be formed at earlier stages.

BEN-ZVI, Z. and BURSTEIN. S. 7-oxo-delta-1-tetrahydrocannabinol: A novel metabolite of delta-1-tetrahydrocannabinol. Research Communications in Chemical

Pathology and Pharmacology 8(2): 223-229 (June, 1974)

A careful analysis of the incubation products of delta-1-tetrahydrocannabinol (THC) with rat liver microsomes revealed the presence of a hitherto

unidentified metabolite. Mass spectral data suggested the 7-oxo derivative;

LiAlH4 reduction of this product gave 7-hydroxy-delta-1-tetrahydrocannabinol

substantiating this assignment. Such an aldehyde is a likely intermediate in

the detoxification of delta-1-THC which leads to acidic products.

BEN-ZVI, Z., MECHOULAM. R. and BURSTEIN, S. Identification through synthesis

of an active delta-1(6)-tetrahydrocannabinol metabolite. Journal of the American

Chemical Society 92: 3468-3469 (1970)

BEN-ZVI, Z., MECHOULAM, R. and BURSTEIN, S.R. Synthesis of delta-1- and delta1(6)-tetrahydrocannabinol metabolites. Tetrahedron Letters 51: 4495-4497

(1970)

BEN-ZVI, Z., MECHOULAM. R., EDERY, H. and PORATH, G. 6-beta-delta-1-

tetrahydrocannabinol. Synthesis and biological activity. Science 174: 951

(1971)

6-beta-Hydroxy-delta-1-tetrahydrocannabinol, a metabolite of delta-1-

tetrahydrocannabinol has been synthesized from delta-1(6)-tetrahydrocannabinol.

It shows high tetrahydrocannabinol-type activity in rhesus monkeys. The implications of this finding are discussed.

83
BERANEK, J.T. Morphine binding by serum globulins from morphine-treated rabbits.

Federation Proceedings 33: 474 (1974)

Reports on increased specific morphine binding by serum globulins

from heroin addicts have raised questions regarding its significance to tolerance

and addiction. Following the lead of Ringle and Herndon, the binding of 14Cmorphine-HCl by sera from rabbits variously treated with morphine has been

examined by precipitation of bound morphine with ammonium sulfate (0.2 ml

serum, 1.3 ml 0.15 M buffer pH 7.3 containing 85 ng = 23,000 cpm labeled

morphine-HCl, 1.5 ml sat. ammonium sulfate; ppt. washed twice with 2.5 ml

half sat. ammonium sulfate). Pretreatment sera bound an average of 0.2 ng.

Among 34 rabbits repeatedly injected SC with solutions of morphine, 3 developed

7-24 fold increases in binding, 16 showed slight increases (max. 4 fold) and the

others were negative. In contrast, two implantations of morphine pellets, 8

weeks apart, elicited responses in all of 19 rabbits, ranging from 7-100 fold.

Interestingly, rabbits that had previously received injections of morphine solutions showed resistance to this regime in that only one showed a 20 fold rise, 6

showed only slight increases and 3 did not respond at all. The binding protein

is concentrated in the globulins precipitable by 1/3 sat. ammonium sulfate.

Binding by this fraction persists after peptic digestion and is associated with

the fraction containing F(ab’)2. The complexes are highly dissociable and the

amount morphine bound is proportional to morphine added over a wide range.

BHARGAVA, H.N., AFIFI, A-H. and WAY, E.L. Effect of chemical sympathectomy on

morphine antinociception and tolerance development. Biochemical Pharmacology

22: 2769-2772 (1973)

BHARGAVA, H.N. and WAY, E.L. Morphine tolerance, dependence and withdrawal and

brain acetylcholine (ACh). The Pharmacologist 16(2): 279 (1974)

Thirty min after administration of morphine sulfate (MS) s.c., doses

greater than 20 mg/kg increased brain ACh in male Swiss Webster or ICR mice

(20-25 g); however, in male Sprague-Dawley rats (180-220 g), a dose of 40 mg/

kg of MS did not alter brain ACh. Mice and rats rendered morphine tolerantdependent (M) by implantation of 1 and 4 pellets, respectively, for 3 days showed

increased brain ACh. Six hr after pellet removel from M mice, this increase

was even higher. Brain ACh levels returned to normal beyond 12 hr after abrupt

withdrawal. Pellet removal from M rats did not affect brain ACh. Administration of naloxone (N) increased brain ACh in naive mice but decreased in M mice

and rats. This decrease in brain ACh in M animals was observed only in those

that jumped after N and not in those that failed to jump. The specific activity

of brain AChE in jumping and non-jumping mice did not differ. Brain choline

levels were unchanged by the above treatments. It appears that N-induced

withdrawal jumping in M animals is associated with an enhanced ACh release.

RICHER, J.L. and MECHOULAM, R. Pharmacological effects of two active constituents of marihuana. Archives internationales de Pharmacodynamie et de Therapie

172: 24-30 (1968)

Delta-1(6)-tetrahydrocannabinol was found to possess analgesic

properties demonstrable on both mice and rabbits. The mechanism of this

action on brain mechanism seems to be different from that of other narcotic

analgetic drugs such as morphine, since delta-1(6)-THC lowers the threshold

of the arousal response elicited by direct stimulation of the reticular formation

and does not revert the blood pressure descend produced by direct stimulation

of the sciatic nerve. The potential usefulness of the drug is discussed.

84
BOLT, A.G. and FORREST, I.S. In vivo and in vitro interactions of chlorpromazine

and melanin. Chapter 4 of Recent Advances in Biological Psychiatry, Vol. X.

New York: Plenum Press, 1968. Pp. 20-28.

In summary, we postulate that 7-hydroxychlorpromazine and melanoprotein interact in the presence of light in vivo as well as in vitro via a complete

charge-transfer reaction. This reaction is considered the basis of the chlorpromazine-induced hyperpigmentation of exposed skin areas in some patients.

The fact that this side effect occurs in less than 1% of chronically dosed patients

is attributed to elevated levels of circulating unconjugated 7-hydroxychlorpromazine, available for interaction with peripheral melanoprotein, which in turn may

also be present in elevated amounts.

BOLT, A.G. and FORREST, I.S. Metabolic studies of chlorpromazine-induced hyperpigmentation of the skin of psychiatric patients. Agressologie 9(2): 201-207

(1968)

BOSIN, T.R., BUCKPITT, A.R. and MAICKEL, R.P. Comparative gas-liquid chromatography of biologically important indoles, and their benzo(beta)thiophene and

1-methylindole analogs. Journal of Chromatography 94: 316-320 (1974)

BOWERS, M.B., JR. Acute psychosis induced by psychotomimetic drug abuse. II.

Neurochemical Findings. Archives of General Psychiatry 27: 440-442

(October, 1972)

Following probenecid administration lumbar cerebrospinal fluid 5-

hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) were measured

before and during phenothiazine treatment in 12 patients who developed psychotic

episodes following the ingestion of a psychotomimetic drug, probably D-lysergic

acid diethylamide (LSD-25) in all but two cases. Compared to nondrug-induced

psychotic patients and inmate controls the drug-induced patients gave evidence

of decreased central 5HIAA formation, findings analagous to those obtained

following the administration of LSD-like drugs to animals. These results persisted during phenothiazine treatment.

BOWERS, M.B. and ROTH. R.H. Interaction of atropine-like drugs with dopaminecontaining neurones in rat brain. British Journal of Pharmacology 44(2): 301-

306 (February, 1972)

1. A variety of atropine-like drugs effective in the treatment of drug-induced

extrapyramidal syndromes have been investigated with regard to their interaction with dopamine-containing neurones in rat brain.

2. Under some conditions benztropine, trihexyphenidyl, atropine and ethopropazine significantly antagonized the chlorpromazine-induced increase in subcortical concentrations of homovanillic acid.

3. Most of the atropine-like drugs investigated also decreased the turnover of

dopamine in the subcortex as measured by following the disappearance of dopamine after administration of alpha-methyl-rho-tyrosine.

4. These findings are suggestive that an imbalance between a dopaminergic and

cholinergic system might be closely linked to the pathogenesis of extra-pyramidal movement disorders.

85
BRAESTRUP, C. Effects of clonidine (catapressan) on synthesis and metabolism of

noradrenaline in the central nervous system of rats. Acta Pharmacologica et

Toxicologica 35 (Supplement I): 22 (1974)

Recently it was demonstrated that the antihypertensive drug clonidine

reduced the endogenous level of 3-methoxy-4-hydroxyplenyleneglycol (MOPEG),

a major noradrenaline (NA) metabolite in the CNS (Braestrup, J. Pharm. Pharmac.

1974, 26, 139-141). The observed decrease in MOPEG was further investigated by

measuring labelled NA and the two most significant NA-metabolites, MOPEG and 3,4-

dihydroxyphenyleneglycol (DOPEG), after intraventricular injection of 3H-dopamine

or 3H-tyrosine. Intraventricular injection of 3H-dopamine in clonidine pretreated

rats, resulted in an increase to 160 per cent of the controls of 3H-NA accumulation

and a decrease to 40 per cent of the controls of both 3H-MOPEG and 3H-DOPEG.

Intraventricular injection of 3H-tyrosine resulted in a small decrease in 3H-NA accumulation

and a 40-50 per cent decrease in 3H-MOPEG and 3H-DOPEG. These results,

obtained on the rat brain in vivo, are in agreement with the contention that

clonidine, by an action on central alpha-adrenoceptors, induces a compensatory

inhibition of NA -release and also NA -synthesis. The decrease in NA-synthesis

apparently is mediated through the tyrosine hydroxylase-step of NA biosynthesis

and not. at the dopamine-beta-hydroxylase-step.

BRAESTRUP, C., NIELSEN, M. and SCHEEL-KRÜGER. J. Accumulation and disappearance of noradrenaline and its major metabolites synthesized from intraventricularly injected 3H-dopamine in the rat brain. Journal of Neurochemistry

(in press)

BRAESTRUP, C., NIELSEN, M. and SCHEEL-KRÜGER, J. Feed back mechanisms in

central noradrenergic neurones in vivo, investigated through changes in

noradrenaline metabolism. Journal de Pharmacologie 5 (Supplement II):

11 (1974)

A new technique was applied for the determination of the two major

noradenaline (NA) metabolites in the cns of rats, 3-methoxy-4-hydroxyphenylglycol

(MOPEG) and 3,4-dihydroxyphenylglycol (DOPEG) mainly in conjugated forms,

after intraventricular (IV) injection of tritium labelled dopamine or NA.

Pretreatment with 6-OH-DA IV or reserpine resulted in almost complete

inhibition of (3H)NA accumulation after IV injected (3H) dopamine, while the

two main NA metabolites were decreased to 15-30% of the control. Intraventricular

injection of (3H)NA in 6-OH-DA pretreated rats resulted in a twofold increase

in (3H)MOPEG while (3H)DOPEG was unchanged. In contrast reserpine, administered

3 h later than (3H) dopsmine, caused a 175% increase of (3H)DOPEG and only a

50% increase of (3H)MOPEG.

The alpha-adrenoceptor antagonists phenoxybenzamine or aceperone

increased (3H)MOPEG and (3H)DOPEG after IV injection of (3H) dopamine, in

contrast the levels of both these metabolites were decreased after administration

of the alpha-adrenoceptor agonist clonidine.

86
BRANCHEY, L., BODNER, S. and FRIEDHOFF, A.J. Effect of chronic morphine

implantation on tyrosine hydroxylase activity in the rat caudate. Research

Communications in Chemical Pathology and Pharmacology 8(4): 707-710

(August, 1974)

Tyrosine hydroxylase (TH) was measured in the caudate of rats implanted with morphine pellets for 3 weeks. During that period the amount of

morphine given was increased from 18.7 mg to 225 mg. A control group was

implanted with placebo pellets. One day after the last implantation TH activity

was found to be significantly decreased in the morphine implanted animals when

compared with the controls.

BRAUDE. M.C., MANSAERT, R. and TRUITT, E.B., JR. Some pharmacologic correlates to marihuana use. Seminars in Drug Treatment 1(3): 229-246 (December,

1971)

BROCHMANN-HANSSEN, E. Aspects of chemistry and biosynthesis of opium alkaloids.

Pharmacognosy and Phytochemistry. Edited by Wagner and Horhammer.

New York: Springer-Verlag, 1970. Pp. 347-369.

BROCHMANN-HANSSEN. E. Opium alkaloids XII: Quantitative determination of morphine in opium by isotope dilution. Journal of Pharmaceutical Sciences 61:

1118-1119 (1972)

For abstract, see Section I. Methodology of Drug Research.

BROCHMANN-HANSSEN, E., CHEN. C.H., CHIANG, H.C., FU, C-C. and NEMOTO,

H. Opium alkaloids XIV: Biosynthesis of aporphines--detection of orientaline

in opium poppy. Journal of Pharmaceutical Sciences 62(8): 1291-1293 (August,

1973)

For abstract, see Section I. Methodology of Drug Research.

BROCHMANN-HANSSEN, E., FU, C-C. and ZANATI, G. Opium alkaloids IX: Detection of coreximine in papaver somniferum L. based on its biosynthesis from

reticuline. Journal of Pharmaceutical Sciences 60(6): 873-876 (June, 1971)

For abstract, see Section I. Methodology of Drug Research.

87
BROCHMANN-HANSSEN, E., LEUNG, A. T. and RICHTER, W. J. Opium alkaloids

XIII. Isolation of 160 hydroxythebaine. Journal of Organic Chemistry 37: 1881

(1972)

For abstract, see Section I. Methodology of Drug Research.

BRONAUGH, R.L. and ERWIN, V.G. Partial purification and characterization of

nadph-linked aldehyde reductase from monkey brain. Journal of Neurochemistry

21: 809-815 (1973)

The activity of NADPH-linked aldehyde reductase (EC 1.1.1.2) in

various regions of monkey brain was determined in vitro. The highest specific

activity of the enzyme was found in areas of the brain stem: including the pons,

medulla and midbrain. A greater than 500-fold purification of the monkey brain

enzyme was obtained by a combination of ammonium sulphate fractionation and

subsequent chromatography on calcium phosphate gel cellulose and DEAE-cellulose. The aldehyde metabolites of the biogenic amines, norepinephrine, serotonin, dopamine and octopamine, were readily reduced by the NADPH-linked

aldehyde reductase. The Km values for 3,4-dihydroxyphenylglycolaldehyde.

3.4-dihydroxyphenylacetaldehyde, and 5-hydroxyindoleacetaldehyde were 12•0

mu-M, 6•1 mu-M, and 27 mu-M, respectively. The maximum velocity (Vmax) for

3.4-dihydroxyphenylglycolaldehyde was, respectively, five-fold or three-fold

greater than that determined for 3,4-dihydroxyphenylacetaldehyde or 5-hydroxyindoleacetaldehyde. The highly purified enzyme derived from monkey brain

was markedly inhibited by barbiturates, diphenylhydantoin, and chlorpromazine,

but not by pyrazole. From data obtained by sucrose density gradient centrifugation and Sephadex chromatography the molecular weight of aldehyde reductase

was determined to be about 70,000 daltons.

BROOKES. L.G. and FORREST, I.S. Chlorpromazine metabolism in sheep. I. In vivo

metabolism. Agressologie 12: 245-251 (1973)

In vivo 3H-chlorpromazine metabolism in sheep was followed by urinary

and fecal excretion of chlorpromazine and its metabolites. using spectrophotometic thin layer chromatographic and radioquantitation techniques. Placental

transfer and passage into the milk and wool were demonstrated for the drug and

its metabolites.

BROOKES, L. G. and FORREST, I. S. Inter-species differences in chlorpromazine

metabolism in vitro. The Pharmacologist 11(2): 273 (1969)

In vitro metabolism of chlorpromazine has been studied in various

mammalian species to provide rapid information on species-specific

metabolic pathways for the detoxication of heterocyclic compounds. Hepatic

microsomal fractions, conventionally prepared, were incubated with chlorpromazine

hydrochloride, previously investigated with regard to its complex biotransformations.

Guinea pig, rabbit, cat, dog, squirrel monkey, sheep, ox, pig, sea lion, eland

and man were the subjects of qualitative and quantitative studies, with tritium

labeled chlorpromazine serving as the substrate for the quantitative work. Apart

from the inter-species differences observed in N-oxidation, S-oxidation, monoand d-demethylation, deamination and hydroxylation, the gradual development of the

drug-metabolizing enzyme systems from fetal to adult stages were followed in

guinea pig, rabbit and man. Metabolic pathways characteristic of man, were found

present in all species except cat and sea lion, which showed a more limited

metabolic potential. Accordingly, cat and sea lion were considered suitable

model systems for simulation of metabolically handicapped populations such

as neonates.

88
BROOKES, L.G. and FORREST, I.S. Intra-species variation in chlorpromazine metabolism. Research Communications in Chemical Pathology and Pharmacology

5(3): 741-758 (May, 1973)

The in vitro metabolism of chlorpromazine was followed, using hepatic

microsomes, from individuals of different ages in man, horse, sea lion, rabbit

and guinea pig. In man and horse, the fetal and adult developmental stages were

compared, whereas in the sea lion, adults and adolescents were used. In rabbit

and guinea pig, the development of pathways for the metabolism of chlorpromazine, was traced from the fetal through adult stages.

In all instances examined, the feti of all species studied, were able to

metabolize chlorpromazine in vitro by the pathways of N-oxidation, S-oxidation

and mono-demethylation. Di-demethylation and oxidative deamination of the

dimethylaminopropyl side chain of chlorpromazine, as well as the ring hydroxylation of the nucleus, were essentially developed postnatally, although prenatal

7-hydroxylation and deamination were observed in a few instances.

Analogous in vivo data were also obtained for man and sheep in neonates

and adults, and for rabbit and guinea pig from the fetal through the neonatal to

the adult stages.

BROOKES, L.G., HOLMES, M.A., FORREST, I.S., BACON, V.A., DUFFIELD, A.M.

and SOLOMON, M.D. Chlorpromazine metabolism in sheep. II. In vitro

metabolism and preparation of 3H-7-hydroxychlorpromazine. Agressologie

12: 333-342 (1971)

Sheep liver microsomes incubated with chlorpromazine produced the

normal spread of known metabolites of the substrate drug usually seen in vitro.

They showed an outstanding capacity for 7-hydroxylation. The fresh microsomal

preparations converted from one-third to more than two-thirds of the substrate

into various 7-hydroxylated derivatives of chlorpromazine. Manipulation of

storage conditions of the microsomal fractions prior to incubation with drug

substrate furthermore resulted in the production of nearly 70% of 7-hydroxychlorpromazine, at the expense of other non-phenolic and phenolic metabolites.

Thus, in sheep liver microsomes the pathways for 7-hydroxlation were found to

be more resistant to deterioration in storage than those for demethylation, Nosidation and sulfoxidation.

BROOKES, L.G., HOLMES, M.A., SERRA, M.T. and FORREST, I.S. Placental

transfer of chlorpromazine in rabbits and guinea pigs. Proceedings of the

Western Pharmacological Society 13: 127-137 (1970)

Guinea pigs and rabbits, chronically dosed with chlorpromazine

throughout their gestation period, were given tracer doses of 3H-chlorpromazine during the last few days of pregnancy. Placental transfer of tracer doses

of chlorpromazine in neonatal and fetal animals was studied, and in some

instances the tissues of maternal animals were similarly examined for comparison with drug content stored in these tissues. It was concluded from results

obtained in 3 litters of guinea pigs and 5 litters of rabbits that from 1 to 4% of

the maternal dose was found in the tissues of the litters. Some chlorpromazine

metabolites detected in fetal and neonatal tissues, but absent in corresponding

placental tissues, may have been produced in utero.

89
BROWN, D.J., MILLER, F.N., LONGNECKER, D.E., GREENWALD, E.K., HARRIS,

P.D. and FORNEY. R.B. The influence of delta-9-tetrahydrocannabinol on

cardiovascular and subcutaneous microcirculatory systems in the bat. The

Journal of Pharmacology and Experimental Therapeutics 188(3): 624-629 (1974)

Information regarding the cardiovascular and subcutaneous microcirculatory response of delta-9-tetrahydrocannabinol (THC) was obtained by direct

observation of the microcirculation in the bat wing, and by blood ‘pressure, heart

rate and body temperature recordings. An LD50 determination (535 mg/kg i.p.)

indicated that doses of 100 and 200 mg/ kg of THC would be well tolerated. These

doses produced significant reduction in heart rate and rectal temperature within

30 minutes of THC administration. Blood pressure remained essentially

unchanged until 85 minutes after injection. At this time, a significant reduction in blood pressure was obtained with the 200 mg/kg dose. No statistically

significant response was noted in the subcutaneous. small artery diameter (30-

45 mu) after THC administration. However, small veins (60-90 mu) exhibited

significant dilatation within 1 hour after the high dose of THC and remained

dilated throughout the experimental period. Early effects on heart rate and

rectal temperature indicate rapid i.p. absorption of THC. Latent effects on

vein diameter and blood pressure may represent a cause/effect relationship.

BURSTEIN. S. and KUPFER. D. Hydroxylation of trans-delta-1-tetrahydrocannabinol

by hepatic microsomal oxygenase. Annals of the New York Academy of Sciences

191: 61 (1971)

BURSTEIN. S., MARTINEZ, J., ROSENFELD. J. and WITTSTRUCK, T. The urinary

metabolites of delta-1-THC. The Pharmacology and Experimental

Psychology Cannabis and Its Derivatives. London: Oxford University

Press, 1972.

BURSTEIN, S. and MECHOULAM, R. Stereospecifically labelled delta-1(6)-tetrahydrocannabinol. Journal of the American Chemical Society 90: 2420 (1968)

BURSTEIN, S., MENEZES, F., WILLIAMSON, E. and MECHOULAM, R. Metabolism

of delta-1(6)-tetrahydrocannabinol, an active marihuana constituent. Nature

225: 87-88 (1970)

BURSTEIN, S. and ROSENFELD, J. The isolation and characterization of a major metabolite of delta-1-THC. Acta Pharmaceutics Suecica 8: 699 (1971)

For abstract, see Section I. Methodology of Drug Research.

BURSTEIN, S. and ROSENFELD, J. and WITTSTRUCK. T. Isolation and characterization of two major urinary metabolites of delta-1-tetrahydrocannabinol. Science

176:422-423 (April, 1972)

Two of the major metabolites which appear in rabbit urine after the

administration of delta-1-tetrahydrocannabinol have been isolated and their

structures have been tentatively established. The available evidence indicates

that they are 7-carboxy-delta-1-tetrahydrocannabinols with an additional hydroxyl

group on the side chain. The substances occur both free and as conjugates.

90
BUSH, M. T. and SANDERS-BUSH, E. Phenobarbital, mephobarbital, and methnrbital,

and their metabolites. Chemistry and methods for determination. Antiepileptic

Drugs. Edited by D. M. Woodbury, J. K. Penry and R. P. Schmidt. New York:

Raven Press, 1972. Pp. 293-302.

For abstract, see Section I. Methodology of Drug Research,

BUXBAUM. D.M., YARBROUGH, G.G. and CARTER, M.E. Biogenic amines and

narcotic effects. I. Modification of morphine-induced analgesia and motor

activity after alteration of cerebral amine levels. The Journal of Pharmacology

and Experimental Therapeutics (in press)

CATLIN, D.H., ADLER, F.L. and LIU, C-T. Immunological studies on heroin addiction. II. Applications of a sensitive hemagglutination-inhibition test for detecting morphine to diagnostic problems in chronic heroin addiction. Clinical

Immunology and Immunopathology 1(4): 446-455 (1973)

For abstract, see Section I. Methodology of Drug Research.

CAUTHEN, S. E. and KIDD, M. R. Properties of purified azolesterases from rabbit

serum. Presented at the American Chemical Society 168th National Meeting.

Atlantic City, New Jersey, September 9-13, 1974.

Atropinesterase (E.C. 3.1.1.10) and cocainesterase have been purified

700 and 200-fold respectively from commercially available, pooled rabbit serum.

Michaelis constants and pH optima have been determined for atropineesterase using

(-)-hyoscyamine and (-)-hyoscine as substrates and for cocainesterase using

cocaine and tropacocaine as substrates. Studies using other substrates have been done with

purified fractions of the enzymes in attempts to clarify conflicting reports in the

literature concerning subsrate specificities. The effects on atropinesterase antivity

of altering configuration around the alcohol bearing carbon atom in the tropine ring

and altering substituents on the bridge nitrogen atom in the substrate will be

discussed. Data regarding relative activities of cocain-esterase with respect

to the two ester functions in the substrate will be presented. Isozymes of the two

enzymes have been reported in electrophoresis studies of both atropinesterase and

cocainesterase from crude rabbit serum; zymograms of purified fractions using

polyacrylamide gel electrophoresis will be presented.

91
CAUTHEN, S. W., KIDD, M. R. and LARRISON, S. B. Substrate concentration and

ionic strength activation of partially purified atropinesterase. Presented at the

American Chemical Society 27th Southwest Regional Meeting, San Antonio, Texas,

December 1-3, 1971.

Atropinesterase (EC 3.1.1.10) was fractionated from commercially available,

pooled rabbit serum. It has been studied with respect to heretofore unreported,

but physiologically significant, substrates; its properties regarding cation requirements have been studied with atropine as substrate. The following methods have thus

far been worked out for enzyme purification: Ammonium sulfate fractionation

followed by dialysis, gel filtration (Sephadex G-200) eluted with potassium phosphate

buffer (0.002M, pH 7.0) and chromatography on DEAE-Sephadex A-50 using a

linear gradient from 0.1 to 0.4N KCl in phosphate buffer followed by diafiltration on

Amicon membrane UM-20E. The ability of the fractionated enzyme to catalyze the hydrolysi

of new substrates, cocaine hydrochloride, atropine methyl nitrate, scopolamine

hydrohromide, homatropine hydrobromide, hyoscyamine hydrobromide and homatropine methyl bromide, was found to be comparable to that observed with atropine

as substrate, except when the methylated alkaloids were substrates. Substrate

concentration related to activation by monovalent cations was examined using

atropine sulfate.

CHATTERJIE, N., FUJIMOTO, J.M., INTURRISI, C.E., ROERIG. S., WANG, R.I.H.,

BOWEN. D.V., FIELD. F.H. and CLARKE, D.D. Isolation and stereochemical identification of a metabolite of naltrexone from human urine. Drug Metabolism and Disposition 2(5): 401-405 (1974)

For abstract, see Section I. Methodology of Drug Research.

CHATTERJIE, N., INTURRISI, C.E., FUJIMOTO, J.M. and ROERIG, S. Species

variation in the stereochemistry of a metabolite of naltrexone. The Pharmacologist 16(2) (Fall, 1974)

For abstract, see Section I. Methodology of Drug Research.

CHEN, H. and DAVIS, F.F. Identification of 14-hydroxy morphine as a microbiological

transformation product of morphine. Journal of Chromatography (in press)

CHENEY, D.L. and GOLDSTEIN, A. The effect of rho-chlorophenylalanine on opiateinduced running, analgesia, tolerance and physical dependence in mice. The

Journal of Pharmacology and Experimental Therapeutics 177(1): 309-315 (1971)

Daily i.p. administration of rho-chlorophenylalanine (PCPA) (320 mg/

kg), which lowered brain serotonin to 34% of its normal level within three days,

failed to inhibit the development of tolerance to opiate-induced running activity

or analgesia. Under these same conditions, PCPA had no effect upon the development of physical dependence. Levorphanol-induced running was potentiated

by PCPA and inhibited when scrotonin levels were restored by administration

of 5-hydrosytryptophan, even in the presence of PCPA. PCPA treatment caused

neither potentiation nor inhibition of levorphanol-induced analgesia.

92
CHENEY, D.L., GOLDSTEIN, A., ALGERI. S. and COSTA, E. Narcotic tolerance and

dependence: Lack of relationship with brain serotonin turnover. Science 171:

1169 (1971)

Serotonin turnover was measured in mouse brain by means of the conversion of radioactivity from labeled tryptophan into serotonin. Animals with

a high degree of tolerance to and physical dependence on morphine did not differ

from control mice.

CHENEY, D.L., GOLDSTEIN, A. and SHEEHAN, P. Rate of development and reversibility of brain tolerance and physical dependence in mice treated with opiates.

Federation Proceedings 29(2): 685 (March-April, 1970)

Previous work (J. Pharmacol. Exp. Ther. 169: 175, 1969) was concerned with tolerance in the whole animal, without regard to separate contributions of metabolic and brain components. Now we have determined relationships between dose, blood level, brain level, and running activity (a measure

of opiate action)--all at different stages in development of tolerance. Tolerance

was induced by injections of levorphanol or implantation of morphine pellets.

Onset and disappearance of physical dependence was estimated by using naloxone

to precipitate the jumping syndrome characteristic of opiate withdrawal in mice.

Our results indicate that a significant part of tolerance, which has a

rapid onset, is accounted for by faster conjugation and excretion. Brain tolerance develops more slowly. It is reversible. Its rate of onset, like that of

metabolic tolerance, is a function of the concentrations of opiate to which the

animal is exposed and the frequency of such exposures. The same description

applies to development and disappearance of the process in brain that is responsible for physical dependence. Continuous treatment with rho-chlorophenylalanine (320 mg/kg) starting 3 days prior to morphine pellet implantation failed to

block development of physical dependence.

CHENOWETH, M. B., DOMINO, E. F. and VAN DYKE, R. A. The distribution

and metabolism of volatile anaesthetic agents. Fourth World Congress of

International Anesthesia, 1939. Pp. 382-387.

It develops that the ‘non-metabolized, stable central nervous system

depressants’ we use as anaesthetics are actually much metabolized, not

particularly stable, and show a remarkable predilection to accumulate

preferentially in places other than the brain.

93
CICERO, T.J., MEYER, E. R. and SMITHLOFF, B.R. Alpha adrenergic blocking

agents: Antinociceptive activity and enhancement of morphine-induced analgesia.

The Journal of Pharmacology and Experimental Therapeutics 189(1): 72-82

(April, 1974)

The effects of reducing the activity of norepinephrine in the nervous

system, either by depleting endogenous levels via dopamine-beta-hydroxylase

inhibition or by blocking its effects at the receptor level, on hot plate reaction

time and on morphine’s analgesic activity, were determined in rats. Inhibition

of dopamine-beta-hydroxylase resulted in a significant prolongation of morphine’s antinociceptive activity on the hot plate. The alpha adrenergic blocker,

phenoxybenzamine, alone nearly doubled reaction time on the hot plate when

10 mg/kg were administered prior to testing. The effect of a minimally effective dose of morphine on hot plate reaction time was significantly enhanced,

both in the initial increase in reaction time after the administration of the narcotic and the duration of its antinociceptive activity. The combined effect of

phenoxybenzamine and morphine on hot plate reaction time was substantially

greater than predicted on the basis of addition of the 2 drugs’ effects. Another

alpha blocker, phentolamine, also produced a slight degree of antinociceptive

activity by itself and an enhancement of morphine induced analgesia, whereas 2

beta adrenergic blockers, propranolol and practolol, were ineffective. The

observed interaction between phenoxybenzamine and morphine was not related

to altered distribution of the narcotic in the brain. Results of these studies

suggest that the action of morphine and related narcotics may be associated with

a reduction in norepinephrine’s activity in the nervous system particularly at

alpha adrenergic receptor sites.

CICERO, T.J., SHARPE, L.G., ROBINS. E. and GROTE, S.S. Regional distribution

of tyrosine hydroxylase in rat brain. Journal of Neurochemistry 19: 2241-2243

(1972)

The rate-limiting step in the biosynthesis of the catecholamines is the

conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (DOPA). a reaction

catalysed by tyrosine hydroxylase (EC = 1.14.3.2) (Levitt, Spector, Sjoerdsma

and Udenfriend, 1965). Although the chemical properties of tyrosine hydroxylase have been extensively examined (Nagatsu, Levitt and Udenfriend, 1964a;

Petrack, Sheppy and Fetzer, 1968; Nagatsu, Sudo and Nagatsu, 1971), there

have been few reports on its distribution in brain. In the present study, we

have examined the regional distribution of tyrosine hydroxylase in the rat brain.

CICERO, T.J., SHARPE, L.G., WILCOX, C.E. and SMITHLOFF, B.R. Effects of

morphine in vivo and in vitro on tyrosine hydroxylase activity in rat brain.

The Journal of Pharmacology and Experimental Therapeutics (in press)

94
CICERO, T.J., WILCOX, C.E., SMITHLOFF, B.R., MEYER, E.R. and SHARPE,

L.G. Effects of morphine, in vitro and in vivo, on tyrosine hydroxylase

activity in rat brain. Biochemical Pharmacology 22(24): 3237-3246

(December, 1973)

The effect of morphine on the synthesis of catecholamines was determined in rat brain. Morphine produced a dose dependent increase in the biosynthesis of the catecholamines. To assess whether morphine might enhance

the synthesis of norepinephrine and dopamine by a direct chemical interaction

with tyrosine hydroxylase, the rate limiting step in their biosynthesis, the

effects of the narcotic on the activity of the enzyme were determined in several

regions of rat brain. The effects of morphine treatment, in vivo, on enzyme

activity were also examined. The results of these studies indicated that acute

injections of morphine had no effect on tyrosine hydroxylase activity, in vitro,

indicating that the drug did not alter the level of an endogenous activator or

inhibitor of tyrosine hydroxylase. Further studies indicated that development

of tolerance to and physical dependence on morphine was not associated with an

increase in the activity of brain tyrosine hydroxylase activity. The results

suggest that morphine does not enhance the biosynthesis of catecholamines by a

direct effect of tyrosine hydroxylase and that tolerance to the narcotic is not

characterized by an induction of this enzyme.

CLINESCHMIDT, B.V. and HORITA, A. The monoamine oxidase catalyzed degradation

of phenelzine-1-14C, an irreversible inhibitor of monoamine oxidase--I. Studies

in vitro. Biochemical Pharmacology 18: 1011-1020 (1969)

Exposure of phenelzine-1-14C to a biotransformation system which

included mitochondria isolated from homogenate of rat liver resulted in a metabolite with thinlayer chromatographic characteristics identical to those of

authentic phenylacetic-1-14C acid.

The conversion of phenelzine to phenylacetic acid was found to be: (1)

relatively insensitive to preincubation of the bioconversion system with cyanide;

(2) dependent upon the presence of O2; (3) abolishing by boiling the mitochondrial

component of the system; and (4) inhibited by preincubation of the biotransformation system with isocarboxazid, pheniprazine, tranylcypromine or pargyline.

These results provide the first substantial evidence for an irreversible

inhibitor of monoamine oxidase (MAO) acting as a substrate of the enzyme, and

the results suggest that degradation of the inhibitor is very likely accomplished

by oxidative dehydrazination, a reaction mechanism previously unknown for MAO.

CLINESCHMIDT, B.V. and HORITA. A. The monoamine oxidase catalyzed degradation

of phenelzine-1-14C, an irreversible inhibitor or monoamine oxidase--II.

Studies in vivo. Biochemical Pharmacology 18: 1021-1028 (1969)

Rats receiving approx. 2.5 mg/kg of phenelzine-1-14C by the intraperitoneal route were placed in metabolism cages and their urine collected for

24 hr. Phenylacetic-1-14C acid was recovered as a major metabolite.

Pretreatment of the animals with tranylcypromine (10 mg/kg) or pargyline (100 mg/kg) prior to injection of radioactive phenelzine markedly reduced

the urinary excretion of phenylacetic-1-14C acid and the excretion of other unidentified metabolites appeared to increase. Inhibition of monoamine oxidase

(MAO) with tranylcypromine or pargyline had no effect on the urinary excretion

of an equimolar dose of phenylacetic-1-14C acid administered by the same route.

Therefore, pretreatment of rats with tranylcypromine or pargyline appears to

95
Clineschmidt, B.V. and Horita, A. The monoamine - II. . . continued

have decreased the bioconversion of the injected phenelzine to phenylacetic

acid. These results provide further evidence that phenelzine, in addition to

being an irreversible inhibitor, is also a substrate of MAO in the intact animal.

CLONINGER, C.R., PACKMAN, P.M., CICERO, T.J., BOSHANS, R.L. and ROBINS, E.

Morphine dependence and enzyme activity in the h,ypothalamus. Biochemical

Pharmacology 23(5): 983-988 (March, 1974)

Tolerance to and physical dependence on morphine were produced in

rats by the implantation of morphine pellets. When both reached peak levels,

the rats were sacrificed and malic dehydrogenase, lactic dehydrogenase and

glucose-6-phosphate dehydrogenase were measured by sensitive microchemical

methods in 8 hypothalamic nuclei and in the cortex, cerebellum and liver. In

the medial portion of the ventromedial nucleus of the hypothalamus, glucose-6-

phosphate dehydrogenase was 20 percent lower in the morphine dependent animals than in the controls. This was the only significant change detected for any

of the 3 dehydrogenases in any of the regions or organs examined. The data

indicate that chronic morphine administration does not produce a generalized

change in the activity of major metabolic pathways in either the brain or liver.

The regionally selective effect on glucose-6-phosphate dehydrogenase activity

may reflect an involvement of the ventromedial hypothalamus in at least some

aspects of the development of tolerance and physical dependence on narcotics.

CLOUET, D.H. Cellular biochemistry of narcotic analgesic drugs in the central nervous

system of the rat. Psychiatric Quarterly 46(3): 384-392 (1972)

Research on the effects of opioids on the biosynthesis, storage, release,

and catabolism of neurotransmitters at the nerve ending and the effects of drugs

on the structure of the nerve ending and its component macromolecules is reviewed.

CLOUET, D.H. Effect of morphine on protein and ribonucleic acid metabolism in brain.

Drug Abuse: Social and Psychopharmacological Aspects. Edited by J. Cole.

Springfield, Illinois: Charles C. Thomas, 1969. Pp. 153-163.

The metabolism of protein and ribonucleic acid (RNA) in rat brain was

examined after the administration of morphine to the animals. Experiments

showed that a single dose of morphine produced profound changes in overall

protein and RNA synthesis in the brain. The inhibition of protein synthesis. as

measured both in vivo and in vitro, may be related to a decrease in polyribosomal activity in promoting amino acid incorporation into protein and a decrease

in the stability of ribosomes in the polysomal structure. The apparent inhibition

of RNA turnover in the brains of morphine treated rats is due to changes in precursor pool size, and the true situation is more likely to be that seen in the

labeling patterns in which RNA synthesis is increased in nuclear fractions from

morphine treated animals. There is little evidence of whether these changes in

protein and RNA synthesis in brains of morphine treated rats are basic phenomena or secondary to changes in other biochemical systems. The changes in

pool size of labeled amino acids and orotic acid in treated animals suggest that

such phenomena as oxidative metabolism or transport may also be involved in

the biochemical response to narcotic drugs.

96
CLOUET, D.H. The effects of drugs an protein synthesis in the nervous system.

Protein Metabolism of the Nervous System. Edited by A. Lajtha. New York:

Plenum Press, 1970. Pp. 699-713.

The effects which drugs have on protein synthesis in the nervous system

of experimental animals fall into two general categories: (1) effects similar to

those produced in other tissues by drugs which are well known as metabolic

inhibitors or antibiotics, and (2) effects produced by drugs which have the

nervous system as their probable site of action and which thus may be

expected to have specific effects on metabolism in nervous tissue. In the

present discussion the effects of metabolic inhibitors, antibiotics, and other,

presumably nonspecific, drugs on protein synthesis or turnover in brain and nerve

will be described briefly, with examples cited from the literature. Another class of

drugs, those which affect a single enzyme system or classes of enzymes, which can

be considered to be affecting a portion of the protein of the nervous system, will be

discussed in terms of representative studies. Major attention will be given to

studies from this laboratory on the responses in nervous tissue to the administration

or addition of narcotic analgesic drugs.

CLOUET, D.H., editor. Narcotic Drugs: Biochemical Pharmacology. New York:

Plenum Press, 1971.

Collection of articles by various authors concerning the chemistry of

narcotic analgesic drugs, the metabolic disposition of narcotic analgesic drugs,

metabolic effects, sites of action, and tolerance and dependence. Additionally,

studies in man regarding the electrophysiological properties and the pharmacologically based therapeutic programs are discussed.

CLOUET, D.H. Protein and nucleic acid metabolism. Chapter 9 of Narcotic Drugs:

Biochemical Pharmacology. Edited by D.H. Clouet. New York: Plenum Press,

1971. Pp. 216-228.

CLOUET, D.H., JOHNSON, J.C., RATNER, M., WILLIAMS, N. and GOLD, G.J. The

effect of morphine on rat brain catecholamines: Turnover in vivo and uptake in

isolated synaptosomes. Journal of Neurochemistry (in press)

CLOUET, D.H. and NEIDLE, A. The effect of morphine on the transport and metabolism of intracisternally-injected leucine in the rat. Journal of Neurochemistry

17: 1069-1074 (July, 1970)

Intracisternally injected L or D-(14C)leucine was retained longer in

the brains of morphine-treated rats than in saline-injected control animals.

This resulted in higher levels of the labelled leucine and of labelled metabolites

of the L-isomer in free pools of brain tissue. However, the absolute levels of

brain amino acids and the relative distribution of radioactivity among L-leucine

metaboliles in brain were unaffected by treatment with morphine, indicating

that no disturbance of leucine oxidation through the citric acid cycle was produced by the drug. The inhibition of protein synthesis caused by acute administration of morphine was calculated to be greater than previously reported

since morphine treatment increased the specific radioactivity of the free pool

of leucine in brain following the intracisternal injection of the labelled amino

acid. Possible mechanisms responsible for these morphine effects are discussed.

97
CLOUET, D.H. and RATNER. M. The biosynthesis of catecholamines in the brains of

morphine treated rats. Committee on Problems of Drug Dependence. Washington, D.C.: National Academy of Sciences, National Research Council, 1970.

P. 7025.

CLOUET, D.H. and RATNER, M. Catecholamine biosynthesis in the brains of morphinetreated rats. Science 168: 854-856 (May. 1970)

In the brains of rats without tolerance to morphine, the accumulation

of (

14C)dopamine formed from (14C)tyrosine injected intracisternally is increased, reaching a maximum in the hypothalamus and striatum 1 hour after

administration of morphine. In tolerant rats, the rate of incorporation of

carbon-14 into dopamine and into norepinephrine in these areas is more than

twice that in animals that have received only one injection of morphine.

CLOUET, D.H. and RATNER. M. Effect of morphine on brain tyrosine hydroxylase

activity. Federation Proceedings 30: 501 (1971)

A partially purified tyrosine hydroxylase was prepared from homogenates of six areas of rat brain and the activity was measured with 3,5 diH3

-

tyrosine as substrate. The enzyme activity was above control in only one treatment group of rats receiving morphine either by injection or by pellet implantation: in the hypothalamus, striatum and midbrain of rat receiving a morphine

pellet plus daily injections of morphine for ten days. On other regimens of drug

administration the enzyme activity was unchanged or lower than control in these

areas and in the other areas of brain. It is possible, however, that the assay

for tyrosine hydroxylase activity in purified preparations did not reflect the

catecholamine synthetic capacity in vivo as tyrosine hydroxylase activity was

found to vary biphasicall when catecholamines or narcotic drugs were added in

concentrations from 10-3 to 10-5 M to the brain homogenates before the enzyme

was isolated for assay. Since administration of morphine is known to alter

brain catecholamine levels and to result in drug uptake into brain, it is possible that the redistribution of these compounds during tissue homogenization

might effect enzyme activity measured in vitro. In the tyrosine hydroxylase

assay itself, the addition of not only dopa, dopamine or norepinephrine, but

also morphine, methadone or levorphanol altered the enzyme activity.

CLOUET. D.H. and RATNER. M. Tyrosine hydroxylase activity in areas of the brains

of morphine-treated rats. Committee on Problems of Drug Dependence.

Washington, D.C.: National Academy of Sciences, National Research Council,

1971, P. 728.

In most animal species the admin. of morphine produces a release and

subsequent depletion of brain catecholamines in the central nervous system. In

animals chronically treated with morphine, this depletion does not occur.

Instead, there is either no change or an increase in the levels of brain catecholamines. Earlier studies from this laboratory have indicated that the rate of in

vivo synthesis of catecholamines in some areas of rat brain is affected by the

admin. of morphine. We found an increased synthesis of dopamine in the hypothalamus and striatum of animals injected with morphine one hour prior to

sacrifice, and an even greater increase in the same areas after the fifth daily

injection of the drug. Since the rate of biosynthesis of catecholamines depends

on the activity of the first enzyme in the biosynthesis pathway, tyrosine hydroxylase, this enzyme was assayed in various areas of the brains of morphine-treated

rats.

98
CLOUET, D.H. and WILLIAMS, N. The binding of narcotic analgesics in synaptosomal

and other particulate fractions. The Pharmacologist 13: 313 (1971)

Narcotic analgesics are localized in the synaptosomal fraction (NEP)

of rat brain after incubation of rat brain homogenate with drug in vitro and in

vivo after injection of the drug in analgesic doses to rats. When radiolabeled

meperidine, methadone, etorphine, morphine or dihydromorphine (DHM) are

incubated at 10-5 M concentration with brain homogenates prior to density

gradient centrifugation, the uptake is 24.8, 7.1. 6.3, 3. 7 and 2.6%, respectively. The extent of the binding and the exact localization in the gradient is

dependent on pH and divalent ions, e.g. the uptake of methadone at pH 7.2 is

decreased from 58% to 16% in 0.01 M CaCl2 and increased to 68% in 0.005 M

EDTA. At pH 6, the particulate uptake of methadone is 37% localized in one

peak at 0.8 M sucrose and at pH 7.2 is 58% with a large peak at 0.8 M and a

smaller one at 1.0 M sucrose in the NEP. Both peaks lose labeled drug when

the crude mitochondrial fraction is ruptured before centrifugation. Similarly,

DHM is lost from a single peak at 1.0 M sucrose after disruption of the NEP.

After its injection, H

3

-DHM is found in the same NEP fraction and is lost by

osmotic shock of the NEP. Neither the localization of DHM in the NEP, nor

its loss on particle rupture is reversed by the administration of antagonists or

by tolerance.

CLOUET, D.H. and WILLIAMS, N. The effect of narcotic analgesic drugs on the uptake

and release of neurotransmitters in isolated synaptosomes. The Journal of

Pharmacology and Experimental Therapeutics 188(2): 419-428 (February, 1974)

The effect of morphine and other narcotic analgesic drugs on the uptake

and release of neurotransmitters in nerve ending preparations isolated from rat

brain was studied. The uptake of carbon-14-dopamine into rat striatal synaptosomes and of carbon-14-norepinephrine into hypothalamic synaptosomes was

inhibited by morphine. Kinetic analyses of dopamine uptake in the presence of

morphine suggested that low affinity uptake was inhibited rather than high affinity

uptake. Narcotic drugs had no direct effect on catecholamine release. The

release of carbon-14-acetylcholine from carbon-14-choline precharged striatal

synaptosomes was inhibited by morphine. The intrasynaptosomal synthesis of

carbon-14-acetylcholine from carbon-14-choline was also inhibited by the same

concentration of morphine. Other opioids also inhibited the release of newly

synthesized carbon-14-acetylcholine from striatal synaptosomes. Levorphanol

inhibited carbon-14-acetylcholine release, while its less active isomer, dextrorphan, did not inhibit release, thus separating the effects of narcotic agonists

by activity. However, another pair of isomers, levo- and dextro-methadone,

were almost equally active as inhibitors of acetylcholine release from striatal

nerve ending preparations.

99
CLOUET, D.H. and WILLIAMS, N. Localization in brain particulate fractions of narcotic analgesic drugs administered intracisternally to rats. Biochemical

Pharmacology 22: 1283-1293 (1973)

Radio-labeled dihydromorphine, morphine, methadone and levorphanol

were administered to rats in pharmacologically active doses by the intracisternal route of administration, and the rats were killed 0.5 or 1 hr later. The

drugs were localized in the fraction of brain containing the pinched-off presynaptic nerve-endings, the synaptosomes. as well as in the soluble portion of

the tissue. The 14C-labeled narcotic antagonists, naloxone and nalorphine,

were also localized in the same particulate fraction of brain. The amount of

drug in the synaptosomal fraction was dependent on the dose of drug, on the

time between drug administration and sacrifice, and on the region of brain,

and was specific for each narcotic agonist and antagonist. The relevance of

this localization of narcotic analgesic drugs in the synaptosomal fractions of

rat brain to the mechanism of action of the drugs remains to be explored.

COCHIN, J., SPIVAK, C. T. and LIPPER, S. Characteristics of the inhibition of

N-demethylation of narcotic drug substrates by various antagonists.

The Pharmacologist 9: 218 (1967)

Previous studies by a number of workers [J. Pharmacol. 121, 107 (1957);

J. Med, Chem. 6, 237 (1963)] described the inhibition of morphine N-demethylation

by nalorphine as a non-competitive or mixed type. Certain aspects of the activity

of nalorphine as an in vivo antagonist led us to reexamine the nature of its in vitro

action. Using concentrations of nalorphine similar to those in previous studies

(1.0 and 2.0 x 10-4M), the inhibition of morphine N-demethylase was found to be of

a mixed type However, with lower concentrations of inhibitor, (0.33, 0. 50 and

0.67 x 10-4 M) the inhibition is competitive. The same kinetics were observed with

naloxone and levallorphan. The inhibition of demethylation of oxymorphone by all

three inhibitors was competitive even at higher concentrations (up to 2.0 x 10-4M).

With meperidine as the substrate, nalorphine proved to be a very weak inhibitor

at the low concentrations at which it was quite effective with other substrates, and

inhibited competitively at higher concentrations. The results seem to support the

hypothesis that narcotic drugs and their antagonists compete for the same enzyme

and receptor sites.

COHN, R.A., WILLIAMS, B.J., NASH, I.B. and PIRCH, J.H. Distribution of 14Cdelta-9-THC in male and female rats. The Pharmacologist 16: 260 (1974)

Previous studies, utilizing a behavior rating technique (Proc. Soc.

Exp. Biol. Med. 140: 1136, 1972). have demonstrated a sex difference in the

behavioral responses of rats to orally administered marijuana extract (ME).

Tn order to eliminate possible sex differences in absorption of ME from the

G.I. tract, ME was administered i.v. to male and female rats in a dose of

delta-9-THC of 1, 2 or 4 mg/kg. Responses of females were significantly

greater than responses of males at each dose. In further studies, tissue distribution of delta-9-THC was examined. 14C-delta-9-THC was diluted with

unlabeled ME to a final concentration of delta-9-THC of 2 mg/ml (14.4 mu-C/

mg). The radiolabeled extract was administered i.v. to 6 male and 6 female

rats in a dose of delta-9-THC of 2 mg/kg (28. 8 mu-C/kg). Forty-five min. after

drug administration, levels of radioactivity of delta-9-THC and metabolites were

significantly higher in brain, liver, muscle, and plasma of female than of male

rats. The higher concentration of delta-9-THC and/or metabolites in the brain

of females may account for their greater behavioral response to ME.

100
COLLINS, R.C., CASHAW, J.L. and DAVIS, V.E. Dopamine-derived tetrahydroisoquinoline alkaloids - - inhibitors of neuroamine metabolism. Biochemical

Pharmacology 22: 2337-2348 (1973)

The formation of salsolinol and tetrahydropapaveroline (THP) in vitro

as aberrant metabolites of dopamine has been established previously. Demonstrating the formation of these compound in vivo is complicated by the probability that they are extensively metabolized. The present studies indicate that

a primary metabolic route for these compounds may be methylation of one or

more of the free hydroxyl groups catalyzed by catechol-O-methyl transferase

(COMT). Through the use of a partially purified COMT preparation from rat

liver, the maximal velocities of salsolinol and THP O-methylation proved to be

three to five times the maximal velocities of norepinephrine and dopamine Omethylation. The Michaelis constants determined for salsolinol, norepinephrine and dopamine are similar, whereas the Km of COMT for THP (0.03 mM)

is approximately one-tenth that of the above substrates. Salsolinol and THF are

competitive inhibitors of dopamine O-methylation in vitro, their calculated

inhibitor constants (Ki values) being 0. 13 and 0.02 mM respectively. The effects of these two alkaloids on rat brain monoamine oxidase (MAO) activity were

also measured. They were found to be equally potent substrate competitive

inhibitors of rat brain MAO in vitro, with calculated Ki values of 0.14 mM

(salsolinol) and 0. 20 mM (THP). These data suggest that, if formed in vivo

under certain pharmacological conditions, aberrant neuroamine-derived alkaloids may alter the metabolic disposition of endogenous neuroamines with resultant modification of adrenergic function.

CREESE, I. and SNYDER, S.H. Receptor binding and pharmacological activity of opiates

in the guinea pig intestine. The Journal of Pharmacology and Experimental

Therapeutics (in press)

CROMBIE, L., PONSFORD, R., SHANI. A., YAGNITINSKY. B. and MECHOULAM, R.

Photochemical production of cannabicyclol from cannabichromene. Tetrahedron

Letters 55: 5771-5772 (1968)

DAVIS, J.M. , JANOWSKY, D.S. and EL-YOUSEF, M.K. The biology of lithium.

Lithium: Its Role in Psychiatric Research and Treatment. Edited by S. Gershon

and B. Shopsin. New York: Plenum Publishing Company (in press)

DAVIS. J.M., JANOWSKY. D.S., EL-YOUSEF, M.K. and SEKERKE, H.J. Psychostimulants and the cholinergic-adrenergic balance. Advances in Neuropsychopharmacology. Praha: Avicenum Press, 1973.

DAYTON, H.E. and INTURRIS; C.E. Urinary excretion of naltrexone and its metabolites

in man, rabbit, monkey and rat. Federation Proceedings 34 (1975)

For abstract, see Section I. Methodology of Drug Research.

101
DeCATO, L., JR., and ADLER, F.L. Neutralization of morphine activity by antibody.

Research Communications in Chemical Pathology and Pharmacology 5(3): 775-788

(May, 1973)

Globulins from a hyperimmune anti-bovine serum albumincarboxymethylmorphine (CMM-BSA) serum reduce the depressant action of morphine upon the

contractions of the electrically stimulated guinea pig ileum. This activity can be

shown to be a stoichiometric function of the specific anti-morphine antibody in the

globulin preparation. Preliminary data indicate that idea obtained from CMM-BSA

immunized guinea pigs are less reactive towards morphine than those obtained from

BSA immunized controls.

DeCATO, L., JR. and ADLER, F.L. Recurrence of morphine excretion after single and

multiple dose administration. Federation. Proceedings 33(3): 473 (March, 1974)

For abstract. see Section I. Methodology of Drug Research.

DENBER, H.C. Studies on mescaline: Intracellular localization. Proceedings of the

7th International Congress on Biochemistry 5: 1031 (1967)

DEWEY, W.L., HARRIS, L.S. and PATRICK, G.A. Annual report on narcotic antagonists.

Committee on Problems of Drug Dependence. Washington, D.C.: National Academy

of Sciences, National Research Council (in press)

DEWEY, W.L., JENKINS, J., O’ROURKE, T. and HARRIS, L.S. The effects of chronic

administration of trans-delta-9-tetrahydrocannabinol on behavior and the cardiovascular system of dogs. Archives internationales de Pharmacodynamie et de Therapie

198: 118-131 (1972)

This daily intravenous administration of delta-9-tetrahydrocannabinol

(delta-9-THC) produced a marked tolerance to the behavioral, effects of this compound

in six mongrel dogs. Similar results were obtained with delta-8-THC in the only dog

tested. The minimal effective acute i.v. dose of delta-9-THC to produce ataxia and

other behavioral changes is 0.5 mg/kg. In one dog, the effects of 161 mg/kg delta-9-THC

given intravenously after chronic treatment were less than those observed following 0.5

mg/kg in a drug naive dog. There were no behavioral responses which would indicate

a withdrawal syndrome following abrupt stopping of the medications. Tolerance to the

behavioral effects of delta-9-THC developed over a range of doses when the injections

were made only once every 8 days. Behavioral tolerance could still be observed 23 days

after the last injection of delta-9-THC in a tolerant dog. Initially delta-9-THC produced

bradycardia in four of seven dogs tested but this changed to tachycardia at higher doses

of delta-9-THC on approximately day 6 or 8 of treatment. There was no significant

change in blood pressure in these dogs after either acute or chronic administration.

102
DEWEY, W.L., McMILLAN, D.E., HARRIS, L.S. and TURK. R.F. Distribution of radioactivity in brain of tolerant and nontolerant pigeons treated with 3H-delta-9-tetrahydrocannabinol. Biochemical Pharmacology 22: 399-405 (1973)

Levels of radioactivity in the brain stem, cerebellum, temporal cortex and

frontal cortex of birds tolerant to delta-9-tetrahydrocannabinol (delta-9-THC) did not

differ significantly from levels in the same tissue of nontolerant birds after administration of 3H-delta-9-THC. Levels of radioactivity in the lungs of both tolerant and

nontolerant birds were similar to the levels of radioactivity in the brain areas after

3H-delta-9-THC; however, higher levels of radioactivity were found in the livers of

both groups of birds than were found in the brains. Approximately 0.1 per cent of the

total dose of radioactivity was in the brain of both tolerant and nontolerant birds 2-5

hr after injection. When pigeons were injected repeatedly (seven times in 2 weeks)

with 3H-delta-9-THC, there was some accumulation of radioactivity in brain and lung,

and an even greater accumulation in liver. These data suggest that tolerance to delta9-THC in pigeons is not due to a decreased concentration of total cannabinoids in the

brain.

DEWEY, W.L., MARTIN, B.R. and HARRIS, L.S. Chronic effects of delta-9-THC in animals:

Tolerance and biochemical changes. Presented at the First International Meeting on

Cannabis, 1974.

Tolerance has been shown to develop to almost every pharmacological effect

of delta-9-THC in laboratory animals. The magnitude of the tolerance is large, it has

a rapid onset, a long duration, and is not the result of either decreased absorption or

altered metabolism. Recent experiments have demonstrated that the distribution of

radioactivity is similar in tolerant and nontolerant dogs following an intravenous injection of 3H-delta-9-THC given 30 minutes prior to sacrifice. However, significantly, less radioactivity was found in the lymph nodes, pituitary, kidney cortex, and

liver of the tolerant dogs. In the brain, the putamen had significantly less radioactivity

following chronic medication. Also, there was significantly less radioactivity in the

gray areas of the tolerant as compared to the nontolerant animals. The gray areas of

the cortex and cerebellum had more radioactivity than the white matter in both groups.

Subcellular fractionation of the brains was performed. Considerable quantities of radioactivity were found in the nerve ending fractions of both groups. The synaptic vesicle

subfraction of the tolerant dogs contained significantly less radioactivity than the

subfraction from nontolerant animals. Solvent extraction followed by thin layer

chromatography revealed that 45% of the total radioactivity in the brain of both groups

was due to the parent compound, delta-9-THC; less than 15% was due to the 11-OH

metabolite. These results suggest that an alteration in metabolism is not responsible

for the tolerance to delta-9-THC in the dog. Experiments in other species are in

progress to elucidate the importance of the role of the reduced levels of radioactivity

in synaptic vesicles in the mechanism of tolerance.

103
DEWEY, W.L., MARTIN, B.R., HARRIS, L.S. and BECKNER, J.S. Disposition of H

3

-delta9-tetrahydrocannabinol in brain of pregnant dogs and their fetuses. The Pharmacologist

16(2): 397 (1974)

Delta-9-tetrahydrocannabinol (THC) has been shown qualitatively to cross the

placental barrier and enter fetal brain. To quantitate the amount of THC that accumulates

in the fetal brain and to determine its subcellular distribution, two pregnant dogs were

given 0.5 mg/kg of H

3

-THC and sacrificed at the time of peak behavioral effect (30

min.). The brains from the mothers and the fully-developed fetuses (n-15) were removed, homogenized in isotonic sucrose and subfractionated by centrifugation. The

concentration of THC plus metabolities (x + SE) in homogenates of mother and fetal

brains was 340 + 27 ng/g and 85 ± 4 ng/g brain, respectively. The radioactivity in

the brain of mothers was located primarily in the crude mitochondrial fraction (45%).

while the rest was distributed among the crude nuclear (24%). microsomes (11%) and

supernatant fractions (15%). The distribution of radioactivity in the fetal brains

differed markedly from that in the maternal brains. In the fetal brains, the crude

mitochondria contained only 19%, whereas the microsomes and the supernatant contained 22 and 32%. respectively. A positive correlation was found between the distribution of radioactivity and phospholipid content in fetal and maternal brains.

DEWEY, W.L. and TURK, R.F. The excretion and metabolism of 3H-delta-9-THC in

intact and bile duct cannulated rats. Federation Proceedings 31(2):506 (MarchApril, 1972)

The excretion and metabolism of 3H-delta-9-tetrahydrocannabinol (THC)

which was administered orally (p.o.) and intravenously (i.v.) in intact and bile

duct cannulated rats were investigated. Approximately 60 to 70 percent of the total

radioactivity given was excreted during 96 hours after the administration to each

group of rats. The excretion of radioactivity was minimal in each group beyond 48

hours after drug administration. The major route of excretion following the i.v.

route in bile cannulated rats was by way of bile (59 percent; feces: 3 percent),

whereas more radioactivity was excreted in feces (42 percent) than bile (21 percent)

when the drug was given p.o. The majority of the radioactivity excreted in the

feces of the orally medicated rats was extractable in petroleum ether (P.E.) and

was shown to be delta-9-THC by thin layer chromatography (TLC). The majority

of the radioactivity excreted in feces in noncannulated rats was not extractable in

P.E. or diethyl ether (D.E.), but appeared in subsequent methanol and water

extracts. It is confirmed by TLC that the radioactivity is associated with metabolites

of delta-9-THC. Less than 1 percent of the radioactivity excreted in bile was extractable in P.E., and only 8 percent was extractable in D.E.; the rest was

associated with more polar metabolites. Less than 10 percent of the radioactivity

given was excreted in the urine of each group. Less than 0.1 percent of the total

excreted in urine was extractable by P. E., and less than 5 percent by D. E.

DlNGELL, J.V., MILLER, K.W., HEATH. E.C. and KLAUSNER, H.A. The intracellular

localization of delta-9-tetrahydrocannabinol in liver and its effect on drug metabolism

in vitro. Biochemical Pharmacology 22: 949-958 (1973)

In the hepatic cell delta-9-tetrahydrocannabinol (THC) is localized in nuclei

and microsomes. The intracellular binding of THC affects hepatic drug metabolism:

nuclei markedly reduce the metabolism of THC by hepatic microsomes; THC inhibits

the microsomal oxidation of aminopyrine and hexobarbital, the conjugation of

estradiol and rho-nitrophenol and enhances the reduction of rho-nitrobenzoic acid. The

metabolism of THC, in vitro, is strikingly inhibited by SKF-525A but not by

desipramine, nortiptyline and iprindole which are potent inhibitors of the oxidation

of other drugs.

104
DOMINO, E.F. Cholinergic mechanisms in narcotic dependence and withdrawal. Journal

de Pharmacologic 5(Supplement 1): 42 (1974)

The role of the central cholinergic system in morphine dependence and withdrawal was studied in male Holtzman rats. Two different methods of producing dependence were used. The first involved bid injections of ascending does of morphine

from 10 to 200 mg/kg l.p. for 2 and 8 weeks. The second method involved morphine

base pellets 75 mg/kg s.c. for 3 days. Morphine withdrawal was precipitated either

by not giving any additional doses of morphine or by nalorphine or naloxone 10 mg/kg

i.p. Total brain acetylcholine (ACH) and its utilization using hemicholinium-3 (HC-3)

or acetylseco hemicholinium (acetylseco-HC-3) was determined using the frog roctus

bioassary or pyrolysis gas chromatography. The surprising finding was that the

pellet method of producing morphine dependence and withdrawal caused no significant

change in total brain ACH or its utilization. On the other hand, chronic morphine

injections for weeks produced a striking decrease in total brain ACH and altered

its utilization during morphine withdrawal, either 48 hr after stopping morphine or

following nalorphine or naloxone administration. It is concluded that the method and

duration of morphine dependence markedly affects the results obtained regarding

central ACH utilization.

DOMINO, E. F. Clinical pharmacology of marijuana and its derivatives. Michigan

Medical Center Journal 37: 1-6 (1967)

DOMINO, E. F. Neuropsychopharmacologic studies of marihuana: Some synthetic and

natural THC derivatives in animals and man. Annals of the New York Academy of:

Sciences 191: 165-191 (1971)

After serving a pharmacologic smorgasbord, what can one conclude about

Cannabis and its natural or synthetic THC derivatives? Perhaps what stands out

most clearly is that these agents are primary depressants of central nervous

system function. However, they possess a unique spectrum of pharmacological

actions with only superficial relation to various other psychoactive drugs. The

chemistry an? pharmacology of marijuana are distinct from other central nervous

system depressants, yet it shares some properties with ethyl alcohol, general

anesthetics like nitrous oxide, and psychotomimetics like LSD-25. The recent

report to the Congress on “Marijuana and Health” emphasizes this as well.

Dosage level is all-important! In low doses these drugs produce an intoxication

that in some ways resembles that of ethyl alcohol or low concentrations of nitrous

oxide. There are, however, definite subjective differences. In Table 4 are summarized some of the comparative aspects of delta-9-THC, ethyl alcohol, morphine

LSD-25, nitrous oxide and scopolamine and phencyclidine on various pharmacological parameters. From a scientific point of view, there is great danger in

presenting any such table because the question of dose and species is always a

critical factor. If the reader accepts such limitations, it is obvious that delta-9-

THC has its own peculiar spectrum of pharmacology. Whether it has therapeutic merit

is impossible to answer affirmatively as yet. We do have available a large variety

of sedatives, analgesics, etc. Only further research will tell whether delta-9-THC and

related compounds will remain of primary social, rather than medical, consequence.

DOMINO, E.F., HUDSON, R.D. and ZOGRAFI, G. Drugs Affecting the Central Nervous

System, Vol. 2. Edited by A. Burger. New York: Marcel Dekker, Inc., 1968.

Pp. 327-397.

105
DOMINO, E.F. and WILSON, A.E. Decreased rat brain acetylcholine utilization following

heroin and cross tolerance to l-methadone. Biochemical Pharmacology (in press)

DOMINO, E.F. and WILSON, A.E. Failure to find a decrease in brain acetylcholine in

morphine pellet implanted rats given naloxone. Psychopharmacologia (in press)

DREW, W.G, and MILLER, L.L. Cannabis: Neural mechanisms and behavior--a

theoretical review. Pharmacology 11: 12-32 (1974)

The hypothesis is advanced that marihuana and especially delta-9-

tetrahydrocannabinol, impair certain aspects of hippocampal neural functioning

which are necessary for normal cognitive operations. It is suggested that many of

the cognitive alterations induced by cannabinoids may be attributable to interference

with cholinergic mechanisms. Both pharmacological and behavioral evidence are

cited to support this hypothesis.

DUARTE-ESCALANTE, O. and ELLINWOOD, E.H., JR. Central nervous system

cytopathological changes in cats with chronic methadrine intoxication. Brain

Research 21: 151-155 (1970)

DUARTE-ESCALANTE, O. and ELLINWOOD, E., JR. Depletion of biogenic amines and

enhancement of cholinargic activity in the olfactory bulb and central olfactory

connections with chronic methedrine intoxication. Arquivos de Neuro-Psiquiatria 28(2):

110-117 (June, 1970)

Macrosmatic animals under the influence of chronic doses of amphetamine

develop stereotyped patterns of sniffing, looking, gnawing and grooming. The most

prominent stereotopy in cast is repetitive sniffing. The purpose of this report

is to present evidence of histochemical changes in the olfactory system of cats,

which had developed a marked sniffing stereotopy with prolonged methedrine

treatment.

DUARTE-ESCALANTE. O. and ELLINWOOD, E.H., JR. Effects of chronic amphetamine

intoxication on adrenegic and cholinergic structures in the central nervous system:

Histochemical observations in cats and monkeys. Current Concepts in Amphetamine

Abuse. Edited by E.H. Ellinwood, Jr. and S. Cohen. Washington, D.C.: U.S.

Government Printing Office, 1972. Pp. 97-106.

Histochemical methods were used to study material from the central nervous

systems of 25 cats and four rhesus monkeys acutely or chronically intoxicated with

methamphetamine. Material from the animals acutely intoxicated showed a decrease

of monoamine fluorescence in the nerve terminals but no changes in cholinergic

activity. The material from chronically intoxicated animals showed: 1) a complete

disappearance of monoamine fluorescence from the nerve terminals and from most

of the reticular neurons in the brainstem; 2) an increase of serotonin fluorescence

in the small neurons of the middle structures of the brain stem and olfactory bulb;

3) an increase of cholinergic activity in reticular areas of the brainstem, cerebellum,

and olfactory system; and 4) structural changes in some reticular neurons from the

medulla oblongata and the pons. From our observations, those changes appear to

be related to a direct and repetitive effect of amphetamine on the enzymatic systems

of both adrenergic and cholinergic mechanisms at the cellular level.

106
EDERY, H., GRUNFELD, Y., BEN-ZVI, Z. and MECHOULAM, R. Structural requirements

for cannabinoid activity. Annals of the New York Academy of Sciences 191:40 (1971)

EIDELBERG, E. and SCHWARTZ, A.S. Consequences of selective brain biogenic depletion

upon the effects of morphine in rats. Committee on Problems of Drug Dependence.

Washington, D.C.: National Academy of Sciences, National Research Council. 1970.

Pp. 6422-6427.

ESTEVEZ. V.S., ENGLERT, L.F. and HO, B.T. Effect of SKF-525-A on the metabolism

of (-)-delta-9-tetrahydrocannabinol in the rat brain and liver. Research Communications in Chemical Pathology and Pharmacology 8(2): 389-392 (June, 1974)

Treatment of rats with SKF-525-A prior to receiving tritium labeled (-)-

delta-9-tetrahydrocannabinol (delta-9-THC) resulted in nearly 50% decrease of

11-OH-delta-9-THC in both the brain and liver as compared with the animals without

SKF-525-A pretreatment. The microsomal oxidation inhibitor also caused a

reduction of the dihydroxylated metabolite, 8,11-(OH)2-delta-9-THC, to 14% of control

values. The large reduction of the acid metabolite in the brain (65% of control) and

the liver (16% of control) by SKF-525-A indicates the oxidative pathway producing the

acid is a microsomal process.

ESTEVEZ, V.S., ENGLERT, L.F. and HO, B.T. A new methylated metabolite of (-)-11-

hydroxy-delta-8-tetrahydrocannabinol in rats. Research Communications in Chemical

Pathology and Pharmacology 6(3): 821-827 (November, 1973)

A new metabolite of (-)-11-hydroxy-delta-8-tetrahydrocannabinol (11-HOdelta-8-THC) was identified in the rat brain and liver as 1-Q-methyl-11-HO-delta8-THC. Pretreatment of animals with SKF-525A resulted in an increased amount

of this methylated metabolite, and a concomitant decrease of two other metabolites,

the dihydroxylated delta-8-THC and an acidic compound.

FANN, W.E., DAVIS, J.M., JANOWSKY, D.S., CAVANAUGH, J.H., KAUFMANN, J.S.,

GRIFFITH, J.D. and OATES, J.A. Effects of lithium on adrenergic function in

man. Clinical Pharmacology and Therapeutics 13(1): 71-77 (1972)

Lithium is an effective agent in the treatment of mania. Since an abnormality of biogenic amines has been postulated to be a causative factor in mania

and depression and since lithium has been found to alter biogenic amines in many

animal systems, the effects of lithium on adrenergic function in man was investigated. The blood pressure response to infused norepinephrine (NE) and tyramine

was investigated in 8 hypomanic patients who were studied during a control period

and after 7 to 10 days of lithium treatment. Lithium decreased the pressor effect

produced by NE by 22 + 0.6 per cent. Lithium failed to alter the pressor effect to

infused tyramine. Lithium failed to alter platelet serotonin content. Lithium decreased the pressor response to infused NE in man.

107
FARROW, J.T. and VANVUNAKIS. H. D-lysergic acid: Binding to subcellular fractions from

rat brain. Nature 237: 164 (1972)

FENIMORE, D.C., FREEMAN. R.R. and LOY, P.R. Determination of delta-9-tetrahydrocannabinol in blood by electron capture gas chromatography. Analytical Chemistry

45(14): 2331-2335 (December, 1973)

For abstract, see Section I. Methodology of Drug Research.

FETTERMAN, P.S., KEITH, E.S., WALLER, C.W., GUERRERO, O., DOORENBOS. N.J.

and QUIMBY, M. W. Mississippi-grown Cannabis sativa L: Preliminary observation

on chemical definition of phenotype and variations in tetrahydrocannabinol content

versus age, sex and plant part. Journal of Pharmaceutical Sciences 60(8): 1246-1249

(August, 1971)

Nine strains of Cannabis sativa L. (marijuana) were grown for research by

the University of Mississippi. The seeds for these strains were obtained from Iowa,

Minnesota, Mexico, Turkey, Italy, France. and Sweden. The cannabinoid content

was determined using GLC, and the material was divided into two chemical phenotypes according to cannabinoid content. These phenotype categories are used to

differentiate between drug-type and fiber-type Cannabis sativa. In addition, the (-)-

delta-9-trans-tetrahydrocannabinol content was determined for both male and female

plants, various plant parts, and a Turkish variety during various stages in its growth.

FETTERMAN, P.S. and TURNER, C.E. Constituents of Cannabis sativa L. I: Propyl

homologs of cannabinoids from an Indian variant. Journal of Pharmaceutical

Sciences 61(9): 1476-1477 (September, 1972)

Cannabidivarin and tetrahydrocannabivarin are shown to be present in an

Indian variant of Cannabis sativa L. (marijuana) in Mississippi. GC and mass

spectrometry were used for identification. Indications are that these compounds are

present as acids in fresh material.

FINK, M. Brain, behavior and anticholinergic drugs. Anticholinergic Drugs, and Brain

Functions in Animals and Man. Edited by P. Bradley and M. Fink. Amsterdam,

the Netherlands: Elsevier, 1967. Pp. xii-xvi.

FINK, M. Drugs, EEG and behavior. Chapter X of Drugs and the Brain. Edited by P.

Black. Baltimore, Maryland: Johns Hopkins Press, 1969. Pp. 149-160.

FINK, M. and ITIL, T. EEG and behavioral aspects of the interaction of anticholinergic

hallucinogens with centrally active compounds. Anticholinergic Drugs and Brain

Functions in Animals and Man. Edited by P. Bradley and M. Fink. Amsterdam,

the Netherlands: Elsevier, 1967. Pp. 149-168.

108
FINK, M., SIMEON, J. and SPERO, M. Clinical and EEG studies of doxepin: An interim

report. Psychosomatics 10: 14-17 (1969)

FISHMAN, J., COTTER. M.L. and NORTON, B.I. Narcotic antagonists. 2. Preparation

and biological stability of naxolone-7, 8-3H. Journal of Medicinal Chemistry 16:

556-557 (1973)

FISHMAN, J., NORTON, B., COTTER, M.L. and HAHN, E.F. Preparation of morphine6-3H and its isotopic stability in man and in rat. Journal of Medicinal Chemistry

17(7): 778-781 (1974)

FISHMAN, J., NORTON, B. and HAHN, E. Differential distribution of opiate agonists and

antagonists in the rat brain as determined by double isotope techniques. Presented

at the meeting of the American Society of Biological Chemists, 1974.

For abstract, see Section I. Methodology of Drug Research.

FISHMAN, J., ROFFWARG, H. and HELLMAN, L. Disposition of naloxone-7, 8-3H in

normal and narcotic-dependent men. The Journal of Pharmacology and Experimental Therapeutics 187(3): 575-580 (1973)

For abstract, see Section I. Methodology of Drug Research.

FOLTZ, R.L., FENTIMAN, A.F, JR., LEIGHTY. E.G., WALTER, J.L., DREWES, H.R.,

SCHWARTZ, W.E., PAGE, T.F., JR. and TRUITT. E.G., JR. Metabolite of

(-)-trans-delta-8-tetrahydrocannabinol: Identification and synthesis. Science 168:

844-845 (May, 1970)

The major metabolite of (-)-trans-delta-8-tetrahydrocannabinol observed

in vivo and formed by hepatic microsomes in vitro is 11-hydroxy-trans-delta-8-tetrahydrocannabinol. The metabolite was identified spectroscopically and was synthesized from trans-delta-8-tetrahydrocannabinol. In tests with rats, the metabolite

produced behavioral effects similar to those imparted by delta-8- and delta-9-tetrahydrocannabinol.

FOOTE, R.S. and JONES, L.A. An analysis of the phytosterols of two varieties of

Cannabis. Agricultural and Food Chemistry 22(3): 534-535 (May-June, 1974)

The quantitative determination of the 3-beta-hydroxysterols in Americangrown (MS-13) and Thailand-grown Cannabis has been accomplished. The Thailand

sample showed no free sterols although it contained the highest total sterol content.

No campesterol was found as the glycoside in the MS-13 and Thailand sample while

the Thailand sample contained no stigmasterol as the glycoside.

109
FORBES, J.E., DEWEY, W.L. and HARRIS, L.S. The effect of narcotics and narcotic

antagonists on ganglionic transmission in rat. Federation Proceedings (in press)

Postganglionic potentials were evoked in the superior cervical ganglia

by supramaximal biphasic stimuli applied to the sympathetic trunk at a frequency

of 1/sec. The evoked postganglionic potentials were recorded from the external

carotid nerve and displayed on a Tektronix oscilloscope after being amplified by a

Grass P5-11 preamplifier. Permanent records were made by photographing the

evoked potentials with a Grass Kymograph camera. The drugs were administered

through a 27 gauge needle inserted into the common carotid artery. Of the pure

narcotics studied, morphine (2. 5 mg/kg), meperidine (1 mg/kg), and methadone

(1 mg/kg), produced inhibition of the evoked postganglionic potentials, Levorphanol

(2.5 mg/kg) had no effect. Pentazocine (1.5 mg/kg) produced inhibition of the

evoked postganglionic potentials while cyclazocine (0.5 mg/kg) and nalorphine

(2.5 mg/kg) were inactive. Naltrexone (1.25 mg/kg) was found to produce inhibition

of the evoked postganglionic potentials while naloxone (2.5 mg/kg) had no effect.

The evoked postganglionic potential induced by the narcotics inhibitions were not

antagonized by naloxone. Because of the lack of tolerance development to the inhibition or antagonism by naloxone, it was concluded that the inhibition of the

evoked postganglionic potentials was non-specific.

FORREST, F.M., FORREST, I.S. and SERRA, M.T. Modification of chlorpromazine

metabolism by some other drugs frequently administered to psychiatric patients.

Biological Psychiatry 2: 53-58 (1970

Phenobarbital Sodium and Aludrox, as representative of sedatives or

antacids frequently prescribed for patients on chronic phenothiazine therapy, were

studied with regard to their effect on urinary chlorpromazine excretion. Phenobarbital as an inducer of additional drug metabolizing enzymes in hepatic microsomes,

was found to increase the rate of urinary chlorpromazine excretion by 10-81%.

Conversely, epileptic patients normally receiving maintenance barbiturates in

addition to chlorpromazine, showed 17-55% decreases in urinary chlorpromazine

excretion when their barbiturates were withdrawn for 7 days. Hence, phenobarbital

sodium may be of interest in cases of acute chlorpromazine toxicity. Aludrox,

acting as a physical absorbent of simultaneously administered chlorpromazine, decreased the urinary chlor excretion rate by 10-45% thus lowering chlor. efficiency.

However, these decreases could be reduced when the two medications were spaced

at 2 hr. intervals.

FORREST, I.S., BOLT, A.G. and ABER, R.C. Metabolic pathways for the detoxication

of chlorpromazine in various mammalian species. Agressologie 9(2): 259-265

(1968)

FORREST, I.S. and BROOKES, L.G. In vivo and in vitro 3H-chlorpromazine in various

mammalian species. Proceedings of the 7th Congress of Collegium Internationale

Neuro-Psychopharmacologicum, Prague, Czechoslovakia, August, 1970.

110
FORREST, I.S., BROOKES, L.G., DENEAU, G.A. and MELLET, L.B. In vivo and in vitro

metabolism of 3H-chlorpromazine in the rhesus monkey. The Pharmacologist 12:

273 (1970)

Urinary and fecal excretion of chlorpromazine and its metabolites was

studied in 8 adult rhesus monkeys chronically dosed with 30 mg/kg per day for

several years. Approximately 20% of the administered dose was found to be excreted

via the urine, while fecal excretion accounted for less than 5%. The urinary metabolites present were similar to those seen in man, but an unknown conjugate, probably

derived from 8-hydroxy-chlorpromazine constituted nearly 10% of the urinary and fecal

drug fractions. Some of the animals also received tracer doses of chlorpromazine,

tritium labeled at position 9 of the nucleus. These served in the estimation of the

biological half-life of chlorpromazine and in the quantification of drug metabolites

isolated by thin layer chromatography. In vitro metabolism of 3-H-chlorpromazine

was also determined using hepatic inicrosomes of untreated rhesus and squirrel

monkeys. Both species of primates showed similarities to man, but differences

between them were significant.

FORREST, I.S., FOX, J., GREEN, D.E., MELIKIAN, A.P. and SERRA, M.T. Total

excretion of 3H-chlorpromazine and 3H-prochloperazine in chronically dosed

animals: Balance sheet. The Phenothiazines and Structurally Related Drugs.

Edited by I.S. Forrest, C.J. Carr and E. Usdin. New York: Raven Press, 1974.

Phenothiazine drugs are administered to large numbers of patients,

frequently for indefinite periods of time and in high daily doses. It therefore seems

important to study their biotransformation, distribution, and excretion in man and

appropriate animal models as parameters which eventually will help elucidate their

mode of action. After 20 years of intensive study of the phenothiazines. even as

simple an aspect as a balance sheet--input versus output under chronic or acute

conditions of drug administration--is a controversial subject. Using three species

of mammals and two phenothiazine drugs tritiated at the metabolically insensitive

position 9 of the nucleus, it was found that under chronic drug dosage, recovery of

the label was essentially complete within 10 to 20 days. Lesser recoveries prevailed under acute conditions. Correlated chemical assays (spectrophotometric or

chromatographic) proved less satisfactory and from 10 to 30% of the daily dose

excreted in urine and feces according to radioquantitation remained unaccounted for.

This discrepancy is tentatively attributed to inadequate methodology for determination of all known and unknown metabolites of the phenothiazine drugs.

FORREST, I.S. and GREEN, D.E. Phenothiazines: Metabolism and analytical detection.

Journal of Forensic Sciences 17: 592-617 (1972)

111
FORREST, I.S., GREEN, D.E., OTIS, L.S. and WÜRSCH. M.S. Excretion of 3H-delta9-tetrahydrocannabinol (THC) in rhesus and squirrel monkeys. Federation

Proceedings 31: 506 (1972)

3H-delta-9-THC was orally administered to Rhesus and Squirrel monkeys

who had previously received 1 mg/kg unlabeled delta-9-THC for 4 days. Urinary

and fecal excretion of the label was followed for 2 weeks and sporadically thereafter. In Rhesus, 22% to 26% of the label was excreted in the urine within 14 days,

while corresponding fecal excretion amounted to 40% to 52%. Fecal excretion of

minor quantities continued for several weeks thereafter, and Rhesus appeared a

suitable model animal for comparison with man. Delta-9-THC metabolism in

Squirrel monkey, however, did not appear comparable to that of man. Within 14

days only 1% to 5% of the label was eliminated with the urine, while between 53% and

60% appeared in the first day’s feces of the animals, indicating very poor absorption

of delta-9-THC. From 88% to 91% of the label was found in the urines and feces of

this species within 2 weeks, while only subsequently detected in the fur of both

species, reaching peak excretion by this route approximately 3 months after ingestion of 3H-delta-9-THC.

FORREST, I.S., GREEN, D.E., ROSE, S.D., SKINNER, G.C. and TORRES, D.M.

Fluorescent-labeled cannabinoids. Research Communications in Chemical

Pathology and Pharmacology 2(6): 787-792 (November, 1971)

Nine different cannabinoids were converted to their 1-dimetliylaminonaphthalene-5-sulfonates. Mixtures of the fluorescent-labeled cannabinoids were

separated by thin layer chromatography. and individual spots were detectable at

the 0.5 nanogram level. This sensitivity appears adequate to develop an assay for

biotransformation products of cannabinoids in human urine after the smoking of a

single cigarette.

FORREST, I.S., GREEN, D.E. and SERRA, M.T. An attempt to bridge some gaps in the

knowledge of chlorpromazine metabolism and excretion. Proceedings of the Western

Pharmacological Society (in press)

FORREST, I.S., GREEN, D.E. and SERRA, M.T. The use of XAD-2 nonionic polymeric

adsorbent in the analysis of chlorpromazine and its metabolites. Psychopharmacology Bulletin 9(2): 20-21 (1973)

FORREST, I.S., GREEN, D.E. and WÜRSCH, M.S. 3H-delta-9-tetrahydrocannabinol (THC)

metabolites in rhesus monkey urine: Efficient new extraction procedures and

implications for metabolite structures. Abstracts of Volunteer Papers. Fifth

International Congress on Pharmacology. San Francisco, California, July, 1972.

Pp. 71.

112
FORREST, I.S., KOSEK, J.C., ABER, R.C. and SERRA. M.T. Rabbit as a model for

chlorpromazine-induced hyperpigmentation of the skin. Biochemical Pharmacology

19:849-852 (1970)

Hyperpigmentation of exposed skin areas, comparable to that seen in less

than 1 per cent of patients chronically dosed with chlorpromazine after intensive

long-term therapy, has been produced in sixteen out of sixteen chronically dosed

pigmented rabbits, receiving between 20-30 mg/kg per day. Thirty-min u.v.

irradiation of a clipped or shaved area produced clear-cut hyperpigmentation of

naturally pigmented skin areas in about 4 weeks. The characteristic occurrence

of granular pigment in the dermis which is normally free of pigment was also

observed. Hyperpigmented rabbits did not develop any concomitant ocular

pathology, as seen in some patients on long-term, high-dosage chlorpromazine

therapy.

FORRES, I.S., OTIS, L.S., ERRA, M.T. and SKINNER, G.L. Passages of

3H-chlorpromazine and 3H-delta-THC into the hair (fur) of various mammals.

Proceedings of the Western Pharmacological Society 15: 83 (1972)

A number of tests were carried out in different species of mammals

receiving tracer doses of chlorpromazine, tritiated at the metabolically insensitive

position 9 of the nucleus. Additional studies were carried out with delta-9-THC

tritiated at positions 2,4,8 and 9 of the nucleus. In this instance we have no

knowledge of the stability of the label nor of the various metabolites excreted with

the urine and feces of primates.

FORREST, I.S., WECHSLER. M.B., BOLT, A.G. and ABER, R.C. Studies on

chlorpromazine metabolites in mammalian tissues. Federation Proceedings

26(2): 353 (1967)

Available procedures have provided partial information on types and

amounts of chlorpromazine metabolites selectively stored in body tissues. The

present method permits estimation of the three groups of drug metabolites, i.e, 1)

the largest group, unhydroxylated basic metabolites; 2) the slightly smaller group,

hydroxylated metabolites of group 1); 3) the glucurosides of group 2). Groups 1)

and 2) were selectively extracted from tissue specimens, and assayed spectroscopically after conversion to their respective radical ions. Group 3) was measured as

group 2) after enzymatic hydrolysis. TLC revealed the following metabolites:

Chemically unchanged chlorpromazine, its nor1-derivative and traces of chlorpromazine sulfoxide; 7-hydroxychlorpromazine, its nor1

-and nor2-derivatives and traces

of their respective glucuronides. Concentrations of these groups of metabolites in

autopsied human tissues are discussed with respect to dosage in patients. with and

without manifestations of late side-effects of drug therapy. It was concluded that the

presence of unconjugated 7-hydroxychlorpromazine in the tissues of man and

experimental animals is a concomitant of normal drug metabolism, and not a toxic

manifestation per se.

FRIEDNOFF, A.J. Biosynthesis of DMPEA and its metabolites in mammalian tissues.

Biological Psychiatry 6(2): 412 (1973)

113
FRIEDHOFF, A.J. and SCHWEITZER, J. W. Amphetamine metabolism in amphetamine

psychosis. Advances in Neuropsychopharmacolopy. Edited by O. Vinar,

Z. Votava and P.B. Bradley. Amsterdam, the Netherlands: North Holland

Publishing Company, 1972. Pp. 267-277.

Although incomplete evidence is available, the kinds of symptons

appearing during amphetamine psychosis vary with the body burden of amphetamine, ranging from symptoms of increased arousal at the lowest level to those

of toxic delirium at the highest. The pharmacological action of amphetamine

appears to be mediated at least in part, through an interaction with catecholamines. A more profound effect on catecholamines, particularly dopamine, may

be involved in the pathogenesis of amphetamine psychosis. Alternatively, a

psychotomimetic metabolite of amphetamine may be produced, although this is

not supported by the studies undertaken.

FRIEDHOFF, A.J., SCHWEITZER, J.W. and MILLER, J. Biosynthesis of mescaline

and N-acetylmescaline by mammalian liver. Nature 237: 454-455 (June, 1972)

FRIEDHOFF, A.J., SCHWEITZER, J.W. and MILLER, J. The enzymatic formation of

3, 4-di-o-methylated dopamine metabolites by mammalian tissues. Research

Communications in Chemical Pathology and Pharmacology 3(2): 293-311

(March. 1972)

In a series of experiments it was demonstrated that a dopamine

metabolite, N-acetyl-3-hydroxy-4-methoxyphenethylamine (i-NAMT), can be

transformed enzymatically to N-acetyl-3,4-dimethoxyphenethylamine (NADMPEA)

by mammalian tissues. It can be concluded, therefore, that a 3,4-dimethoxy

derivative of a catechol structure is a possible product of catecholamine metabolism.

FRIEDHOFF, A.J., SCHWEITZER, J.W. and MILLER, J. The formation of a dimethoxy

derivative of dopamine in mammalian brain and liver, Proceedings of Symposium

on Mechanisms of Regulation of Biogenic Amines, Lodz, Poland, 1972.

GALLAGER. D.W., SANDERS-BUSH, E. and SULSER, F. Dissociation between behavioral

effects and changes in metabolism of cerebral serotonin following delta-9-tetrahydrocannabinol. Psychopharmacologia 26: 337-345 (1972)

Behavioral changes, reaction times in analgesic tests and effects on abolism

of cerebral serotonin (5 HT) were monitored in male Sprague-Dawley following the

administration of delta-9-tetrahydrocannabinol (THC) as a propylene of serum complex.

THC (5.5 mg/kg i.p. and 1.0 mg/kg i.v.) produced charactic and reproducible

behavioral effects, including catalepsy and squealing, as well as significant increases

in the reaction time as determined in both the hot plate and tail flick tests for analgesis.

Intraventricular injection of THC caused many of the changes seen after systemic

administration of the drug. The levels of 5 ITT and the principle metabolite, 5-hydroxyindoleacetic acid (5HIAA) were measured in the brain and brainstem following THC. No

significant change in the level of either was observed. Moreover, THC did not alter

the turnover of cerebral 5 HT as determined by the probenecid method and did not change

the increase in 5 HT following the administration of pargyline.

114
GAONI, Y. and MECHOULAM, R. Hashish XIV. The iso-tetrahydrocannabinols.

Israeli Journal of Chemistry 6:679 (1968)

Synthetic routes we described which lead to ISO-THC’s, a new series of

structural isomers of the natural delta-THC. In this group of compounds a

dihyrobenzopyran ring system is formed by cyclizatron of one of the phenolic groups

of a cannabinoid with the C1 carbon in the terpene moiety of the molecule.

GAONI, Y. and MECHOULAM, R. The isolation and structure of delta-1-tetrahydrocannabinol

and other neutral cannabinoids from hashish. Journal of the American Chemical

Society 93: 217-223 (1971)

The isolation and elucidation of the structures of delta-1-tetrahydrocannabinol

(delta-1-THC), cannabigerol. cannabichromene, and cannabicyclol are described. A

facile conversion of cannabidiol into delta-1-THC takes place on treatment with boron

trifluoride etherate. The absolute configuration of the chiral centers at C-3 and C-4

of delta-1-THC is established as R.

GARRETT, E.R., BRES, J., SCHNELLE, K. and ROLF, L.L., JR. Pharmacokinetics of

saturably metabolized amobarbital. Journal of Pharmacokinetics and Biopharmaceutics

2(1): 43-103 (1974)

For abstract, see Section I. Methodology of Drug Research.

GARRETT, E.R. and HUNT, C.A. Physicochemical properties, solubility and protein binding

of delta-9-tetrahydrocannabinol. Journal of Pharmaceutical Sciences 63(7): 1056-1064

(July, 1974)

For abstract, see Section I. Methodology of Drug Research.

GARRETT, E.R. and HUNT, C.A. Picogram analysis of tetrahydrocannabinol and application

to biological fluids. Journal of Pharmaceutical Sciences 62(7): 1211-1214 (July, 1973)

GARRETT, E.R. and TSAU, J. Stability of tetrahydrocannabinols I. Journal of Pharmaceutical

Sciences 63(10): 1563-1574 (October, 1974)

For abstract, see Section I. Methodology of Drug Research.

GAZTANGA, P., ABRAMS. R., SIMEON, J., JONES, T. and FINK, M. Clinical evaluation

of GP-41299: An antianxiety agent of the doxepin type. Arzneimittel-Forschung 22:

1903-1905 (1972)

115
GERBER, N., SMITH, R., OLSEN, G.D., LEGER, R.M. and LYNN, R.K. Investigation of

methadone (M) metabolism by gas chromatography (GC) and mass spectrometry (MS).

Proceedings of the Sixth International Congress of Pharmacology, Helsinki, Finland,

July 20-25, 1975.

A specific gas chromatographic assay has been developed for the quantification

of M and its primary metabolite. 2-ethylidene-1, 5-dimethyl-3.3-diphenylpyrrolidine (P).

This involves extraction of M and P from samples (plasma. blood. urine, homogenates)

at pH 9.8. reextraction of an aliquot of solvent with 0.1 N HCL, alkinization of the

latter with NH40H and final extraction into chloroform. The partition coefficient of M

between 1-chlorobutane and pH 9.8 buffer is greater than 70. When Swiss-Webster mice

weighing between 25-35 gm were given 530 mg of racemic M ip, approximately 50% of

the drug was metabolized in about 30 min. Pre-treatment of mice with sodium

phenobarbital (100 mg/kg ip daily for 4 days) caused a twofold increase in the rate of

metabolism of M. Moreover, mice given one or the other isomer of M eliminated the

d-isomer more rapidly than the l-, and a much larger fraction of the d-isomer was

found unchanged in the urine at 200 min. In the isolated perfused rat liver there was an

initial rapid decline of M in the perfusate followed by a slower decline (

t

1/2=114 min)

after 30 min. When either isomer of M or the racemic mixture was used the concentration of P increased in the mouse and in the perfusate of the isolated liver. GC-MS

of methylated (CH31, DMSO1) glucuronic acid conjugates from bile gave molecular

ions at m/e 525, 555, 511, 541, indicating the presence of mono- and di-hydroxylated

glucuronides of P and the pyrroline metabolite.

GESSNER, P.K. Pharmacological studies of 5-methoxy-n, n-dimethyltryptamine, LSD

and other hallucinogens. Psychotomimetics. Edited by D. H. Efron. New York:

Raven Press, 1969. Pp. 105-118.

GESSNER, P. K. and GESSNER, T. Inhibition of ethanol acetaldyhyde disappearance in vivo by

diethyldithiocarbamic acid methylester, a metabolite of disulfiriram. Presented

at the Fifth International Congress on Pharmacology, Volunteer Abstracts

81 (1972)

GOLDSTEIN, A. Accurate measurement of urinary morphine. New England Journal of

Medicine 286: 1417 (1972)

GOLDSTEIN, A. Biochemistry and pharmacology of the addictive process. Abstracts

of the 119th Annual Meeting of the American Pharmaceutical Association,

Vol. 2. Washington, D.C.: The American Pharmaceutical Association, 1972.

P. 31.

GOLDSTEIN, A. and GOLDSTEIN, D.R. Enzyme expansion theory of drug tolerance and

physical dependence. Chapter XIX of The Addictive States Association for Research

in Nervous and Mental Disease, Vol. XLVI. Baltimore, Maryland: The Williams

and Wilkins Company, 1968. Pp. 265-267.

116
GOLDSTEIN, A. and JUDSON, B.A. Alcohol dependence and opiate dependence: Lack of

relationship in mice. Science 172: 290-292 (April 1, 1971)

According to a recently proposed hypothesis, physical dependence upon

alcohol is due to the formation of an endogenous opiate. We tested the hypothesis by

determining whether or not ethanol-dependent mice would show typical opiatedependent behavior (withdrawal jumping syndrome) when challenged with the opiate

antagonist naloxone. Our results do not support the hypothesis.

GORODETZKY, C.W. Abuse liability of etdrphine (M99). II. Detectability in the urine by

common screening methods after subcutaneous administration in man. Federation

Proceedings 33(3): 487 (March, 1974)

A single dose of 100 mu-g of M99 was administered subcutaneously to 7.

subjects and all urine samples were collected for 1 day prior to and 3 days following

drug administration. Each sample was analyzed for the presence of opiates by the

AbuscreenR radioimmunoassay (RLA) and the EMITR homogenous enzyme immunoassay, with cutoffs for “positives” of 40 and 500 ng/ml urinary morphine standards

respectively. Samples were analyzed for M99 by TLC with iodoplatinate after XAD-2

resin extraction (sensitivity = 0.2 mu-g M99/ml of urine). Under blind conditions

all samples were analyzed unhydrolysed and the last pre-drug and first 2 post-drug

samples after both acid and glucuronidase hydrolysis. No samples gave a “positive”

opiate result in either immunoassay and no M99 was detected in the TLC analyses

in any urine sample. It is estimated that if as little as 14% of the administered dose

had been excreted as free M99 in the first 2 hours or as little as 20% in the first 3 to

5 hours, M99 would have been detected in the TLC analyses. M99 is probably

extensively metabolized and/or excreted by routes other than the urine. It is

concluded that a highly euphorogenic dose of M99 is unlikely to be detected in urine

samples subjected to the routine screening procedures of RIA, EMIT and TLC

preceded by XAD-2 resin extraction. Thus, it is unlikely that the abuse of M99

could be diagnosed by commonly used urine screening methods.

GORODETZKY, C.W. Efficiency and sensitivity of two common screening methods of detecting

morphine in urine. Clinical Chemistry 19(7): 753-755 (1973)

For abstract, see Section I. Methodology of Drug Research.

GORODETZKY, C.W. Time course of morphine (M) detection in human urine after IV

morphine. Federation Proceedings 32(3): 764 (March, 1973)

Two single doses of M, 6 and 12 mg/70 kg were administered IV at weekly

intervals in random order to 10 subjects and all urine was collected for 1 week and

pooled into 4 to 8-hr. samples. Each sample was analyzed under blind conditions

by the following methods: 1. extraction unhydrolysed by organic solvent (OS) and

ion exchange resin impregnated paper (IE) and after acid hydrolysis (OSH, IEH) with

detection by TLC after spraying with iodoplatinate; 2 FRAT; 3 Technicon Autoanalyzer

(TECH): 4 radioimmunoassay (RIA). False positives on pre-drug control urines were

0% for OS, IE, IEH and RIA, 1.3% for OSH, 9% for FRAT, and 3% for TECH. Results

are shown below for % of urines positive for M for 96 hrs. after drug.

GORODETZKY, C.W., ANGEL, C.R., BEACH, D.J., CATLIN, D.H. and YEH, S.Y.

Validity of screening methods for drugs of abuse in biological fluids. I. Heroin.

Clinical Pharmacology and Therapeutics 15(5): 461-471 (May, 1974)

For abstract. see Section I. Methodology of Drug Research.

117
GORODETZKY, C.W. and KULLBERG. M.P. Time course of morphine (M) detection

in human urine after i.v. heroin (H) by XAD-2 resin and TLC. The Pharmacologist

16(2): 193 (Fall, 1974)

Three single doses of H, 2.5, 5 and 10 mg/kg, were administered IV at

weekly intervals in random order to 8 subjects and all urine was collected for 1 week

and pooled into 4 to 8 hr. samples. Each sample was analyzed under blind conditions by TLC with iodoplatinate preceded by XAD-2 resin extraction unhydrolyzed

(X) and after acid hydrolysis of urine (XH) or urine-loaded resin (XRH) (Clin Chem.

20:177, 1974). Adding M to normal urine, the concentration detectable 99% of the

time (95% C.L.) by X was 80(65-100) ng/ml. False positives on pre-drug control

urines were 0% for X and XH and 1% for XRH.

GORODETZKY, C.W. and KULLBERG, M.P. Validity of screening methods for drugs of

abuse in biological fluids. II. Heroin in plasma and saliva. Clinical Pharmacology

and Therapeutics 15(6): 579-587 (June, 1974)

For abstract, see Section I. Methodology of Drug Research.

GROCE, J.W. and JONES, L.A. Carbohydrate and cyclitol content of cannabis.

Agricultural and Food Chemistry 21(2): 211-214 (March-April, 1973)

The carbohydrate and cyclitol content of Cannabis sativa grown in the

United States (MS-23), Thailand, and Viet Nam was determined via silylation and

gas chromatographic techniques, and the methods of isolation are described.

MS-13 contained the carbohydrates ribitol, fructose, alpha- and beta-D-glucose,

and sucrose and the cyclitols (+)- quebrachitol, D(-)-bornesitol, and myo-inositol.

Only the Thailand sample contained (+)-inositol, whereas only the Viet Nam sample

contained erythritol. The carbohydrate-cyclitol content was MS-13 greater than

Thailand greater than Viet Nam.

GROSS, S.J., SOARES, JR., WONG, S.L.R. and SCHUSTER, R.E. Marihuana

metabolites measured by a radioimmune technique. Nature (in press)

HAHN, D.L. and GOLDSTEIN, A. Amounts and turnover rates of brain proteins in

morphine-tolerant mice. Journal of Neurochemistry 18: 1887-1893 (1971)

Mice were injected intracerebrally with radioactive leucine 30 min before

decapitation. A double-label technique was used; e.g. (

3H) leucine in control,

untreated mice and (

14C) leucine in morphine-tolerant (dependent) mice. Proteins

were extracted sequentially from mouse brain with aqueous buffer, Triton X-100,

and sodium lauryl sulphate. Each extract was subjected to electrophoresis on

discontinuous, porosity-gradient acrylamide gels. When the protein patterns from

untreated, acutely morphinized mice were compared with those from morphinetolerant (dependent) mice, we observed no differences in the amounts of protein

or of radioactivity in any of the 55 discrete bands.

118
HARIK, S.I., MOLLENBERG, M.D. and SNYDER, S.H. Ornthine decarboxylase turnover

slowed by alpha-hydrazinoornithine. Molecular Pharmacology 10:41-47 (1974)

Alpha-hydrazino-ornithine is a potent and selective inhibitor of ornithine

decarboxylase (L-ornithine carbosy-lyase, EC 4.1.1.17). When added to rat

hepatoma cells at the time of dilution, alpha -hydrazino-ornithine elicits a doserelated increase in ornithine, decarboxylase activity and a concomitant prolongation

of the apparent half-life of the enzyme from 10 min to 28 min. as determined by

the rate of decline of ornithine decarboxylase activity after inhibition of protein

synthesis by cycloheximide. Similarly, systemic administration of alphahydrazino-ornithine to nephrectomized rats induces a dose-related enhancement

of ornithine decarboxylase activity in the normal and regenerating liver, which is

associated with prolongation of the apparent half-life of the enzyme. In both intact

liver and hepatoma cells in culture, the decrease in the turnover rate of the

enzyme can account for its increased activity.

HARIK, S.I., PASTERNAK. C.W. and SNYDER, S.H. An enzymatic-isotopic microassay for

putrescine. Biochimica et Biophysica Acta, 304: 753-764 (1973)

A highly sensitive enzymatic isotopic microassay procedure for the measurement of putrescine (1,4-diaminobutane) is described. The method depends on the

enhancement by putrescine of the decarboxylation of S-adenosyl-L-(carboxy-14C)

methionine by baker’s yeast (Saccharomyces cerevisiae) S-adenosyl-L-methionine

decarboxylase in the presence of varying amounts of putrescine. The quantity of

14CO2

 evolved is a linear function of the amount of putrescine present. This

method was used to measure the putrescine content of various tissues.

HARIK, S.I., PASTERNAK, G.W. and SNYDER, S.H. Putrescine: A sensitive assay

and blockade of its synthesis by alpha-hydrazine ornithine. Polymines in Normal

and Neoplastic Growth. Edited by D.H. Russell. New York: Raven Press, 1973.

Pp. 307-321.

A highly sensitive and specific enzymatic-isotopic microassay procedure

for the measurement of putrescine is described. The method depends on the

enhancement by putrescine of the decarboxylation of 14C-SAMe by baker’s yeast

SAMeDC. The quantity of 14CO2 evolved is a linear function of the amount of

putrescine present in the incubation mixture. The method can reliably measure

20 pmoles of putrescine, only small amounts of tissue (0.5 to 4mg) are required

for the assay, and the technique is simple to perform so that 100 samples can be

assayed in one working day.

This method was used to measure the putrescine content of various tissues.

Data collected by this methodwere much lower than those obtained by other workers

for the rat and mouse brain and liver, but our values were corroborated by an amino

acid analyzer technique. Putrescine tissue levels correlated well with ODC activity

and may serve as an indicator of the activity of this enzyme in tissues where ODC

activity cannot be detected readily.

Alpha-HO was found to be a potent and specific in vitro inhibitor of E. coli,

and rat prostate ODCs. However, when given to rats it greatly enhanced the activity of

hepatic and prostatic ODC.

HARRISON, S.D., JR., CHIU, P. and MAICKEL, R.P. Polyamide thin-layer

chromatographic separation of DOPA metabolites and related compounds. Journal of

Chromatography 85: 151-153 (1973)

For abstract, see Section I. Methodology of Drug Research.

119
HENDLEY, E.D. and SNYDER, S.H. Stereoselectivity of catecholamine uptake in noradrenergic

and dopaminergic peripheral organs. European Journal of Pharmacology 19: 56-66

(1972)

The stereoselectivity of noradrenaline uptake was studied in several

adrenergically innervated peripheral organs of the rabbit and rat, as well as in the

isolated rabbit retina. (-)- and (+)-noradrenaline bitartrate, and (-)-and (+)-amphetamine

sulfate, were compared as relative antagonists of the neuronal membrane catecholamine

uptake mechanism in the various organs, in order to determine stereoselectivity at both

the alpha and beta carbons of noradrenaline. It was not possible to demonstrate

stereoselectivity unless optimal conditions prevailed. These included the use of finely

divided tissues (less than 0.5 mm on a side), of linear uptake rates, and of nonsaturating levels of amines.

In the rabbit vas deferens and iris/ciliary, where noradrenaline is the

predominant catecholamine and is present in high endogenous concentrations, there

was a marked preference for (-)-noradrenaline and for (+)-amphetamine, in contrast

with the rabbit retina where dopamine is the chief catecholamine and in which no

stereoselectivity was demonstrable. These results confirmed earlier findings in the

rat brain in which catecholamine uptake was stereoselective in noradrenergic brain

regions but not in the corpus straitum, a dopaminergic region (Coyle and Snyder,

1969).

Cardiovascular tissues of the rabbit exhibited a reversal of the usual

stercoselectivity, i.e. (+)-noradrenaline had more affinity than ( )-noradrenaline in

the rabbit atrium, left ventricle and thoracic aorta, and (-)-amphetamine was more

potent an inhibitor of catecholamine uptake than (+)-amphetamine in the thoracic

aorta. Amphetamine stereoisomers were equipotent in the tissues of the rabbit

heart. Unlike cardiovascular tissues of the rabbit, ventricular slices of the rat

displayed a marked preference for ( )-noradrenaline and for (+)-amphetamine.

HENDLEY, E.D., SNYDER, S.H., FAULEY, J.J. and LaPIDUS, J.B. Stereoselectivity

of catecholamine uptake by brain synaptosomes: Studies with ephedrine,

methylphenidate and phenyl-2-piperidyl carbinol. The Journal of Pharmacology

and Experimental Therapeutics 183(1): 103-116 (1972)

In this study we examined the stereoselectivity of catecholamine uptake

into synaptosomes prepared from rat cerebral cortex or corpus striatum with

isomers of ephedrine, methylphenidate and phenyl-2-piperidyl carbinol, compounds

possessing two asymmetric carbons, hence, four possible stereoisomers. The four

ephedrine isomers were more potent inhibitors of catecholamine uptake in the

cerebral cortex than in the corpus striatum. There was a 100-fold variation in potency

among the ephedrine isomers in the cerebral cortex but only a 7-fold variation in

the corpus striatum. The optimal configuration at the alpha (S) and beta (R) carbons

(erythro configuration) for activity of the ephedrines in both brain regions corresponds

to the configurations of (+)-amphetamine and (-)-norepinephrine, respectively. In

contrast. the four phenyl-2-piperidyl carbinol isomers were more potent in the

corpus striatum than in the cerebral cortex, and the configuration of the most potent

isomer was R at both alpha and beta carbons, i.e., threo. Also unlike the ephedrines.

there was a greater variation in potency among the various phenyl-2-piperidyl carbinol

isomers in the striatum than in the cerebral cortex. The methylphenidates, like

phenyl-2-piperidyl carbinol, were more potent inhibitors of catecholamine uptake in

the corpus striatum than in the cerebral cortex, and the threo racemate of

methylphenidate was about 100 times more active than the erythro racemate in both

areas. Although ephedrine, amphetamine and norepinephrine isomers show much less

stereoselectivity in the corpus striatum than in the cerebral cortex, phenyl-2-piperidyl

carbinol and methylphenidate isomers display more stereoselectivity in the corpus

striatum than in the cerebral cortex. The relative activity among phenyl-2-piperidyl

carbinol and methylphenidate isomers in inhibiting catecholamine uptake is opposite to

that of ephedrine isomers.

120
HERNDON, B.L., BAEDER, D.H. and RINGLE. D.A. An immunoglobulin model of the

morphine receptor. Federation Proceedings 33: 571 (1974)

An immunoglobulin, directed against the morphine configuration, can be

produced in rabbits by subcutaneously implanting pellets made of morphine free base.

If we assume this small molecule becomes immunogenic by covalent coupling to an

endogenous carrier, this reaction (through the immunoglobulin it produces) could be

used in binding studies as a model to interpret the nature of the morphine “receptor”,

perhaps a more physiologic model than one which uses pre-coupled morphineprotein complexes. Nine compounds, structurally related to morphine, were obtained.

Pellets from their free bases were prepared and implanted in rabbits. After 3 courses,

sera were tested for binding of 14C-morphine and 14C-codeine. Levorphanol and

morphine produced high binding titers but with different affinities for the labeled

morphine and codeine. In other tests, rabbits with antibody produced by morphine

pellets were “boosted” with the morphine congener pellets and their sera studied.

Compounds that produced binding sera when implanted alone also boosted morphine

binding. We found no relationship between analgesic potency and a compound’s ability

to form an immunoglobulin that binds labeled morphine or codeine and are studying

the possible relationship of immune memory to a drug’s re-addiction potential.

HILL, J.H., WAINER, B.H., FITCH, F.W. and ROTHBERG, R.M. Delayed clearance

of morphine from the circulation of rabbits immunized with morphine -6-hemisuccinatebovine serum albumin. Journal of Immunology (in press)

Morphine clearance from the circulation of normal rabbits and rabbits with

circulating anti-morphine antibody was studied. Individual animals were injected

with a saline solution containing 99 parts unlabelled morphine and one part 14Cmorphine at a dose of 6 mg morphine/kg body weight. The rabbits were bled at

various times after morphine injection and the amount of morphine present in the

serum at each time interval was determined by liquid scintillation. Morphine

could be detected in the serum of normal animals for one week following injection

and up to 12 weeks following injection in at least one animal with antibodies to morphine.

The rate of morphine clearance in animals immunized to morphine-6-hemisuccinatebovine serum albumin (M-6-HS-BS A) was not significantly different from normal during

the first four hours after morphine injection. However, by 24 hours after injection, the

rate of morphine clearance in M-6-HS-BSA immunized animals was significantly slower

than in normal animals. The amount of morphine present in the sera of the rabbits

24 hours after injection was related to the antibody concentration and independent of

antibody affinity. However, the rate of morphine clearance at times greater than

24 hours was related to the relative average antibody affinity and independent of antibody

concentration.

121
HILL, J.H. WAINER, B.H., FITCH, F.W. and ROTHBERG, R.M. The interaction of

14C-morphine with sera from immunized rabbits and from patients addicted to heroin.

Clinical Experimental Immunology 15: 213-224 (1973)

An intravenous injection of morphine reduced the binding of 14C-morphine by

sera from rabbits immunized with morphine-6-hemisuccinated bovine serum albumin.

Treatment of the sera with dialysis against glycine buffer (pH3) followed by dialysis

against phosphate buffered saline (PBS), conditions known to dissociate antigen-antibody

complexes, restored approximately 76% of the original binding capacity. The heterogeneity

of the antibody affinities was shown in both early ‘nonavid’ and hyperimmune ‘avid’ antisera

by the demonstration of at least two distinct populations of antibodies. One population of

antibodies formed loosely bonded antigen-antibody complexes and these complexes completely

dissociated within 30 min. The second population had different dissociation times in the

‘nonavid’ and ‘avid’ antisera (15 and greater than 72 hr. respectively). The presence of the

low affinity antibody resulted in different degrees of reduction of detectable binding by the

standard washing procedures usually employed in the radioimmunoassay used in these

studies. Washing caused less reduction in the amount of antigen bound by the more ‘avid’

antisera.

Seventy-three per cent of sixty-three serum samples from heroin addicts studied,

contained opioid capable of inhibiting the binding of morphine in the radioimmunoassay

employed. Methadone at concentrations likely to be present in sera did not interfere with

the binding of 14C-morphine. Sera from thirty-one of the patients were treated by dialysis

against glycine buffer and PBS and then studied for the capacity to bind morphine. Only

of these thirty-one sera and none of the thirty-two sera that were not pretreated bound

14C-morphine suggesting that an immune response to heroin is not a significant

contributing factor to opioid tolerance or the development of complications, such as

pulmonary oedema, following opioid administration.

HITZEMANN, R.J. and LOH, H.H. Effect of morphine on the transport of dopamine into mouse

brain slices. European Journal of Pharmacology 21: 121-129 (1973)

The effect of various concentrations of morphine on the transport of dopsmine

(DA) into slices from the mouse brain cortex and diencephalon was investigated. It

was observed that sub-analgetic levels of morphine, 3.5 X 10-8 M, produced mixed

inhibition in the cortex and uncompetitive inhibition in the diencephalon. When the

concentration of morphine was increased to within the therapeutic range (3. 5 X 10-6),

a greater effect on DA affinity rather than reaction velocity was observed in the

cortex although the inhibition remained mixed. Only the increase in inhibition of DA

transport observed by increasing the morphine concentration from 3. 5 X 10-8 to

3.5 X 10-6M was blocked by the morphine antagonist naloxone. Increasing the morphine

concentration in the diencephalon changed the type of inhibition from uncompetitive to

mixed kinetics.

HO, B.T., ESTEVEZ, V.S. and ENGLERT, L.F. Effect of repeated administration on the

metabolism of (-)-delta-9-tetrahydrocannabinols in rats. Research Communications

in Chemical Pathology and Pharmacology 5(1): 215-218 (January, 1973)

Chronic administration of (-)-delta-9-tetrahydrocannabinol (delta-9-THC) to

rats increases the metabolism of the compound in the liver but not in the lungs. Kidneys

and brain remain inactive in metabolizing delta-9-THC.

HO, B.T., ESTEVEZ, V.S. and ENGLERT, L.F. The uptake and metabolic fate of

cannabinoids in rat brains. Journal of Pharmacy and Pharmacology 25(6): 488-490

(June, 1973)

122
HO, B.T., ESTEVEZ, V. and FRITCHIE, G.E. The fate of 2, 5-dimethoxy-4-methylamphetamine

(STP, DOM) in monkey and rat brains. Brain Research 29: 166-169 (1971)

HO, B.T., ESTEVEZ, V., ENGLERT, L.F. and McISAAC, W. M. Delta-9-tetrahydrocannabinol

and its metabolites in monkey brains. Journal of Pharmacy and Pharmacology 24(5):

414-416 (May, 1972)

HO, B.T., McISAAC, W.M., WALKER, K.E. and ESTEVEZ. V. Inhibitors of monoamine

oxidase. Influence of methyl substitution on the inhibitory activity of betacarbolines.

Journal of Pharmaceutical Sciences 57(2): 269-273 (February, 1968)

A number of tetrahydro and aromatic beta-carbolines, mostly with a

methyl substituent at various positions, were synthesized and their in vitro

inhibitory activities on monoamine oxidase evaluated. Substitution of a methyl

group at the N-9 nitrogen of metahydro-beta-carboline gave a potent competitive

inhibitor of the enzyme. Methyl groups at C-1 of both tetrahydro and aromatic

beta-carbolines generally reduced the potency, whereas introduction of a methyl

group at the N-2 nitrogen of tetrahydro-beta-carboline gave a compound of

equal activity.

HO, I.K., LOH, H.H. and WAY, E.L. Influence of 5,6-dihydroxytryptamine on morphine

tolerance and physical dependence. European Journal of Pharmacology 21: 331-

336 (1973)

The intracerebral administration of 5.6-dihydroxytryptamine (5,6-DHT)

in the mouse inhibited the development of tolerance to and physical dependence

on morphine induced by morphine pellet implantation. Reduction in tolerance

development by 5,6-DHT was evidenced by the decreased amount of morphine

necessary to produce analgesia and reduction in dependence development by

the increase in the amount of naloxone necessary to induce precipitated withdrawal jumping in comparison with morphine-implanted animals receiving

saline. Further evidence that 5,6-DHT reduced dependence development on

morphine was evidenced by the fact that 5,6-DHT decreased the loss in body

weight which occurred after abrupt morphine withdrawal. At the dose of

5,6-DHT used in this study (60 mu-g of the creatinine sulfate dihydrate 24 hr

prior to morphine pellet implantation), the 5-HT level in the brain 4 days

later was 75% of that of the control group while catecholamine levels remain

unchanged. These studies substantiate the suggestion from this laboratory

that central serotonergic system may be associated in the development of

morphine tolerance and dependence.

123
HO, I.K., YAMAMOTO I., LOH, H.H. and WAY, E. L. Enhancement of pentobarbital

responses after morphine addiction. The Pharmacologist 16(2): 193 (1974)

To assess the responses to pentobarbital in morphine dependence,

ICR male mice were rendered dependent on morphine by pellet implantation for

3 days. On administering 75 mg/kg i.p. sodium pentobarbital, the sleeping time

of such animals was found to be more than 2-fold longer than that of control animals implanted with a placebo pellet. The toxicity of pentobarbital in the morphine

tolerant-dependent group was also increased, as evidenced by the decrease in

LD50 of pentobarbital to 70% of that of the control group. In morphine pellet implanted mice, the activity of microsomal metabolizing enzyme, as measured by

N-demethylation, was 35% inhibited. After a single dose of Na-pentobarbital,

60 mg/kg i.p., the brain levels of pentobarbital in the morphine group at 5, 15,

39 and 60 min were 35, 89, 41 and 99% higher, respectively, than that of the control

group. Thus, it appears that the response to pentobarbital is enhanced after chronic

morphinization and the effect may be attributed to increased brain uptake of pentobarbital after the development of tolerance and physical dependence on morphine.

HODGSON, J.R., BRISTOW, R.L. and CASTLES, T.R. Repression of RNA transcription

during the development of analgesic tolerance to morphine. Nature 248(5450): 761-763

(April, 1974)

Following reports suggesting that ribonucleic acid (RNA) and protein

synthesis are important for the development of morphine induced analgesic tolerance

and dependency. the effect of chronic morphine drugging on the intracellular site

of RNA synthesis -- nuclearchromatin -- was studied. It was found that

brain chromatin from rats tolerant to morphine synthesized RNA more slowly than

that from nontolerant rats. The results do not support any relationship between

analgesia and brain chromatin template activity. It was further found that changes in

brain chromatin template activity correlated chronologically with the onset and

disappearance of morphine induced analgesic tolerance.

HODGSON, J.R., WOODHOUSE, E. J. and CASTLES, T.R. Brain chromatin template

activity of rats treated with delta-9-tetrahydrocannabinol. Canadian Journal of

Physiology and Pharmacology 51(5): 401-403 (1973)

Brain chromatin isolated from rats given a 10MG/KG intraperitoneal

injection of delta-9-tetrahydrocannabinol exhibited a significantly lower capacity

to promote RNA synthesis than chromatin from vehicle treated rats. The effect

was not caused by either ribonuclease or an RNA polymerase inhibitor extracted

with the chromatin.

HOLLISTER, L.E. Cannabidiol and cannabinol in man. Experientia 29: 825-826

(1973)

HOLLISTER, L.E. Human pharmacology of marihuana: What next? Psychopharmacology,

Sexual Disorders and Drug Abuse. Edited by T. A. Ban, J.R. Boissier,

G.J. Gessa, H. Heimann, L. Hollister, H.E. Lehmann, I. Munkvad, H. Steinberg,

F. Sulser, A. Sundwall and O. Vinar. Amsterdam, the Netherlands: North-Holland

Publishing Company, 1973. Pp. 705-706.

124
HOLLISTER, L.E. Marihuana in man. Three years later. Science 172: 21-28 (April, 1971)

The past 3 years of renewed research on the effects of marihuana in man

has added little not previously known about the clinical syndromes produced by the

drug. The major advance has been a quantification of dose in relation to clinical

phenomena, and a beginning of an understanding of the drug’s metabolism. The

crucial clinical experiments in regard to the social questions about marihuana,

such as the possible deleterious effects from chronic use, cannot be answered by

laboratory experiments. These must be settled by close observations made on

those who experiment on themselves. It should be possible, within a relatively

short time, to determine whether marihuana has any medical utility, but the

future would appear to be no more promising than the past in this regard. The

mechanisms by which marihuana alters mental functions are not likely to be

answered in man, nor even answered soon by animal studies. As marihuana may

be unique among drugs in that more experimentation has been accomplished in man

than in animals, it may be necessary to look to additional animal studies to provide

leads for pertinent future studies in man.

HOLLISTER, L.E. Structure-activity relationships in man of cannabis constituents, and

homologs and metabolites of delta-9-tetrahydrocannabinol. Experientia

11: 3-11 (1974)

Clinical studies of a variety of cannabis constituents and THC isomers,

homologs and metabolites have elucidated some structure-activity relationships.

The fundamental structure of THC is required for pharmacological activity.

but potency may be altered greatly among different double-bond isomers, by

changing length of side-chain or by metabolic hydroxylations. No material has been

found in nature, either in cannabis itself or in the metabolites of THC, which differs

qualitatively from THC.

HOLLISTER, L.E., KANTER, S.L., BOARD, R.D. and GREEN, D.E. Marihuana metabolites

in urine of man. III. Unchanged delta-9-tetrahydrocannabinol. Research Communications in Chemical Pathology and Pharmacology 8(4): 579-584 (August 1974)

Positive identification of unchanged delta-9-tetrahydrocannabinol (THC)

in the urine of man has been made following single oral doses of 30 mg in four

subjects. Unchanged THC was found only in small amounts, approximately 0.01 -

0.005% of amount administered, and for only a few hours following drug administration.

HOLLISTER, L.E., KANTER, S.L., MOORE, F. and GREEN, D.E. Marihuana metabolites

in urine of man. Clinical Pharmacology and Therapeutics 13(6): 849-855 (NovemberDecember, 1972)

Single closes of hashish extract containing 20 mg. of delta-9-tetrahydrocannabinol

(THC) were followed by excretion of what appeared to be both cannabinol and cannabidiol

but no unchanged THC. A new material in the urine appeared to be a compound related

to a cannabinoid. The pattern of metabolism of cannabinoids appears to differ between

different subjects. Following single doses of the same amount of THC alone, only a

new drug-related metabolite could be found in the more polar range. With repeated dose

a material in the cannabinoid range was excreted in small amounts. On the whole,

repeated doses of hashish extract or THC as given in the present schedule did not lead to

any significant accumulation of drug or metabolites.

125
HOLLISTER, L.E. and MOORE, F.F. Urinary catecholamine excretion after mescaline

in man. Biochemical Pharmacology 17: 2015-2017 (1968)

HOLLISTER, L.E. and TINKLENBERG, J.R. Subchronic oral doses of marihuana

extract. Psychopharmacologia 29: 247-252 (1973)

Subchronic oral doses of marihuana revealed no evidence of sensitization

to the effects of two test doses of drug as compared to interval treatment with

placebo. Slight evidence of tolerance to dizziness and tachycardia from the drug

was noted, but not necessarily as a function of the amount of intervening drug

exposure.

HORN, A.S. and SNYDER, S.H. Chlorpromazine and dopamine: Conformations-l

similarities that correlate with the antischizophrenic activity of phenothiazine

drugs. Proceedings of the National Academy of Sciences 68(10): 2325-2328

(October, 1971)

Phenothiazines and butyrophenones are known to alter dopamine (3,4-

dihydroxyphenethylamine) metabolism in the brain in a fashion suggesting that

they may block dopamine receptors. We observed, using Dreiding molecular

models, that dopamine in its solid-state conformation is superimposable upon

a portion of the known x-ray structure of chlorpromazine (2-chloro-10-(3-

dimethylaminopropyl)-phenothiazine). The ability of phenothiazine drugs to mimic

the dopamine-like conformation correlates with their antischizophrenic efficacy.

These structure-activity relationships explain the importance of a substituent in

ring a, a three-carbon side chain bearing the amino group, and a hetero atom between rings a and c.

HORN, A.S. and SNYDER, S.H. Steric requirements for catecholamine uptake by rat

brain synaptosomes: Studies with rigid analogs of amphetamine. The Journal

of Pharmacology and Experimental Therapeutics 180(3): 523-530 (1972)

The effects of cis - and trans-2-phenylcyclopropylamine and 1- and 2-

amino-indanes, all rigid analogs of amphetamine, were examined for their

ability to inhibit catecholamine uptake into synaptosomes from the hypothalamus

and corpus striatum. Trans-2-phenylcyclopropylamine (tranylcypromine) was found

to be a more potent inhibitor in both brain areas than the cis-isomer. Studies on

the separate optical isomers of tranylcypromine showed that the (–)-isomer was

more active than the (+) -form in both the hypothalamus and corpus striatum.

2-Aminoindane was a better inhibitor than 1-aminoindane in both regions of the

brain. The above results suggest that the conformation of amphetamine at the

catecholamine uptake site is with the side chain fully extended and the amino

group above the plane of the ring, i.e., in an anti conformation. It is also

suggested that knowledge of the differential antidepressant efficacy of (+)-and (–)-

tranylcypromine might indicate the extent to which the drug’s antidepresant activity

is related to inhibition of monoamine oxidase activity or to impairment of

catecholamine reuptake.

126
HUANG, J.T. and TAKEMORI, A.E. Accumulation of etorphine in rat brain slices.

The Pharmacologist 16: 248 (August, 1974)

3H-Etorphine (3. 3 Ci/mmole) was used to study the accumulation of

this narcotic into slices of various brain areas. With 2 x 10-10M etorphine in the

medium, the T/M (tissue conc/medium conc) was significantly higher in slices of

striatum (9.2) and thalamus 11.5) than in cortex (7.6) or fourth ventricular floor

(8.2). However, the uptakes by slices of all brain areas were similar when 1.5 x

10-8M etorphine was used. At very low conc of etorphine and using cortical and

striatal slices, the uptake was saturable with maximum uptakes of 6.97 x 10-10

and 2.36 x 10-10 mole/gm/15 min respectively and uptake

constants of 1.34 x 10-9 and 1.97 x 10-9 M respectively.

At conc above 15 nM, the accumulation appeared to be nonsaturable.

Dinitrophenol, fluoride, azide, iodoacetamide or Ca++ did not affect the saturable

uptake of etorphine but N-ethylmaleimide or temperature of 0°C decreased the

accumulation. Other organic bases such as hexamethonium or N-methylnicotinamide

did not influence the uptake of etorphine. The saturable etorphine uptake was

relatively stereospecific i.e. levorphanol was a more potent inhibitor of the uptake

than dextrorphan. Etorphine uptake by brain slices from morphine-tolerant rats did

not differ from that of non-tolerant rats.

HUANG, J.T. and TAKEMORI, A.E. Accumulation of methadone by choroid plexus in vitro.

Neuropharmacology (in press)

HUG, C.C., JR. Characteristics and theories related to acute and chronic tolerance

development. Chemical and Biological Aspects of Drug Dependence. Edited by

S. Mule and H. Brill. Cleveland, Ohio: Chemical Rubber Company Press, 1972.

Pp. 307-358.

IDANPAAN-HEIKKILA. J.E., FRITCHIE, G.E. and McISAAC. W.M. Pharmacological and

behavioral studies of STP. Relationship to tissue distribution. Advances in Mental

Science: Drug Dependence, Vol. 2. Austin, Texas: University of Texas Press,

1969. P. 24.

IWAMOTO, E.T., HO, I.K. and WAY, E.L. Elevation of brain dopamine during naloxoneprecipitated withdrawal in morphine-dependent mice and rats. Proceedings of

the Western Pharmacological Society 16: 14-18 (1973)

IWATSUBO, K. and CLOUET, D.H. The effects of narcotic analgesic drugs on the levels

and the rates of synthesis of cAMP in six areas of rat brain. Federation Proceedings

32: 536 (1973)

The acute administration of narcotic analgesic drugs to experimental animals

produces transient effects on both the levels and the rates of biosynthesis of biogenic

amines in brain. The sensitivity of post-junctional elements to drug exposure has not

been determined directly, although cAMP, has been shown to antagonize the analgetic

effects of morphine. We have isolated synaptosomal membrane fractions from

various areas of rat brain, and examined the effects of adding narcotic drugs on the

adenylate cyclase activity of the preparations. At 1 mM concentration, morphine, levoand dextro-methadone, levorphanol and dextrophan inhibited adenylate cyclase activity,

by more than 50% in most areas. There was no stereospecificity, since the optical

isomers, levorphanol and dextrorphan, were also equally inhibitory at 0.1 mM concentration. Unless the narcotic drugs are concentrated at the synaptic membrane, it

is unlikely that the drug concentration in vivo would be high enough to be inhibitory.

The levels of cAMP were measured in the same brain areas removed from rats killed

by microwave irradiation after the injection of morphine in acute dose. The levels of

the ‘second messenger’ tended to decrease during the period two hours after drug administration, with significant decreases in cAMP levels in homogenates of medulla

and hypothalamus. 127
JATLOW. P. Ultraviolet spectrophotometric analysis of drugs in biological fluids.

American Journal of Medical Technology 39(6): 231-236 (June, 1973)

For abstract, see Section I. Methodology of Drug Research.

JOHNSON, C.L., KANG, S. and GREEN, J.P. Conformational analysis by a combined

molecular-orbital-classical procedure. Conformation of Biologiccal Molecules and

and Polymers, the Jerusalem Symposia on Quantum Chemistry and Biochemistry,

Vol. V. Jerusalem, Israel: The Israel Academy of Sciences and Humanities,

1973. Pp. 517-529.

JOHNSON, J. C. and CLOUET, D.H. Studies on the effect of acute and chronic morphine

treatment on catecholamine levels and turnover in discrete brain areas of rats.

Federation Proceedings 32: 757 (1973)

For acute studies, male, Sprague-Dawley rats received 5, 20, or 60 mg/kg

morphine (M) base s.c. and were sacrificed 15, 30, or 60 min after treatment. For

chronic studies rats received 60 mg/kg daily for 5 days and were sacrificed 60 min

after the 5th injection, or rats were implanted with an M pellet. Ten min before

sacrifice all rats received 5 mu-g 14C-tyrosine (T) intracisternally. Brains were

removed and dissected into 6 areas: 1) cerebellum, 2) medulla, 3) hypothalamus,

4) striatum, 5) midbrain and 6) cortex. The levels of dopamine (DA) norepinephrine

(NE) and T were measured fluorimetrically and the incorporation of 14C-T into the

amines determined by liquid scintillation spectrometry. With acute M treatment NE

levels decreased at 30 min and returned to normal or above normal values by 60 min

in all brain areas while DA was decreased at 30 min and normal at 60 min in area 4.

With chronic treatment NE levels remained decreased in areas 2 and 5 and elevated in

areas 3 and 6 while DA levels were elevated in area 4. T levels and T specific activity

were found not to change significantly with acute or chronic M treatment. NE synthesis

was decreased by acute M treatment in areas 3 and 4 while DA synthesis was increased

in areas 2,3,4 and 5. Chronic M treatment decreased NE synthesis in area 3 and

elevated DA synthesis in all areas studied.

128
JONAS, W. and SCHEEL-KRÜGER. J. Amphetamine induced stereotyped behavior correlated

with the accumulation of O-methylated dopamine. Archives internationales de

Pharmacodynamie et de Therapie 177: 379-389 (1969)

Amphetamine provokes in rats pretreated with reserpine a marked central

excitation: The initial locomotor activity is followed by a phase with a characteristic

stereotyped behaviour consisting of sniffing, licking and gnawing.

Biochemical analyses were performed of the brain amines depamine,

noradrenaline and their respective O-methylated metabolites 3-methoxytyramine

and normetanephrine.

In rats pretreated with the monoamincoxidase-inhibitor nialamide only,

amphetamine induced an increased accumulation of both 3-methoxytyramine and

normentanephrine.

An additional dose of reserpine clarified that amphetamine still provoked

a significantly increased accumulation of 3-methoxytyramine correlated with the

stereotyped behaviour while the levels of the other brain amines were decreased

to undetectable low levels.

Hyperthermia was excluded as a causative factory for this isolated metabolic

effect of amphetamine.

The result thus seems to indicate that the amphetamine induced stereotyped

behaviour in these reserpinized rats is correlated with an increased turnover of

dopamine.

JONES, R. Significance and characteristics, of drug dependence: Characteristics of drug

dependence to cannabis. Chemical and Biological Aspects of Drug Dependence.

Edited by S.J. Mule and H. Brill. Cleveland, Ohio: Chemical Rubber Company

Press, 1972. Pp. 65-81.

JUCHAU, M.R. and HORITA, A. Metabolism of hydrazine derivatives of pharmacologic

interest. Drug Metabolism Reviews 1(1): 71-100 (1972)

Hydrazine and its derivatives represent a group of highly reactive

chemicals which are utilized extensively for many varied purposes. They

are capable of producing a wide spectrum of biological effects, some of

which are useful therapeutically, others of which are definitely harmful.

The manner and rate of biotransformation of these compounds play a major

role in determining the nature of the observed effects. Acetylation appears

to be the most important mode of biotransformation with respect to

inactivation of such compounds, whereas hydrolysis, oxidation, and

reduction frequently result in the formation of metabolites with potent

biological effects. Biotransformation appears to be essential to the

capacity of many of these compounds to inhibit monoamine oxidase.

Conversion to substances which contain a free – NH2 group is frequently

requisite to inhibition of this important enzyme system. Other biotransformation reactions tend to terminate the inhibitory effect on

monoamine oxidase but may result in the formation of compounds which

inhibit other biochemical systems.

KAIKO, R.F. and INTURRISI, C.E. Human biotransformation and exertion of

orally administered cyclazocine: A method and its application.

The Pharmacologist 15(2) (Fall, 1973)

For abstract, see Section I. Methodology of Drug Research.

129
KAIKO, R.F. and INTURRISI, C.E. The quantitation of cyclazocine and its

metabolities in human urine by use of gas-liquid chromatography.

Journal of Chromatography 100: 63-72 (1974)

For abstract, see Section I. Methodology of Drug Research.

KANDEEL, E.M., ANDERSON, L. J., BLOCK, J.H., WHITE, A.I. and MARTIN, A.R.

Substituted tetralins IV: Synthesis and stereochemistry of 4,4-disubstituted

1,2,3,4-tetrahydro-2-naphthoic acids. Journal of Pharmaceutical Sciences

61(8): 1231-1234 (August, 1972)

The syntheses of four 4-methyl-4-phenyl-1,2,3,4-tetrahydro-2-

naphthoic acids are described. The sterospecific cyclization of the

cis-isomers and proton NMR studies establishing cis-trans product rations

are also reported.

KANDEEL, E.M. and MARTIN, A.R. Substituted tetralines. 5. Analgesic properties

of some diastereoisomeric N, N-dimethyl-4-phenyl-1,2,3,4 -tetrahydro-2-

naphthylamines. Journal of Medicinal Chemistry 16: 947-948 (1973)

KANG, S. Conformation and electronic structures of pilocarpine, a muscarinic

agonist. International Journal of Quantum Chemistry: Quantum

Biology Symposium 1: 109-117 (1974)

The electronic structures and conformations of pilocarpine, a

muscarinic agonist, have been studied by the INDO molecular orbital

method and the classical potential function method.

A conformation of pilocarpine congruent with other potent

muscarinic agonists was observed in the allowed conformational energy

range. This conformation is near psi = 60° and theta = 260°. It is

suggested that the lower muscarinic agonist potency of pilocarpine

relative to acetylcholine is probably due to the lower pKa value

(pKa = 6.07) of the imidazole ring nitrogen. rather than to the molecular

conformation.

KANG, S. and GREEN, J.P. Steric and electronic relationships among some

hallucinogenic compounds. Proceedings of the National Academy of

Sciences 67(1): 62-67 (September, 1970)

Stereochemical considerations and total valence electron calculations suggest congruities among the ostensibly dissimilar hallucinogenic

compounds, D-lysergic acid diethylamide (LSD), indolealkylamines, and

methoxylated amphetamines. In LSD the aromatic benzene ring A and the

N-6 nitrogen are essential for hallucinogenic activity; these sites may

react with the receptor. The conformations of amphetamines and

indolealkylamines at the receptor are such that the aromatic benzene ring

lies like ring A of LSD and the alkylamino nitrogen lies like the N-6 of

LSD. Ring A may interact with the receptor by forming a pi-molecular

complex, as suggested by the correlation between hallucinogenic activity

and energy of the highest occupied molecular orbital (EH) of congeneric

series. The N-6 nitrogen of LSD and the sterically congruent nitrogen

of the other hallucinogenic compounds may react with the receptor by

forming a donor acceptor complex of the n-psi or n-rho type. Other

portions of the hallucinogenic molecules confer a favorable EH: these

include the methoxy and hydroxyl groups of the amphetamines (and

mescaline), and the indolealkylamines; and the pyrrole ring of LSD and

the indolealkylamines.

130
KANG, S., JOHNSON, C.L. and GREEN, J.P. The conformation of 5-hydroxytryptamine. Journal of Molecular Structure 15: 453-457 (1973)

KANG, JOHNSON, C.L. and GREEN, J.P. Theoretical studies on the conformations of psilocin and mescaline. Molecular Pharmacology 9(5):

640-648 (September, 1973)

Molecular orbital calculations and classical potential function

calculations were carried out to examine the proposal that the conformations of the hallucinogenic tryptamines and phenylalkylamines are

such that their 6-membered aromatic rings and their alkylamino nitrogens

are congruent with the A ring and N(6) nitrogen atom of lysergic acid diethlamide (the nitrogen of the D ring). The congruent conformation of

psilocin is psi[C(9)--C(3)--C(beta)--C(alpha)]= 46 ± 10 degrees, alpha [C(3)

C(beta)--C(alpha)--N]= 230 ± 20 degrees, theta1[C(beta)--C(alpha)--N--

C(1N)] = 180 ± 10 degrees, and theta2[C(beta)--C(alpha)--N--C(2N)=

300 ± 10 degrees; that of mescaline is psi[C(2)--C(1)--C(beta)--c(alpha)]

147 ± 10 degrees and eta[C(1)--C(beta)--C(alpha)--N]= 160 ± 20 degrees.

These results show that congruence of psilocin and mescaline with

lysergic acid diethylamide is energetically permissible.

KANTER, S.L., HOLLISTER, L.E., MOORE, F. and GREEN. D.E. Marihuana

metabolites in urine of man. IV. Extraction procedures using diethyl

ether. Research Communications in Chemical Pathology and Pharmacology 9(2): 205-213 (October, 1974)

For abstract, see Section I. Methodology of Drug Research.

KANTER, S.L., HOLLISTER, L.E., MOORE, F. and GREEN, D.E. Marihuana

metabolites in urine of man. II. Underscribed metabolite following oral

ingestion of delta-9-tetrahydrocannabinol. Research Communications in

Chemical Pathology and Pharmacology 7(1): 79-84 (January, 1974)

A major metabolite derived from the metabolism of THC administered orally to man has been detected by an improved thin-layer

chromatographic technique. It appears in the urine within the first 12

hours following the drug and persists for at least 36 hours. By various

types of exclusion, it is not the 11-hydroxy, 8-beta-hydroxy, 8-alphahydroxy, or 8, 11-dihydroxy metabolite of delta-9-THC.

131
KARLER. R., CELY, W. and TURKANIS, S.A. Anticonvulsant activity of delta-9-

tetrahydrocannabinol and its 11-hydroxy and 8-alpha, 11-dihydroxy

metabolites in the frog. Research Communications in Chemical Pathology

and Pharmacology 9(3): 441-452 (November, 1974)

In the frog (Rana pipiens) delta-9-tetrahydrocannabinol (delta-9-THC)

exhibits pronounced anticonvulsant activity against maximal electroshock.

A study of the metabolic fate of 3H-delta-9-THC demonstrated that delta-9-

THC is rapidly metabolized to several unidentified metabolites, as well as

to mono- and dihydroxylated products; brain amounts of both the hydroxylated

metabolites and delta-9-THC were measured as a function of time, but none

of these measurements correlated quantitatively with the time course of

anticonvulsant activity. Both 11-hydroxy- and 8-alpha, 11-dihydroxy-delta-9-

THC metabolites displayed anticonvulsant activity. All the cannabinoids

tested were much more potent in the frog than in the rat or mouse; but there

was no such disparity in the potency of diphenylhydantoin and phenobarbital

in the different species. The unanticipated pharmacological activity of the

metabolite, 8-alpha, 11-dihydroxy-delta-9-THC, emphasizes the complexity

of delta-9-THC and its numerous effects.

KHANNA, K.L., ROSENBERG, H. and PAUL, A.G. Biosynthesis of mescaline.

Chemical Communications. 1969. London, England: The Chemical Society,

1969. P. 315.

A pathway of biosynthesis of mescaline from 3,4-dihydroxy

phenethylamine via m-O-methylation is proposed.

KHANNA, K.L., TAKIDO, M., ROSENBERG, H. and PAUL, A.G. Biosynthesis of

phenolic tetrahydroisoquinoline alkaloids of peyote. Phytochemistry 9:

1811-1815 (1970)

Data are presented supporting a proposed pathway of biosynthesis of

the phenolic tetrahydroisoquinoline alkaloids of peyote from dopamine. It

is suggested that meta-O-methylation of dopamine, hydroxylation in the

5-position. para-O-methylation and finally cyclizations yield anhalamine,

anhalidine, anhalonidine and pellotine.

132
KIDD, M.R., ELLIS, R.D. and CAUTHEN. S.E. The properties of fractionated

rabbit serum cocainesterase. Presented at the American Chemical Society

28th Southwest Regional Meeting, Baton Rouge, Louisiana, December 6-8,

1972.

Cocainesterase has been purified 334-fold from commercially available,

pooled rabbit serum using the following methods: ammonium sulfate fractionation,

Sephadex G-75 gel filtration, elution from QAE-Sephadex using a linear gradient of

from 0.1 to 0.4 N KCl in phosphate buffer, and elution from alumina Cgamma gel.

The enzyme was assayed by following the titration of acid produced upon hydrolysis.

The yield of the most highly purified preparation was about 50% and its specific

activity was 0.32 mu-moles base uptake/min/mg protein. Michaelis constants were

determined for cocaine and tropacocaine with the purified enzyme and found to be

1.7 X 10-4M and 3.9 X 10-4M respectively. Also, the following compounds were

tested as possible substrates: atropine sulfate, atropine methyl bromide, scopolamine

HBr, acetyl-beta-methyl choline chloride, pilocarpine HCl, hyoscyamine sulfate,

and eucatropine HCl. The purified preparation was tested for other esteratic

activities known to be present in rabbit serum. Acetylcholinesterase was shown to be

absent from the purified enzyme and shown to be separated from it in the gel

filtration step: atropinesterase activity was separated from cocainesterase on the

ion-exchange column. However, activity with phenyl acetate, tributyrin and

phenyl butyrate was observed.

KINZER, G.W., FOLTZ, R.L., MITCHELL, R.I., BATTELLE and TRUITT, E.B., JR.

The fate of the cannabinoid components of marihuana during smoking.

Bulletin on Narcotics 26(3): 41-54 (July-September, 1974)

Cannabis of known origin was used to prepare cigarettes, The cigarettes

were smoked by machine under conditions which simulated the smoking

patterns of a typical marihuana smoker. Both the smoke condensate and the

marihuana plant extract were analyzed by gas chromatography and mass

spectrometry. It was found that approximately 50 per cent of the delta-9-

tetrahydrocannabinol in the marihuana was destroyed during the smoking

process. Analysis for the cannabinoid acids was achieved by trimethylsilylation followed by gas chromatography. The trimethylsilylated

cannabinoids were identified on the basis of their mass spectra. Some of

the delta-9-tetrahydrocannabinolic acid and the cannabidiolic acid were found

to survive the smoking process.

133
KNAPP, S., MANDELL, A.J. and GEYER. M.A. Effects of amphetamines on

regional tryptophan hydroxylase activity and synaptosomal conversion

of tryptophan to 5-hydroxytryptamine in rat brain. The Journal of

Pharmacology and Experimental Therapeutics 189(3): 676-689 (1974)

The acute administration of d-amphetamine, methamphetamine

p-chloroamphetamine. and l-amphetamine reduced the conversion of

tryptophan to serotonin (5-HT) in synaptosomes from the rat striatum.

d-Amphetamine was approximately twice as potent as l-amphetamine

in decreasing conversion activity. In contrast, fenfluramine increased

this index of nerve ending 5-HT biosynthesis. None of the amphetamines

studied affected synaptosomal uptake of 14C-L-tryptophan when measured

in the same tissue preparations in which conversion activity was studied.

The activity of solubilized tryptophan hydroxylase in the striatal

synaptosomes was decreased by d-amphetamine treatment to the same

extent that conversion activity was, accounting for the decrease in conversion activity. Tryptophan hydroxylase activity in the lateral midbrain

after d-amphetamine was decreased to the same extent that it was in the

nerve ending, but the decrease in the lateral midbrain preceded that

observed in the nerve ending. Enzymic activity in the medial midbrain

area was unaffected by d-amphetamine. At a concentration of 100 mu-M

none of the amphetamines studied had a demonstrable effect on

tryptophan hydroxylase activity in vitro. At 100 mu-M in vitro and

10 mg/kg in vivo, the two major amphetamine metabolites in the rat,

p-hydroxyamphetamine and p-hydroxynorephedrine, failed to influence

regional tryptophan hydroxylase activity or synaptosomal conversion of

tryptophan to 5-HT. The short latency of the amphetamine-induced

changes in nerve ending 5-HT synthetic activity contrasts with the delay

of days to weeks in response to such agents as lithium and morphine as

we have previously reported.

KOKOSKI, R.J., SANDS, F.L. and KURLAND. A.A. Morphine detection by thinlayer chromatography in a urine-screening program. A comparison of

ion-exchange-resin loaded paper extraction with direct solvent extraction.

Committee on Problems of Drug Dependence, 1969. Washington, D.C.:

National Academy of Sciences, National Research Council, 1969.

KRUMHOLZ, W.V., SHEPPARD, C. and MERLIS, S. Clinical evaluation of butaperazine

(AHR 712). Current Therapeutic Research 9(4): 220-224 (April, 1967)

Twenty-four male chronic psychotic patients with an average age of

39 years and an average duration of overt illness of 11 years were given

butaperazine, a new antipsychotic drug, for a period of 12 weeks in doses

between 10 mg. and 100 mg. daily. The optimal therapeutic dose seemed

to be around 30 mg. daily. Extrapyramidal disturbances were observed

in 16 patients at different dose levels. At higher dose levels, minor nonextrapyramidal side effects were observed.

Laboratory tests revealed no significant pathological changes.

Five patients showed interesting positive behavior changes and were

continued for another 24 weeks on butaperazine. The authors remained with

the impression that butaperazine may have some value in the treatment of

chronic schizophrenic patients.

134
KUBENA, R.K., PERHACH, J.L., JR. and HERBERT, B., III. Corticosterone

elevation mediated centrally by delta-1-tetrahydrocannabinol in rats.

European Journal of Pharmacology (14)1: 89-92 (1971)

Assays of peripheral plasma corticosterone, 45 minutes after

intraperitoneal injection of 2 to 16 mg/kg of delta-1-tetrahydrocannabinol,

showed strong pituitary adrenal activation which persisted undiminished

after a week of daily doses. Experiments were performed on a total

of 230 male albino rats. Blockage of the steroid activation, by hypophysectomy or by pretreatment with pentobarital and morphine, indicated

a hypothalmic or other central locus of this action of delta-1-tetrahydrocannabinol. (Author Abstract Modified)

KUCZENSKI, R. Effects of catecholamine releasing agents on synaptosomal dopamine

biosynthesis: Multiple pools of dopamine or multiple forms of tyrosine

hydroxylase? Neuropharmacology (in press)

The effects of agents, which are known to induce release of catecholamines from synaptosomes, were assessed on the synthesis of dopamine

from tyrosine. as reflected in the evolution of 14CO2 from L-(1-14C) -

tyrosine, in intact rat striatal synaptosomes. At a time when release has

occurred, whereas reserpine inhibits the synthesis of dopamine from

tyrosine, with an ED50 of 1 x 10-8 M, tyramine (ED50 of 1 x 10-5 M) and

amphetamine (ED50 of 1.4 x 10-6 M) enhance the rate of synthesis. The

presence of nialamide (10-4 M) or pargyline (10-3M) has no effect on

synaptosomal dopamine synthesis in the absence or presence of amphetamine, tyramine, or reserpine. Neither reserpine, tyramine, nor

amphetamine affect the activity of tyrosine hydroxylase or dopa decarboxylase in the absence of synaptosomal structural integrity. Nor do

these drugs affect the accumulation of 3H-tyrosine into synaptosomes.

The data are consistent with the existence of at least two pools of

synaptosomal dopamine, one of which can interact with tyrosine

hydroxylase. Two hours after pretreatment of rats with 5 mg/kg Damphetamine, the level of synaptosomal dopamine biosynthesis is decreased by 39%. The rate of dopamine synthesis in synaptosomea from

amphetamine-pretreated rats was assessed in the presence of reserpine

and tyramine. The data are not consistent with alterations in pool size

as the only mechanism affecting synaptosomal dopamine synthesis. A

mechanism is discussed involving an equilibrium of tyrosine hydroxylase

between active and inactive conformers in the presence of an inhibitory

pool of dopamine.

135
KUCZENSKI, R. Striatal tyrosine hydroxylases with high and low affinity for tyrosine:

Implications for the multiple-pool concept of catecholamines. Life Sciences

13: 247-255 (1973)

Synaptic membrane-bound tyrosine hydroxylase from rat striatum

exhibits a decreased Km for cofactor and a decreased Km for substrate

over values obtained for the soluble enzyme. The proximity of this

fraction of the catecholamine biosynthetic apparatus to the probable site

of neurotransmitter release and its higher affinity for substrate provide

for a mechanism by which newly synthesized transmitter may be preferentially released.

KUHAR, M.J., SHASKAN, E.G. and SNYDER, S.H. The subcellular distribution of

endogenous and exogenous serotonin in brain tissue: Comparison of

synaptosomes storing serotonin. norepinephrine, and gamma-aminobutyric

acid. Journal of Neurochemistry 18: 333-343 (1971)

We have studied the subcellular distribution of exogenous and

endogenous serotinin in slices from the hypothalamus and midbrain of

several species. In a procedure which appears to label the endogenous

pools, tissue slices were incubated with low concentrations of

(

3H)5-HT (5 x 10-8M), for 45 min, when there was apparent equilibrium

between (

3H)5-HT of tissue and medium. After the tissue slices were

homogenized in 0.32 M-sucrose and subjected to differential centrifugation. the distribution of exogenous and endogenous 5-HT in pellets

and supernatant fluid was similar.

In some experiments, the crude mitochondrial pellets were resuspended in 0.32 M-sucrose, layered on linear, continuous density

gradients of sucrose (1.5-0. 32M), and centrifuged for short times

(incomplete equilibrium centrifugation). The subcellular distribution

of particulate tritium, total tritium, and particulate endogenous 5-HT

was the same in portions of the gradients containing synaptosomes.

The peak distribution of (

3H)5-HT in sucrose gradients was separable

from the peak for (

14C)GABA by four to five fractions; potassium (a

marker for cytoplasm occluded within synaptosomes) occurred in the

regions of the gradients containing most of the labelled compounds.

The distribution of monoamine oxidase activity (a mitochondrial marker)

overlapped the distribution of (

3H)5-HT after a 15 min centrifugation

but appeared in denser regions of the gradient after centrifuging for

2 h. Particles containing (

3H)5-HT and (14C)NE were slightly but consistently separable in synaptosomal fractions isolated from the

hypothalamus or midbrain of rat, guinea pig and hamster.

136
KUHN, C.M. and SCHANBERG, S.M. Metabolism of D-amphetamine by rat brain

in vivo and in vitro. The Pharmacologist 16: 228 (1974)

The ability of brain tissue to hydroxylate amphetamine (A) to phydroxyamphetamine (P) and norephedrine (N) is the subject of some

controversy, although the metabolism of A to P and p-hydroxynorephedrine (PNE) has been demonstrated in some organs of the rat. To

study this problem, brain slices were incubated with tritiated (

3H) A

for one hour. Metabolites were extracted. dansylated and then

separated by TLC. At lower concentrations of A, only P and PNE were

identified, but at the higher concentration N also could be isolated. In

addition rats were injected intracisternally with 3H-A, and A and metabolites were isolated at various times after injection. P, N and PNE

could be isolated 15 min. after injection. However, while the concentration of P and N declined rapidly over 4 hours the amount of PNE

increased gradually during this same period. Brains obtained from

animals injected i.p. with the same dose of 3H-A did not contain

measurable levels of hydroxylated metabolites. These data suggest

that A can be metabolized to P and NE by rat brain tissue.

KULLBERG, M.P. and GORODETZKY. C.W. Studies on the use of XAD-2 resin for

detection of abused drugs in urine. Clinical Chemistry 20(2): 177-183

(1974)

For abstract, see Section I. Methodology of Drug Research.

KULLBERG, M.P., GORODETZKY, C.W. and CONE, E.J. Identification of etorphine

(E) in human urine after a single 100 mu-g dose. The Pharmacologist

16(2): 193 (Fall, 1974)

Urine was collected for 24 hrs. prior to and following subcutaneous

administration of 100 mu-g E to 4 drug-free subjects. Post-drug samples

were combined into single 24-hour samples for 3 subjects and two 12 -

hour samples for one subject, and analyzed as follows: 1. The two 12-

hour samples were extracted on an XAD-2 resin column, eluted with

CHCl3, concentrated, extracted with 1N HCl, adjusted to pH 8.5 and

reextracted with CHCl3, evaporated to dryness and redissolved in 100

mu-l of ethyl acetate: 2. two 24-hour samples were extracted on XAD-2

resin colums. eluted with MeOH/H2O/NH4OH, evaporated to dryness,

redissolved in H2O, subjected to beta-glucuronidase nycrolysis, extracted

with CHCl3 then 1N HCl and then OHCl3. and finally evaporated to dryness

and redissolved in ethyl acetate: 3. one 24-hour sample was subjected to

beta-glucuronidase hydrolysis then extracted as in 1. Urine extracts were

analyzed for E with a Finnigan 1015D GC/MS using mass fragmentography

to monitor the two major ions at m/e 413(M+l) and 395[(M+1) -18]

by methane chemical ionization. E was detected in all post-drug urine

extracts by occurrence of the major ions, ion ratios, and retention time

compared to authentic E and extracts of pre-drug control urine. The

sensitivity for detection of pure E was 5-10 ng.

137
KUPFER. D., LEVIN, E. and BURSTEIN, S.H. Studies on the effects of delta-1-

tetrahydrocannabinol (delta-1-THC) and DDT on the hepatic microsomal

metabolism of delta-1-THC and other compounds in the rat.

Chemico-Biological Interactions 6: 59-66 (1973)

LABRECQUE, G. and DOMINO, E.F. Tolerance to and physical dependence on

morphine: Relation to neocortical acetylcholine release in the cat.

The Journal of Pharmacology and Experimental Therapeutics 191:

189-200 (1974)

LANG, D.W., DARRAH, H.K., HEDLEY-WHYTE, J. and LAASBERG, L.H.

Increased 35S-methionine in brain of morphine addicted rats. Federation

Proceedings 33: 1486 (1974)

Effect of morphine (MS) on protein synthesis in rat brain was

evaluated in tolerant and acute rats. Male Wistar-Lewis rats were

randomly divided to control, tolerant and acute groups (N=10). The rats

were made tolerant by giving MS (25 mg/kg b.i.d.) for either 42 or 84 d.

An aqueous solution of 35S methionine (0.5 mu-C/gbw) was administered

IV. All groups were then sacrificed at 20 min., 1 hr and 2 hrs after 35Smethionine IV. The 35S-activity in TCA precip proteins and supernate

from cortex, hypothalamus, putamen, corpus callosum, thalamus,

cerebellum, kidney and liver was determined. In addition the activity

of label in lipid, saline soluble and insoluble proteins of whole brain for

tolerant and control (N=12) rats was determined. The 35S-activity in

brain proteins of acute rats did not differ from those of controls. The

six brain areas in tolerant rats after 1 and 2 hrs injection of 35S-methionine

showed a 15%, then 30% increase in activity (dpm/mg protein). Proteins

from putamen and corpus callosum had w/w 60% of the 35S-activity found

in hypothalamus and cortex. There was no difference in 35S-activity in

kidney and liver of control and tolerant rats. The activity of the label in

brain lipids was 2% of that found in proteins in both tolerant and control

groups. Protein synthesis in morphine tolerant rat brain is significantly

(less than 0.01) increased as judged by incorporation of 35S-methionine.

LAWRENCE, R.H., JR. and WALLER, G.R. GC-MS/Probe-MS analysis of

cannabinoid in resin glands of Cannabis sativa L. Presented at the 13th

Annual Meeting of the Phytochemical Society of North America, Pacific

Grove, California, 1973. P. 24.

For abstract, see Section I. Methodology of Drug Research.

LAWRENCE, R.H., JR. and WALLER, G.R. Glandular structures of Cannabis

sativa L. and cannabinoid production. Presented at the 50th Annual

Meeting of the American Society of Plant Physiologists, Cornell

University, Ithaca, New York. Plant Physiology 53: s-13 (1974)

For abstract, see Section I. Methodology of Drug Research.

138
LAWRENCE, R. H., JR. and WALLER, G.R. The role of specialized epidermal

gland in the production of cannabinoids in Cannabis sativa L. Proceedings

of the 9th IUPAC International Symposium on Chemistry of Natural

Products, Ottawa, Canada, Abstract 24C, 1974.

For abstract, see Section I. Methodology of Drug Research,

LAWRENCE, R.H., JR., WALLER, G.R. and KINNEBERG, K.F. An improved method

of sample introduction in gas chromatography-mass spectrometry of biological materials. Analytical Biochemistry 62(1): 102-107 (November, 1974)

For abstract, see Section I. Methodology of Drug Research.

LEMBERGER. L., MARTZ, R., RODDA, B., FORNEY, R. and ROWE, H.

Comparative pharmacology of delta-9-tetrahydrocannabinol and its

metabolite, 11-OH-delta-9-tetrahydrocannabinol. Journal of Clinical

Investigation 52(10): 2411-2417 (October, 1973)

A comparison of the psychologic and physiologic effects of intravenously administered delta-9-tetrahydrocannabinol (delta-9-THC) and

11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-delta-9-THC) was carried

out in nine casual marihuana smokers. A marked tachycardia and

psychologic “high” occured within 3-5 min after the i.v. administration

of 11-OH-delta-9-THC (1 mg) to all subjects. In contrast, the peak

psychologic “high” was delayed 10-20 min after the i.v. administration

of delta-9-THC (1 mg). There was some individual variation in response

among subjects. Psychologic effects correlated well with plasma levels

of unchanged (

3H)11-OH-delta-9-THC. About 75% of the administered

radioactive dose was excreted in urine (25%) and feces (50%) after

(

3H)11-OH-delta-9-THC administration. The disposition, excretion, and

metabolism of (

3H)11-OH-delta-9-THC appear to be similar to that

previously reported after (

14C)delta-9-THC administration. These findings, in conjunction with the marked psychologic high seen after 11-OHdelta-9-THC, suggest that in man, delta-9-THC, the active constituent

in marihuana, is converted to 11-OH-delta-9-THC, which is in part

responsible for the psychologic effects.

LEMBERGER, L., SILBERSTEIN, S.D., AXELROD, J. and KOPIN, I.J.

Marihuana: Studies on the disposition and metabolism of delta-9-

tetrahydrocannabinol in man. Science 170: 1320-1322 (December, 1970)

139
LEMBERGER. L., TAMARKIN. N.R., AXELROD, J. and KOPIN, I.J. Delta-9-

tetrahydrocannabinol: Metabolism and disposition in long-term marihuana

smokers. Science 173: 72-74 (July, 1971)

Radioactively labeled delta-9-tetrahydrocannabinol (delta-9-THC)

administered intravenously to chronic marihuana smokers disappeared

from the blood plasma with a half-life of 28 hours as compared to 57

hours for nonusers of marihuana. Apparent volumes of distribution did

not significantly differ between the two groups. Within 10 minutes after

administration of delta-9-THC, 11-hydroxy-delta-9-THC is present in

the plasma of nonusers and chronic users. This metabolite was also

present in urine and feces of nonusers and long-term marihuana smokers.

In addition, polar metabolites were excreted in urine and feces of both

groups for more than 1 week.

LIN, S.C., SUTHERLAND, V.C. and WAY, E.L. Brain amino acids in morphine

tolerant and non-tolerant rats. Proceedings of the Western Pharmacological

Society 16: 8-13 (1973)

LINDER, C. and FISHMAN, J. Narcotic antagonists. 1. Isomeric sulfate and acetate

esters of naloxone (N-allylnoroxymorphone). Journal of Medicinal Chemistry

16(5): 553-556 (1973)

For abstract, see Section I. Methodology of Drug Research.

LIRAS, P., ATHENHOLT, T. and UMBRECHT, W.W. Microbial transformations of

morphine by bacteria. Developments in Industrial Microbiology (in press)

LOEW, G.B. and JESTER, J.R. Quantum chemical studies of meperidine and

prodine. Journal of Medicinal Chemistry (in press)

Extensive quantum chemical calculations have been made of the conformational behavior of meperidine, desmethyl. alpha ± beta ± prodine,

using PCILO, a semi-empirical molecular orbital method. For this

series of opiates. a phenyl-equatorial conformation was preferred over a

phenyl-axial one, with the equatorial conformer most favored in the most

potent compounds.

Using the low energy equatorial conformer obtained for each compound,

we were able to successfully account for their observed potency variation.

We could further deduce that a flexible phenyl, rather than piperidine, ring

site was probably involved in accommodation of these compounds at the

morphine receptor.

140
LOEW, G.H. and BERKOWITZ, D.S. Quantum chemical studies of morphine-like

opiate narcotics: Effect of N-substituent variations. Journal of Medicinal

Chemistry (in press)

Quantum chemical calculations including extensive conformational

variations are performed on three morphine-like analgesics with varying

N-substituents using the PCILO and INDO methods. The three compounds,

morphine, nalorphine, and N-phenethyl-morphine have been shown experimentally to exemplify opiate narcotic agonism, antagonism, and increased agonism respectively. In this study, these properties are

correlated with the electronic and conformational results. The electronic

properties of the fused ring skeleton including specifically the cationic

region around the nitrogen are relatively unaffected by varying N-substituents. The properties studied include net charges, bond polarities, and

the nature and energy of the highest filled and lowest empty molecular

orbitals. The conformationai behavior appears to be the main cause of

differing receptor binding and interaction with the active site and is discussed in these terms.

LOH, H.H., HITZEMANN, R.J. and WAY, E.L. Effect of acute morphine administration of the metabolism of brain catecholamines. Life Sciences 12(Part

I): 33-41 (1973)

The effects of sub-analgetic and analgetic doses of morphine (5-20

mg/kg) on the metabolism of intravenously administered (

14C)-tyrosine

(200 uCi/kg) in the mouse brain were investigated. A significantly increased conversion of (

14C)-tyrosine to the (14C)-catecholamines was

observed only at an analgetic dose of morphine. Furthermore, morphine

increased the specific activity of brain (

14C)-tyrosine and this effect was

blocked by naloxone. a morphine antagonist.

LOMAX, P., GROSS, S.J. and CAMPBELL, C. Immunological blockade of the

hypothermic effect of delta-9-tetrahydrocannabinol in the rat.

Pharmacology of Thermoregulation. Edited by E. Schenbaum and P. Lan.

Basel, Switzerland: Karger, 1973. Pp. 488-490.

LOPATIN, D.E., WINKELHAKE, J.L. and VOSS, E.W., JR. Immunochemical

characterization of lysergyl derivative incorporated into protein.

Molecular Pharmacology 10(5): 767-775 (September, 1974)

A derivative of d-lysergic acid diethylamide (LSD), lysergylder,

previously shown to be covalently coupled to secreted low molecular weight

peptides, was shown during incubation in vitro of immune lymphoid cells

with LSD to possess structural features closely resembling the parent

molecule. Binding studies of LSD and lysergylder ligands with antibodies

directed against both lysergic acid and lysergylder suggested that both antibodies

possessed similar specificity. (

3H)LSD and (3H)lysergylder were bound by

anti-lysergyl antibody with average intrinsic a-sociation constants (Ko) of

3.5 X 105 M-1 and 7.8 X 105

 M-1, respectively. Both ligands were bound

by anti-lysergylder antibody with Ko values of 1-2 X 105 M-1. Single-point

equilibrium dialysis experiments indicated that both antibody populations

bound the derivative in preference to LSD. Mild alkaline hydrolysis of LSD

was shown to generate a molecular species which was bound by anti-lysergylder

antibody with the same energy as lysergylder. Alkaline hydrolysis had no

effect on lysergylder. These data suggest generation of a demethylated

derivative of LSD during incubation of LSD in vitro.

141
LYNN, R.K., SMITH, R., OLSEN, G.D., LEGER, R.M. and GERBER, N.

Studies of the metabolism of methadone (M) and methodology for isolation

and quantification of the drug and its primary metabolite, 2-ethylidene1, 5-dimethyl-3, 3-diphenylpyrrolidine (P) using gas chromatography (GC)

and mass spectrometry (MS). Federation Proceedings (in press)

For abstract, see Section I. Methodology of Drug Research.

McISAAC, W.M. Pharmacologic Studies on the Structure-Activity Relationship of

Indolealkylamines. New York: Academic Press, 1969. Pp. 247-268.

McISAAC, W.M. Preliminary metabolism on 3H-STP in the rat and rabbit.

Advances in Mental Science, Drug Dependence. Austin, Texas:

University of Texas Press, 1972. Pp. 21-23.

McISAAC, W.M., HARRIS, R.T. and HO, B.T. Behavioral correlates of brain

distribution of tetrahydrocannabinol. Acta Pharmaceutics Suecica 8:

671-706 (1971)

McMILLAN, D.E., DEWEY, W.L., TURK, R.F., HARRIS, L.S. and MCNEIL, J.H., JR.

Blood levels of 3H-delta-9-tetrahydrocannabinol and its metabolites in

tolerant and nontolerant pigeons. Biochemical Pharmacology 22: 383-397

(1973)

Pigeons were made tolerant to the behavioral effects of l-delta-9-

trans-tetrahydrocannabinol (delta-9-THC) by repeated intramuscular injections. The tolerant birds. as well as birds that had not received

delta-9-THC previously, were injected with 3H-delta-9-THC and blood

samples were drawn over a period from 1 min to 2 weeks after injection.

High levels of radioactivity appeared in the blood 1 min after injection

and peak levels were reached in 30 min. after which there was a gradual

decline with some radioactivity still present after 2 weeks. The levels of

radioactivity in the petroleum ether-extractable fraction (mostly delta-9-

THC by thin-layer chromatography (TLC)), in the diethyl ether-extractable

fraction (mostly hydroxylated metabolites by TLC), and in the residue

fraction of the plasma were also determined over the 2-week period. There

were no differences between tolerant and nontolerant birds in levels of

radioactivity in total plasma, or in any of the plasma fractions. In other

experiments, seven injections of 3H-delta-9-THC were given to pigeons

over a 2-week period during which behavioral tolerance developed. Radioactivity gradually accumulated in the plasma of these birds: however, most

of the radioactivity was accounted for in the residue fraction, with levels of

radioactivity in the petroleum ether-extractable fraction and the diethyl

ether-extractable fractions remaining at about the same levels after seven

injections as after one injection. These results suggest that tolerant birds

handle an injection of delta-9-THC in much the same manner as nontolerant

birds, and that levels of delta-9-THC and its metabolites are as high as or

higher in the blood of tolerant birds than they are in the blood of nontolerant

birds. Thus, tolerance to delta-9-THC in the pigeon does not appear to be

metabolic in origin.

142
McMONIGLE. J.J, and HORITA, A. Bioactivation of 5-oxo-(D-trans-2-phenylcycloprophyl)-

L-2 pyrrolidone carboxamide( EX 4883) into monoamine oxidase inhibitor by a

soluble fraction enzyme system. Archives internationales de Pharmacodynamie et de

Therapie 178(1): 53-61 (March, 1969)

Numerous studies have emphasized that many drugs undergo biochemical

transformation, and the resulting metabolites may be different chemically as well

as producing different pharmacological actions. Included among these drugs are

several monoamine oxidase (MAO) inhibitors, such as modaline (1,3) and

furazolidone (6). The present paper describes another MAO inhibitor which

appears to require biotransformation prior to its exerting anti-MAO activity.

This was surmised when the compound 5-oxo-N-(D-trans-2-phenylcyclopropyl)-

L-2-pyrrolidone carboxamide (EX 4883) was examined as a MAO inhibitor and

found to be active in liver homogenates but not in isolated liver mitochondria.

This study was undertaken to prove that EX 4883 is bioactivated prior to exerting

its anti-MAO action, and to examine the characteristics of the bioactivating

system.

MAICKEL. R.P., BRAUNSTEIN, M.C., McGLYNN, M., SNODGRASS, W.R. and WEBB,

R.W. Behavioral, biochemical, and pharmacological effects of chronic dosage

of phenothiazine tranquilizers in rats. The Phenothiazines and Structurally

Related Drugs. Edited by I.S. Forrest, C.J. Carr and E. Usdin. New York:

Raven Press, 1974.

For abstract, see Section I. Methodology of Drug Research.

MAICKEL, R.P., FEDYNSKYJ, N.M., POTTER, W.Z. and MANIAN, A.A. Tissue

localization of 7- and 8-hydroxychlorpromazines. Toxicology and Applied

Pharmacology 28: 8-17 (1974)

For abstract, see Section I. Methodology of Drug Research,

MAICKEL, R.P. and HARRISON, S.D., JR. Inability of rat brain homogenate to oxidize

amphetamine. Biochemical Pharmacology 23:1146-1147 (1974)

MANDELL. A.J. Frontiers in the neurobiology of euphoria. American Handbook of

Psychiatry, Vol. VI. Edited by S. Arieti, D.A. Hamburg and H.K. H. Brodie.

New York: Basic Books, 1972.

For abstract, see Section I. Methodology of Drug Research.

MANDELL, A.J., editor. New Concepts in Neurotransmitter Regulation. New York:

Plenum Press, 1973.

Proceedings of a conference on drug abuse and metabolic

regulation of neurotransmitters, La Jolla, California, July, 1972.

MANDELL. A.J., SEGAL, D.S. and KUCZENSKI, R. Metabolic adaptation to antidepressant drugs -- A neurochemical paradox. Catecholamines and Behavior.

Edited by A. Friedhoff. New York: Plenum Press, 1974.

MANDELL, A.J., SEGAL. D.S. and Kuczenski. R. Metabolic adaptation to antidepressant

drugs -- Implications for pathophysiology and treatment in psychiatry.

Catecholamines and Behavior. Edited by A. Friedhoff. New York: Plenum Press, 1974.

143
MANNO, B.R. and MANNO. J.E. The marihuana dilemma: Has it been resolved?

Toxicology Annual. Edited by C.L. Winek. New York: Marcel Dekker, Inc.

(in press)

MANNO. J., MANNO. B., WALSWORTH, D. and HERD, R. Analysis and interpretation of

the cannabinolic content of confiscated marihuana samples. Journal of Forensic

Sciences 19(4): 844-890 (1974)

For abstract, see Section I. Methodology of Drug Research.

MARCH, J.E., DONATO, D., TURANO, P. and TURNER, W.J. Interpatient variation

and significance of plasma levels of chlorpromazine in psychotic patients.

Journal of Medicine 3:146-162 (1972)

Blood plasma from 50 chronic schizophrenics under long-term

therapy with chlorpromazine was examined at 1.5 h after a morning dose and

12-15 h after an evening dose of medicine. The daily dose ranged from 150 to

3, 600 mg. Extractions were carried out with dichloromethane. The extracts

were shaken with 2.5 ml H2SO4-Fe3+ color reagent, and the absorbance read

at 530 nm. The limit of sensitivity using 20 ml of plasma was 0.15 mu-g/ml,

at which level the plasma concentration of chlorpromazine and its

metabolites in patients on 150 mg/day was measurable both at 1.5 and 12 h after

medication. There was wide variation in plasma levels between individuals.

As dose increased so did the levels at 1.5 and 12 h. Implications for clinical

studies are discussed.

MARSHALL, I. and SMITH, C.B. The role of tyrosine hydroxylase in changes in brain

catecholamine synthesis after acute and chronic administration of morphine to

mice. Committee on the Problems of Drug Dependence. Washington, D.C.:

National Academy of Sciences, National Research Council, 1973. P. 351.

MARTIN, B.R., DEWEY, W.L. and HARRIS, L.S. Pharmacology of marihuana

constituents. Virginia Journal of Science 25: 101 (1974)

Delta-8- and delta-9-tetrahydrocannabinol (THC), the active constituents

of marihuana, are rapidly converted in vivo to their 11-hydroxy metabolites. It

has been postulated that 11-hydroxylation of THC is a prerequisite to behavioral

and pharmacological activity. We have accumulated evidence which indicates

that delta-9-THC itself may be active. Thirty minutes after the intravenous

injection of H

3

-delta-9-THC (0.5 mg/kg) dogs were sacrificed, and the brains

were removed, homogenized and extracted with petroleum ether and diethyl

ether. Thin layer chromatography of these extracts revealed that 41% of the radioactivity was unchanged due to delta-9-THC. TLC of extracts from fetal dog brains

showed that 60% of the radioactivity was unchanged delta-9-THC. The presence

of high quantities of delta-9-THC and very low quantities of 11-hydroxy-delta-9-THC

in dog brain at the time of peak activity do not support the hypothesis that only the

11-hydroxy metabolite is active. In addition, two analogs of delta-8-THC, 11-methyland 9-nor-delta-8-THC, were investigated for cannabinoid-like activity. 11-methyldelta-8-THC is probably not converted to 11-hydroxy-delta-8-THC; whereas, 9-nordelta-8-THC cannot be. In the unanesthetized dog, these analogs produce a

cannabinoid-like effect on overt behavior. The intravenous minimal effective doses

are 0.1-0.2 mg/kg for both delta-8-THC and delta-g-nor delta-8-THC, and 0.8-1.0

mg/kg for 11-methyl-delta-8-THC. In the anesthetized dog 9-nor-delta-8-THC

is as effective as delta-8-THC in producing bradycardia and hypotension: whereas,

11-methyl-delta-8-THC is less effective.

144
MARTIN, B.R., DEWEY, W.L. and HARRIS, L.S. Subcellular distribution of 3H-delta9-tetrahydrocannabinol in brains of nontolerant and tolerant rats. Proceedings

of the Sixth International Congress of Pharmacology, Helsinki, Finland,

July 20-25, 1975 (in press)

An i.p. injection of 10 mg/kg of delta-9-THC produced significant

hypoactivity in rats. Tolerance to this effect was not observed following 6

but was seen after both 12 and 19 daily injections. The distribution of

radioactivity one hour after the i.p. administration of 10 mg/kg of 3H-delta-9-

THC was investigated in three groups of rats. One group had not been previously pretreated (naive), and the others had received either 6 or 19 daily

injections of unlabeled delta-9-THC. There were no significant differences in

plasma levels of radioactivity among the three groups. The radioactivity in

the brains from naive rats was distributed among the following subcellular

fractions: 25% in crude nuclear, 49% in crude mitochondria (CM), 8% in

microsomes (MS), and 8% in supernatant (S). Cholinergic synaptosomes,

noncholinergic synaptosomes, and synaptic vesicles were isolated from CM,

and they contained 15%, 16%, and 12%, respectively, of the brain radioactivity,

The brain subcellular distribution of radioactivity was similar for all three

groups. The most notable exceptions were the MS and S fractions of the

pretreatment groups which contained significantly more radioactivity than did

those of the naive group. As tolerance developed, there was no reduction in

the concentration of radioactivity in the synaptic vesicles. We have previously

reported that the development of tolerance to delta-9-THC in dogs was

associated with a significant decrease in the quantity of radioactivity found in

the synaptic vesicle fraction.

MARTIN, B.R., DEWEY, W.L., HARRIS, L.S. and BECKNER, J. Marihuana-like

activity of new synthetic tetrahydrocannabinols. Pharmacology

Biochemistry and Behavior (in press)

The pharmacological profile and potency of 11-Methyl-delta-8,

9-nor-delta-8, and 9-nor-delta-9-tetrahydrocannabinol in laboratory

animals was similar to that of delta-8- and delta-9-tetrahydrocannabinol.

Each produced static-ataxia in unanesthetized dogs, bradycardia and

hypotension in anesthetized dogs, and decreased spontaneous activity in

mice. Two of these analogs cannot be converted to 11-hydroxy metabolites

which indicates that 11-hydroxylation of delta-8- or delta-9-tetrahydrocannabinol

may not be a prerequisite for biological activity of tetrahydrocannabinols.

MARTIN, B.R., DEWEY, W.L., HARRIS, L.S. and BECKNER, J.S. Subcellular

localization of H

3

-delta-9-tetrahydrocannabinol in dog brain after acute or

chronic administration. The Pharmacologist 16(2): 395 (1974)

To ascertain if an alteration in the cellular or subcellular

localization of delta-9-tetrahydrocannabinol (THC) in brain is responsible

for tolerance, dogs received either one IV injection of 0.5 mg/kg of H

3

-THC

(70 mu-c/mg) or six daily IV injections of 0.5 mg/kg of THC followed by an

injection of H

3

-THC. Dogs were sacrificed 30 min. after the injection of

H

3

-THC, and their brains were removed for cellular and subcellular localization of H

3

-THC. The pattern of distribution of radioactivity was similar

for both groups of dogs. The greatest amount of radioactivity was in

rostral and caudal colliculi, pituitary, hippocampus, thalamua, and geniculate

bodies. Radioactivity in the gray matter of the cerebral cortex and

cerebellum was 70.4 DPM/mg of tissue, whereas only 38.1 DPM/mg was

found in the white matter. Also, the localization of radioactivity in the subcellular fractions was similar for both groups. The subcellular localization

for the cerebral cortex was as follows: crude nuclear fraction (20%), crude

mitochondrial (45%), microsomal (11%), and supernatant (15%). Thin layer

chromatography of pet, ether and diethyl ether extracts of cerebral cortex

showed that greater than 40% of the radioacitivy was unchanged THC.

145
MARTIN, B.R., HARRIS, L.S. and DEWEY, W.L. Behavioral and pharmacological

properties of 11-methyl- and 9-nor-delta-8-tetrahydrocannabinol.

Federation Proceedings 33: 540 (1974)

It has been demonstrated that delta-8-tetrahydrocannabinol (THC)

is rapidly metabolized to 11-hydroxy-delta-8-THC in the body, and it has

been postulated that this metabolite is responsible for the activity of delta8-THC. We have investigated the pharmacological properties of two

analogs of delta-8-THC, 11-methyl- and 9-nor-delta-8-THC. The former

is probably not converted to an 11-hydroxy metabolite, the latter cannot be.

In the unanesthetized dog these analogs produce prance-like placement of

feet, static ataxia, hyperreflexia and a decrease in spontaneous activity.

This profile of behavior is the same as that seen after delta-8- or delta9-THC. The intravenous minimal effective doses are 0.2-0. 4 mg/kg

for both delta-8-THC and 9-nor-delta-8-THC and 0.8-1.0 mg/kg for 11-

methyl-delta-8-THC. In the anesthetized dog 9-nor-delta-8-THC is

again as effective as delta-8-THC in producing bradycardia and

hypotension: as before, 11-methyl-delta-8-THC is somewhat less

effective. In mice delta-8-THC, 9-nor-delta-8-THC, and 11-

methyl-delta-8-THC have no effect on hexobarbital-induced sleeping time

and exhibit no antinociceptive activity as measured in the tall flick or hot

plate test. Each compound has some activity in the phenylquinone

writhing test, delta-8-THC being more active than either analog.

MECHOULAM. R. Cannabinoid chemistry. Marijuana. Chemistry, Metabolism,

Pharmacology and Clinical Effects. Edited by R. Mechoulam.

New York: Academic Press, 1973. Pp. 1-88.

MECHOULAM, R. Chemistry and cannabis activity. Ciencia e Cultura 25(8): 742 (1973)

MECHOULAM, R. Marihuana chemistry. Review. Science 168: 1159 (1970)

MECHOULAM, R., BEN-ZVI, Z., AGURELL, S., NILSSON, I.M., NILSSON. J.L.G.

EDERY, H. and GRUNFELD. Y. Delta-6-tetrahydrocannabinol-7-oic acid,

a urinary delta-6-THC metabolite: Isolation and synthesis. Experientia

29: 1193 (1973)

MECHOULAM, R., BEN-ZVI, Z. and GAONI, Y. Hashish XIII.On the nature of the

Beam test. Tetrahedron Letters 24: 5615 (1968)

The purple colour produced by treatment of cannabidiol (1) with 5%

ethanolic potassium hydroxide (Beam test) is due to the anions of the

hydroxy-quinone II and its dimer III. Compounds II and III are formed from I

by air oxidation during the reaction. The diquinone III is reduced in the mass

spectrometer to a M

+

 + 4 species (probably the dihydroquinone).

MECHOULAM, R., BEN-ZVI, Z., SHANI, A., ZEMLER, H., LEVY, S., EDERY, H.

and GRUNFELD. Y. Cannabinoids and cannabis activity. Cannabis and Its

Derivatives. Pharmacology and Experimental Psychology. Edited by W.D.M.

Paton and J. Crown. Fairlawn, New Jersey: Oxford University Press, 1972.

146
MECHOULAM. R., BEN-ZVI, Z., VARCONI, H. and SAMUELOV, Y. Cannabinoid

rearrangements. Synthesis of delta-5-tetrahydrocannabinol. Tetrahedron Letters

29: 1615-1619 (1973)

1-beta, 6-beta-Epoxy-hexahydrocannabinol acetate (1) in the presence

of borontrifluoride rearranged to 6-oxo-hexahydrocannabinol acetate and to the

aldehyde. Hydroboration of delta-6-THC gave the 6-hydroxy hexahydrocannabinols

and 8a. The latter was converted into delta-5-THC. This THC isomer shows no

cannabis-type activity in rhesus monkeys.

MECHOULAM, R., BEN-ZVI, Z., YAGNITINSKY. B. and SHANI, A. A new

tetrahydrocannabinolic acid. Tetrahedron Letters 28: 2339 (1969)

MECHOULAM, R., BRAUN, P. and GAONI, Y. Hashish XI. A stereospecific synthesis

of (-)-delta-1- and (-)-delta-1(6)-tetrahydrocannabinol. Journal of the American

Chemical Society 89: 4551 (1967)

MECHOULAM, R., BRAUN, P. and GAONI, Y. Syntheses of delta-1-tetrahydrocannabinol

and related cannabinoids. Journal of the American Chemical Society 94: 6159 (1972)

Addition of citral to the lithium derivative of olivetol dimethyl ether,

followed by reaction with p-toluenesulfonyl chloride, gave (±)-cannabidiol dimethyl

ether. Demethylation afforded (±)-cannabidiol, which was converted into

(±)-delta-1-tetrahydrocannabinol (delta-1-THC) in a low overall yield. An improved

synthesis of (±)-delta-1-THC was achieved by the reaction of citral with olivetol in

the presence of 1% boron tri-fluoride etherate. Reaction of (+)- or (–)-verbenol with

olivetol under the same conditions gives (+)- or (–)- delta-6-THC, respectively.

This reaction can be further improved (to 48%) by a stepwise synthesis through the

intermediate 4 trans-(2-olivetyl) pinene. Addition of hydrogen chloride to the double

bond of (+)-or (–)-delta-6-THC, followed by dehydrochlorination, leads to (+)- or

(–)-delta-1-THC. A method for the preparation of (3-2H)-delta-1-THC is described.

MECHOULAM, R. and EDERY. H. Structure-activity relationships in cannabinoid series.

Marijuana. Chemistry, Metabolism, Pharmacology and Clinical Effects. Edited

by R. Mechoulam. New York: Academic Press, 1973. Pp. 101-133.

MECHOULAM, R. and GAONI, Y. Hashish X. The absolute configuration of delta-1-

tetrahydrocannabinol, the major active constituent of hashish. Tetrahedron

Letters 12: 1109-1111 (1967)

MECHOULAM, R. and GAONI. Y. Recent advances in the chemistry of hashish. Review

article. Progress in the Chemistry of Organic Natural Products. (Fortschritte

der Chemie Organischer Naturstoffe). Edited by L. Zechmeister. New York:

Springer-Verlach-Verlag, 1967.

MECHOULAM, R., SHANI, A., YAGNITINSKY, B., BEN-ZVI, Z., BRAUN. P. and GAONI,

Y Some aspects of cannabinoid chemistry. Botany and Chemistry of Cannabis. .

Edited by C.R.B. Joyce and S.H. Curry. London, England: 7. and A. Churchill,

1970. Pp. 93-117.

MECHOULAM, R., VARCONI. H., BEN-ZVI, Z., EDERY, H. and GRUNFELD, Y.

Synthesis and biological activity of five tetrahydrocannabinol metabolites.

Journal of the American Chemical Society 94: 7930 (1972)

147
MECHOULAM, R. and YAGEN. B. Stereoselective cyclizations of cannabinoid 1,5 dienes.

Tetrahedron Letters 60: 5349 (1969)

MECHOULAM, R., YAGNITINSKY, B. and GAONI, Y. Hashish XII. Stereoelectronic

factor in the chloranil dehydrogenation of cannabinoids. Total synthesis of

dl-cannabichromene. Journal of the American Chemical Society 90: 2418 (1968)

MEDZIHRADSKY, F., MARKS, M.J. and CARR, E.A., JR. Energy-dependent uptake of

benzomorphans by leukocytes. Biochemical Pharmacology 21: 1625-1632 (1972)

Pentazocine rapidly enters the brain after i.p. administration to rats.

Using leukocytes as model mammalian cells, the uptake of this drug was studied,

Morphologically intact and metabolically active rat leukocytes accumulated

pentazocine in vitro against a concentration gradient. The 6- to 10-fold

concentration of the drug was dependent upon the presence of glucose in the

incubation medium and was strongly affected by metabolic inhibitors present

in millimolar concentrations. The uptake showed saturation kinetics in the

concentration range of 1.7-14 X 10-5 M pentazocine and was competitively

inhibited by analogue benzomorphan derivatives. Ouabain as well as sodiumfree extracellular media had no effect on the uptake of pentazocine. The

transport system for pentazocine in the leukocyte apparently differs from the

relatively nonspecific amine pump which accumulates various organic bases

in the blood platelet.

MEDZIHRADSKY. F., MARKS, M.J. and METCALF, J.I. Cellular transport of CNS

drugs in leukocytes. Biochemical Advances in Psychopharmacology (in press)

MEDZIHRADSKY. F. and NANDHASRI. P.J. Effects of some analgesics and

antidepressants on the (Na+ + K+)--adenosine triphosphatase from

cortices of brain and kidney. Biochemical Pharmacology 21: 2103-

2109 (1972)

The effects of benzomorphans, tricyclic antidepressants, monoamine

oxidase (MAO) inhibitors and chlorpromazine on the microsomal (Na+ + K

+

)-

adenosine triphosphatase (ATPase) from beef cerebral cortex were studied.

As a comparison, the interaction of these drugs with the corresponding

enzyme from kidney cortex as also investigated. In addition to

chlorpromazine, the benzomorphans and the tricyclic antidepressants inhibited

the brain enzyme considerably, whereas the MAO inhibitors had little

effect. The (Na+ + K

+

)-ATPase from kidney was not affected by the

benzomorphans or MAO inhibitors, but its activity diminished in the presence

of the tricyclic antidepressants and chlorpromazine.

MELIKIAN, A.P. and FORREST, I.S. Dansyl derivatives of delta-9- and delta-8-

tetrahydrocannabinols. Journal of Pharmaceutical Sciences 61: 1025-1026 (1973)

MELIKIAN, A.P., GREEN. D.E., SKINNER, J.L. and FORREST, I.S. Isolation of

in vivo delta-9-tetrahydrocannabinol metabolites from primate urine.

Proceedings of the Western Pharmacological Society 16: 234-239 (1973)

148
MEYERHOFF, J.L. and SNYDER, S.H. Gilles de la Tourette’s Disease and minimal

brain dysfunction: Amphetamine isomers reveal catecholamine correlates

in an affected patient. Psychopharmalogia 29: 211-220 (1973)

Graduated doses of d- and l-isomers of amphetamine were

administered on several occasions in double blind fashion to a patient with’

symptoms of both Gilles de la Tourettes disease and minimal brain

dysfunction. d-Amphetamine markedly increased the frequency of ticking

while l-amphetamine did not alter the tics. By contrast both isomers

decreased the patient’s hyperactivity to a similar extent. Based on the

known differential influence of amphetamine isomers upon brain

norepinephrine and dopamine, these findings suggest that aggravation of

the tics is mediated by brain norepinephrine, while brain dopamine

plays a major role in the alleviation of the symptons of minimal brain

dysfunction.

MILLER, R.J., JOLLES, C. and RAPOPORT. H. Morphine metabolism and

normorphine in papaver somniferum. Phytochemistry 12: 597 (1973)

MISRA, A.L., BLOCH, R., VADLAMANI, N.L. and MULE, S.J. Physiological

disposition and biotransformation of levo-methadone-1-3H in the dog.

The Journal of Pharmacology and Experimental Therapeutics

188(1): 34-44 (1974)

A method with minimal sensitivity of 1 to 2 ng, previously developed

for levo-methadone after small doses has been used to estimate this drug in

selected anatomical areas of the central nervous system and the peripheral

tissues of the dog. After a 2 mg/kg (free base) s.c. dose of levo-methadone1-3H to the dog, peak levels of drug in plasma (143 ng/ml) and in different

anatomical areas of the central nervous system (1270-2029 ng/g) occurred

at two hours. Measurable quantities of drug persisted in different areas of

the dog brain and peripheral tissues for at least three weeks. At the same

time the concentrations in plasma were barely detectable at periods of one

and three weeks after drug administration. High levels of methadone were

observed in lung, liver, spleen, kidney, heart and intestine with somewhat

lower concentrations in muscle and fat. The approximate half-life of levomethadone in dog plasma after a 2 mg/kg s.c. dose was six to seven hours

and that in temporal cortex, hypothalamus, cerebellum and caudate nucleus

ranged between three and four hours. The mean percentages of free drug

excreted in the urine and feces of dogs 96 hours after a single 2 mg/kg s. c.

dose were 19.4%. conjugated acid-hydrolyzable metabolites, 5.4% and

total radioactivity, 68.3%. The values of conjugated metabolites and total

radioactivity in dogs given chronic injections of methadone were significantly

lower than those in acute animals. levo-Methadone was extensively

metabolized by: 1) N-dealkylation and cyclization to substituted pyrrolidine

and pyrroline metabolites; 2) N-oxidation; 3) hydroxylation in the para

position of the aromatic nucleus; 4) keto group reduction; 5) glucuronide

conjugation of resultant hydroxyl groups; and 6) minor conversion of secondary

and primary amines. Persistence of levo-methadone and a metabolite in

selected anatomical areas of the central nervous system of the dog and the

binding of the metabolite to a specific brain protein could conceivably lead to

a biochemical alteration of the receptor site and result in a reduced ability

of the drug to initiate a pharmacological response. Possible relevance of

these observations to the phenomena of pharmacological tolerance and the

protracted course of the withdrawal syndrome observed with methadone are

described.

149
MISRA. A.L. and MITCHELL, C.L. Determination of morphine-N-methyl-C14oxide

in biological materials, its excretion and metabolites in the rat. Biochemical

Medicine 5: 379-383 (1971)

A method for determination of morphine -N-methyl-14C oxide in

biological materials has been described which gave approximate recoveries

of N-oxide as 94, 82, and 77% from urine or plasma, liver and brain tissue,

respectively. On subcutaneous injection of 20 mg/kg of morphine N-methyl-14Coxide, male Sprague-Dawley rats excreted 80.6-91.5% of total radioactivity

in urine and feces, 19.6-41.2% as free N-oxide, 6.2-24.3% as free morphine

and 3.6-6.9% as morphine-3-glucuronide. Column and thin-layer

chromatography established morphine, morphine-3-glucuronide, and

normorphine (5-10%) as principal urinary metabolites of morphine N-oxide in

the rat. Evidence for the formation of N-oxide as a metabolite of morphine in

the central nervous system of rats was not obtained. Morphine N-oxide can be

converted nonenzymatically to morphine and normorphine by ferrous iron and

cysteine.

MISRA, A.L. and MITCHELL, C.L. Metal ion-catalyzed interaction of peroxidase

with morphine and protein. Experientia 27: 1442-1444 (1971)

MISRA, A.L., MITCHELL, C.L. and WOODS, L.A. Persistence of morphine in

the central nervous system after a single injection and its bearing on

tolerance. Nature 232: 48-50 (1971)

MISRA, A.L. and MULE, S.J. Persistence of methadone-3H and metabolite in rat

brain after a single injection and its implications on pharmacological

tolerance. Nature 138: 155-156 (July, 1972)

MISRA, A.L. and MULE, S.J. Stereoselectivity and differential metabolism in vivo

of dextro and laevo-methadone-1-3H. Nature 241: 281-283 (January, 1973)

150
MISRA, A.L., MULE. S.J., BLOCH, R. and VADLAMANI, N. L. Physiological

disposition and metabolism of Levo-methadone-1-3H in nontolerant and

tolerant rats. The Journal of Pharmacology and Experimental

Therapeutics 185(2):287-299 (1973)

A method is described for the estimation of levo-methadone-1-3H in biological materials which has a minimal sensitivity of 1 to 2 ng. After a dose of levo -

methadone-1-3H 10 mg kg s.c., to male Wistar rats, the mean peak levels were 1798

ng/ml in plasma at 0.5 hour and 4502 ng/g in brain at 1 hour, respectively.

Measurable quantities of drug persisted in brain (20 ng/g)) and other tissues

up to three weeks or longer, even though no measurable amounts of drug

were present in plasma after 24 hours. Orally administered drug (10 mg/

kg) produced levels in plasma and brain approximately 1/25 of those

observed after subcutaneous injection. The drug was localized in lung,

liver, kidney and brain, with lower concentrations in heart and muscle.

The mean percentages of free drug excreted in 96-hour urine and feces

after injection of 10 mg/kg s.c. were 11.37 and 14.78, respectively.

The total radioactivity values in urine and feces were 19.49% and 29.8%,

respectively. After an injection of 10 mg/kg s.c., the concentrations of

drug in brain and plasma of tolerant rats were consistently lower than

those in nontolerant rats at each time interval. After oral administration

of methadone (50 mg/kg), the concentrations at 0.5 and 1 hour in brain and

plasma of tolerant rats were higher and subsequently dropped to values

lower than those observed in the nontolerant rats. The approximate halflives of drug in brain and plasma of nontolerant rats after 10 mg/kg s.c.

injections were 2. 4 and 3. 7 hours, respectively, and in tolerant rats 1.5

and 1.7 hours, respectively. By the oral route (50 mg/kg), half-lives in

brain and plasma of nontolerant rats were approximately 14 and greater

than 8 hours respectively, and in tolerant rats, 3.1 hours in brain and

1.4 hours in plasma. The rate of disappearance of drug from plasma

and brain was faster in the tolerant rats and there was evidence for a

faster rate of metabolism of drug in these animals. The drug was

extensively metabolized and in addition to known substituted pyrrolidine,

pyrroline and N-oxide metabolites, evidence of six other phenolic

glucuronide-conjugated amines was obtained. Four had the characteristics

of a phenolic teritary amine, one a secondary amine and the other a primary

amine, respectively. Evidence for the presence of a phenolic primary

methadone metabolite with structural similarity to norepinephrine was

obtained in rat brains at the time of peak analgesia. Later, this metabolite

conjugated with protein persisted in brain along with free methadone.

These observations, coupled with consistent differences in physiological

disposition of methadone in brain and plasma of nontolerant and tolerant

rats. may have relevance to the mechanism of pharmacological tolerance

and the protracted withdrawal syndrome observed with methadone.

MISRA, A.L., VADLAMANI, N.L., MULE, S.J. Chromatographic separation of

methadone, some of its metabolites and congeners. Journal of

Chromatography 67: 379-381 (1972)

MOLE, M.L., JR. and TURNER, C.E. Phytochemical screening of Cannabis

sativa L. H. Choline and neurine in the roots of a Mexican variant.

Acta Pharmaceutica Jugoslavica 23(4): 203-205 (1973)

For abstract, see Section I. Methodology of Drug Research.

151
MULE S.J., CASELLA, G. and CLOUET, D.H. The localization of levo-H3

-methadone

in isolated synaptic membranes of rat brain. Committee on Problems of Drug

Dependence. Washington, D.C.: National Academy of Sciences, National

Research Council, 1972.

It certainly appears from these studies that a degree of specificity

is associated with localization of 3H-methadone in the mu 1 (1.0) synaptic

membrane fraction of brain. The extent of this specificity especially in relation

to the narcotic receptor is now under investigation.

MULE. S.J. and CLOUET, D.H. Pharmacological and biochemical aspects of opiate

dependence. Psychopharmacologia 26: 116 (1972)

The chronic use of narcotic analgesic drugs induces a drug-dependent

state that has distinguishing characteristics which are quite different from the

characteristics of the dependence induced by the use of other classes of drugs.

In order to define the opiate-dependent state, objective criteria which

characterize physiological and psychological dependence will be described.

The chemical aspects of narcotic drug action will be considered including

localization of opiates in subcellular sites in the brain, the possible relation

of this localization to the opiate receptor, biotransformation of drugs, and its

correlation with pharmacological action. With this background the theories

associated with the development of tolerance, physical and psychic dependence,

such as pharmacological denervation supersensitivity, pharmacological

redundancy, silent and active receptors, depression and repression of enzymes,

macromolecular biosynthesis, and the role of neurotransmitters with special

emphasis upon norepinephrine, acetylcholine, dopamine and serotonin will be

discussed, as will the role of physical dependence in the perpetuation of drugseeking behavior and its relationship to relapse.

MULE. S.J. and MISRA, A.L. Disposition and metabolism of levo-methadone-1-methyl3H in the rat. Federation Proceedings 31: 528 (1972)

NIELSEN, M., EPLOV, L. and SCHEEL-KRÜGER. J. The effect of amitriptyline.

desipramine and imipramine on the in vivo brain synthesis of 3H-L-dopa

in the rat. Psychopharmacologia (in press)

152
NIELSEN, M. The effects of amitriptyline, desipramine, imipramine and protriptyline on

the in vivo brain synthesis of 3H-noradrenaline from 3H-1-dopa in the rat.

Acta Pharmacologica et Toxicologica 35(Supplement I): 43 (1974)

In rats 3H-L-DOPA was given after a peripheral decarboxylase inhibitor

Ro 4-4602 (50 mg/kg) and the effect of 30 min pretreatment with amitriptyline

(10 mg/kg), desipramine (10 mg/kg), imipramine (10 mg/kg) or protriptyline

(10 mg/kg) on the brain formation of 3H-dopamine (3H-DA), 3H-noradrenaline

(3H-NA) and their major metabolites was investigated. Protriptyline, desipramine

and imipramine produced a decrease in the brain level of labelled noradrenaline

and its metabolites 3-methoxy-4-hydroxyphenylglycol and 3,4-dihydroxyphenylglycol

60 min after 3H-L-DOPA. These findings thus strongly indicate that protriptyline,

desipramine and imipramine inhibit 3H-NA synthesis from 3H-L-DOPA. Amitriptyline

produced no effect on 3H-NA metabolism.

The accumulation of labelled dopamine and its metabolites was increased

by amitriptyline, while the other thymoleptics showed only tendencie to increase

3H-DA accumulation and metabolism. The thymoleptic drugs produced no

significant effect on endogenous brain noradrenaline and dopamine.

Experiments on the effect of tricyclic antidepressant drugs on central

3H-NA metabolism with the use of 3H-L-Tyrosine, 3H-DA or 3H-NA as labelled

precursors are in progress.

NILSSON, I.M., AGURELL, S., NILSSON, J.L.G., OHLSSON, A., LINDGREN. J.E.

and MECHOULAM, R. Metabolism of 7-hydroxy-delta-1(6)-tetrahydrocannabinol

in the rabbit. Acta Pharmaceutica Suecica 10:97 (1973)

The distribution, conversion and elimination of 7-hydroxy-delta-1(6)-

THC-3H has been studied in the rabbit. The compound was quickly distributed

from the blood after i.v. injection and rapidly converted to metabolites. After

10 min. less than half of the radioactivity in blood was due to the originally

administered compound.

NILSSON, J.L.G., NILSSON, I.M., AGURELL. S., BEN-ZVI, Z. and MECHOULAM, R.

Synthesis of a potential urinary THC metabolite. Acta Pharmaceutica Suecica

9:215 (1972)

7-Hydroxy-delta-1, 6-THC was methylated on the phenolic hydroxyl

groups whereupon the hydroxymethyl group was oxidized, using chromic acid

or MnO2 to the corresponding crystalline aldehyde 7. This was further

oxidized to the corresponding carboxylic acid methyl ester 8 using MnO2 and

NaCN in methanol. When the ester 8 was compared chromatographically with the

methylated acidic metabolites of delta-1-THC, the metabolite(s) turned out to be

more polar than the synthetic compound, indicating that the metabolite(s) appear

to have more polar groups than the synthetic molecule.

153
PAL, B.K., GOLDSTEIN, A. and LOWNEY, L. Stereospecific binding of the morphine

congener levorphanol by mouse brain preparations. Federation Proceedings

30: 272 (1971)

Since the pharmacological effects of opiates are highly stereospecific

(only D(-) isomers are active), the present investigation was undertaken to

study the stereospecific binding (SSB) of levorphanol by mouse brain

preparations. SSB is measured as the difference in binding of radioactive

levorphanol under two conditions: (1) in the presence of a large excess of

nonradioactive dextrorphan, the L(+) isomer, and (2) in the presence of a

large excess of nonradioactive levorphanol.

Our results show that among the different subcellular fractions of

mouse brain, only one fraction has the SSB capacity. This material initially

sediments with crude nuclei but subsequently floats on 2 M sucrose when the

crude nuclear preparation is centrifuged through this medium. The SSB

capacity of this membrane preparation is not extractable either by 0.5%

triton-X 100 or by 0.1% sodium lauryl sulfate in cold, although 70% of the

protein is solubilized by either of these treatments. The SSB is pH

dependent, the optimum pH being in the range of 7.2 to 7.4. The SSB is

inhibited by Ca2+ and Mg2+. although the same concentration of Na+ has

no effect. The SSB is stimulated by ethylenediamine tetraacetate. Iodoacetic acid, p-chloromercuribenzoate and beta-mercaptoethanol have no

significant effect on SSB.

PASTERNAK, G.W. and SNYDER, S.H. Identification of novel high affinity opiate

receptor binding in rat brain. Nature (in press)

PASTERNAK, G.W. and SNYDER, S.H. Opiate receptor binding: Effects of

enzymatic treatments. Molecular Pharmacology 10: 183-193 (1974)

A variety of enzymatic treatments have been examined with regard

to their effect on stereospecific (

3H) naloxone binding to rat brain

homogenates. Opiate receptor binding is sensitive to very low concentrations

of trypsin (EC 3.4.4.4) and chymotrypsin (EC 3.4.4.5). Trypsin appears to

decrease the number of opiate receptor binding sites. while chymotrypsin

primarily lowers their affinity for opiates. Receptor binding is drastically

reduced by very low concentrations of phospholipase A (EC 3.1.1.4), is

decreased by higher concentrations of phospholipase C (EC 3.1.4.3), and

appears relatively insensitive to phospholipase D (EC 3.1.4.4) and neuraminidase

(EC 3.2.1.18). Small amounts of RNase (EC 2.7.7.16) and DNase (EC 3.1.4.5)

are without effect. Trypsin and chymotrypsin decrease receptor binding in a

biphasic fashion, suggesting the presence of more than one population of sites

sensitive to protcolysis. By contrast, the phospholipases degrade binding in a

monophasic fashion. Thus the opiate receptor appears to be a membranebound complex whose stereospecific binding is dependent upon the integrity of

both proteins and phospholipids.

PASTERNAK, G.W., WILSON, H.A. and SNYDER, S.H. Differential effects of protein

modifying reagents on receptor binding of opiate agonists and antagonists.

Molecular Pharmacology (in press)

154
PATRICK, G.A., DEWEY, W.L., HARRIS, L.S., DAVES, E.D. and NEUMANN, J.H.

Relationship of brain morphine concentration to tail-flick activity and

tolerance and dependence development in chronically infused rats. The

Pharmacologist 16(2): 71 (1974)

Rats were treated chronically with morphine (M) sulfate by the i.p.

infusion technique of Teiger. Brain M concentration was measured throughout the infusion and withdrawal periods by a fluorometric technique similar

to that of Kupferberg et al. The onset of analgesia was within 60 minutes of

the beginning of infusion, and brain M levels were measurable at that time.

The rate and degree of tolerance development was dependent upon the

infusion schedule employed. Some tolerance was observed after 24-48 hours

of infusion, but tolerance was greatest only after 48 hours or more of

infusion at a rate of 200 mg M sulfate/kg/day. Tolerance appeared to be

both cellular and metabolic in nature, since tail-flick response decreased

while brain M was elevated, and brain M level began to decline as the

infusion period was lengthened. Upon cessation of the infusion, brain M

levels declined precipitously within 6 hours, but tolerance to the analgesic

effect of M was evident for a longer period. Loss of body weight was

maximal (20-25%) at 24 hours after the infusion was stopped; however, this

sign of dependence was not observed if a pellet of naloxone was implanted at the beginning of the infusion regimen.

PAUL, A.G., KHANNA, K.L., ROSENBERG, H. and TAKIDO, M. Biosynthesis of

peyote alkaloids. Chemical Communications, 1969. London, England: The

Chemical Society, 1969. P. 838.

A pathway of biosynthesis of mescaline and the phenolic

tetrahydroisoquinoline alkaloids of peyote is suggested.

PAUL, A.G., ROSENBERG, H. and KHANNA, K.L. The roles of 3,4,5-

trihydroxy-beta-phenethylamine and 3,4-dimethoxy-beta-phenethylamine

in the biosynthesis of mescaline. Lloydia 32(1): 36-39 (March, 1969)

Following the injection of 8-14C-normescaline and 8-14C-3,4-

dimethoxy-beta-phenethylamine into plants of L. williamsii, radioactive

mescaline was isolated, characterized, assayed for specific activity,

and degraded. The data indicate that both of these compounds serve as

precursors of mescaline. However, the low percentage of incorporation

of normescaline suggests that it is not a direct precursor. The

relatively high percentage of incorporation of 3,4-dimethoxy-betaphenethylamine strongly supports the hypothesis that this compound is a

direct precursor of mescaline, arising from dopamine by O-methylation.

PAUL, S.M., HSU, L,L. and MANDELL, A.J. Extrapineal N-acetyltransferase

activity in rat brain. Life Sciences 15(12): 2135-2143 (1973)

For abstract, see Section I. Methodology of Drug Research.

155
PERT, C.B., PASTERNAK, G. and SNYDER, S.H. Opiate agonists and antagonists

discriminated by receptor binding in brain. Science 182: 1359-1361

(December, 1973)

Receptor binding of opiate agonists and antagonists can be differentiated in vivo and in vitro. Administration of either rapidly elevates

stereospecific (

3H) dihydromorphine binding to mouse brain extracts by 40 to

100 percent, but antagonists are 10 to 1000 times more potent than agonists;

as little as 0.02 milligram of naloxone per kilogram of body weight significantly

enhances opiate receptor binding. Sodium enhances antagonist binding in vitro

but decreases agonist binding, a qualitative difference that may be relevant to

the divergent pharmacological properties of opiate agonists and antagonists.

PERT, C.B. and SNYDER, S.H. Opiate receptor binding: Enhancement by in vivo

opiate administration. Biochemical Pharmacology (in press)

PERT, C.B. and SNYDER, S.H. Opiate receptor binding of agonists and antagonists

affected differentially by sodium. Molecular Pharmacology 10: 868-879 (1974)

Receptor binding of the tritiated opiate antagonists naloxone, nalorphine,

and levallorphan is enhanced by sodium ion. while binding of the tritiated agonists

oxymorphone, dihydromorphine, and levorphanol is diminished. This differential

effect of Na+ is highly specific, since it is elicited by Na+ and Li+

but not by other monovalent or divalent cations. The relative effectiveness of nonradioactive opiates in inhibiting (

3H) naloxone binding in

the absence and presence of Na+ in vitro correlates impressively with their

relative agonist-antagonist properties in vivo. It is hypothesized that sodium

allosterically transforms opiate receptor sites from conformations which bind

agonists more readily to conformations which bind antagonists more readily.

This hypothesis is supported by the competition of opiate agonists and antagonists

for receptor sites, the marked temperature dependence of binding, the similar

extent of binding of tritiated agonists and antagonists at maximal saturation, the

concurrent increruse in naloxone binding Bites and decrease in dihydromorphine

binding Bites caused by the addition of Na+, and the ability of Na+ to increase

(

3H) dihydromorphine dissociation with no effect on (3H) naloxone dissociation.

PERT, C.B. and SNYDER, S.H. Opiate receptor: Demonstration in nervous tissue.

Science 179: 1011-1014 (March, 1973)

Tritiated naloxone, a powerful opiate antagonist, specifically binds to

an opiate receptor of mammalian brain and guinea pig intestine. Competition

for the opiate receptor by various opiates and their antagonists closely

parallels their pharmacological potency. The opiate receptor is confined to

nervous tissue.

PERT, C.B. and SNYDER, S.H. Properties of opiate-receptor binding in rat brain.

Proceedings of the National Academy of Sciences 70(8): 2243-2247 (August, 1973)

Naloxone, a potent opiate antagonist, binds stereoespecifically to opiatereceptor sites in rat-brain tissue. The binding is time, temperature, and pH

dependent and saturable with respect to /

3H/ naloxone and tissue concentration.

The /

3H/ naloxone-receptor complex formation is bimolecular with a dissociation constant of 20nM. 15 Opiate agonists and antagonists compete for the same

receptors, whose density is 30 pmol/g. Potencies of opiates and their antagonists

in displacing /

3H/ naloxone binding parallel their pharmacological potencies.

156
PETERS, M. A. The effect of acute and chronic methadone treatment on the in vitro

n-demethylation of methadone by microsomal enzymes of male and pregnant and

nonpregnant female rats. Archives internationales de Pharmacodynamie et de

Therapie 205(2): 259-266 (October, 1973)

Male rats were found to metabolize (N-demethylate) methadone about

twice as fast as female rats. Acute treatment tended, to increase the rate of

metabolism in male rats but not in female rats, while chronic treatment had

little effect in either sex. Pregnancy tended to decrease the rate of metabolism,

however, the only significant difference between pregnant and nonpregnant female

rats was seen in the chronically treated group. Increaeing certain cofactor

concentrations caused a greater increase in the rate of metabolism in male rats

than in female rats. Microsomes from fetal livers of all treatment groups were

totally devoid of metabolic activity. The kinetic studies would suggest that the

decrease in metabolism caused by pregnancy is a competitive type inhibition,

while the increased metabolism seen in the male appears to be both qualitatively

and quantitatively different from the female since both the Km and Vmax were

significantly different.

PILLARD, R.C. Medical progress. Marihuana. New England Journal.of Medicine

283:294-303 (August, 1970)

PLAIN, W. M., CAUTHEN, S. E. and KIDD, M. R. Human Berum tropacocainesterase.

Presented at the American Chemical Society 30th Southwest Regional Meeting,

Houston, Texas, December 9-11, 1974.

An enzyme which catalyzes the hydrolysis of tropacocaine has been

partially purified from pooled human serum using ammonium sulfate fractionation,

DEAE-Sephadex ion exchange chromatography and gel filtration. Reports in the

literature conflict with respect to whether this enzyme is identical to pseudocholinesterase,

acylcholine acyl-hydrolase (E.C. 3.1.1.8). Attempts have been made to resolve this

conflict on the basis of substrate specificity and inhibition studies. Samples of

individual human sera were examined using analytical scale polyacrylamide gel

electrophoresis in attempts to determine the distribution of tropacocainesterase.

POLLOCK, S.H. and FUJIMOTO, J.M. A partial characterization of naloxone and

naltrexone-6-ketone reductases in rabbit and chicken. The Pharmacologist

16: 225 (1974)

The stereospecific identification of the reduction products of the narcotic

antagoniets (naloxone and naltrexone) by N. Chatterjie et al. (this meeting) goes

hand in hand with this work in which the enzyme systems are partially characterized.

Both the hepatic enzyme from the rabbit and the chicken which respectively produce the 6-beta-OH and 6-alpha-OH reduction products are NADPH dependent

enzymes occurring in the soluble cell fractions. The enzyme assay conlisted of

purified enzyme protein mixture; 7.9 mu-mol glucose-6-phosphate; 0.25 mu-mol

NADP; and 2 units glucose-6-phosphate dehydrogenase in a final volunie of

1 ml 0.05 M KH2P04/NaOH buffer (pH 7.4) with N-allyl-1, 3-14C naloxone or

3H-15, 16-naltrexone. The Km’s of both naloxone and naltrexone are similar

(ca. 10-4M) for both enzymes. The shapes of the pH-activity curves are similar.

The rabbit enzyme is inhibited more by 6-alpha-OH dihydromorphine derivatives

than the chicken enzyme. These enzymes do not appear to be involved in reduction of certain other ketones. The rabbit liver enzyme is a better model

than the chicken for the human metabolic pathway of naltrexone reduction since

in man and the rabbit the reduced product has the 6-beta-OH configuration.

157
RANDRUP; A. and MUNKVAD, I. Mechanisms by which amphetamines produce stereotypy,

agression and other behavidural effects. Psychopharmacologia

26 (supplement): 37 (1972)

The dopaminergic systems in the forebrain (nucleus caudatus, putamen and

some adjacent areas) appear to have effects, in mammals, on many perhaps all types

of behaviour, and these effects tend in the extreme to change the whole pattern of

behaviour into a stereotyped, apparently aimless one. At the same time each type

of behaviour e.g. locomotion, aggressive and other social activities, drinking etc.

appear to be influenced also by other brain systems. The behavioural effects of a

drug, which like amphetamines acts on several brain systems (dopaminergic,

noradrenergic, serotonergic and possibly others) are therefore bound to be complicated. For example: smaller doses of d-amphetamine cause increase in locomotion of rats while larger doses cause inhibition. The increased locomotion can

be stereotyped, consisting in repetition of a fixed route in a restricted part of the

cage. Brain dopamine plays a role in these locomotor effects, but locomotion is

also influenced by brain noradrenaline. Recent findings about the mechanisms by

which amphetamines produce their behavioural effects will be reviewed. Real and

apparent contradictions in the most recent publications about experiments with

brain lesions will be discussed; the extent of lesions in the striatum and the slow

recovery of behaviour after such lesions seem to be important items in this context.

RAZDAN, R.K., DALZELL, H.C. and HANDRICK, G.R. Hashish. A simple one-step

synthesis of (-)-delta-1-tetrahydrocannabinol (THC) from p-mentha-2, 8-dien-1-ol

and olivetol. Journal of the American Chemical Society 96(18): 5860-5865

(September, 1974)

Optically pure (-)-delta-1-THC was produced in 50% yield (glc; isolated

yield 31%) in a single-step synthesis from cis/trans-(+)-p -mentha-2, 8-dien-1-ol

and olivetol in the presence of 1% boron trifluoride etherate and anhydrous

mxnesium sulfate in methylene chloride at 0°. The product was readily

separated by column chromatography. The other major product formed was

trans-delta-8-iso-THC. By the same, procedure (-)-cannabidiol was bbtained on

a preparative scale when greater than 0.5% boron trifluoride etherate or wet

p-toluene-sulfonic acid was used. A mechanistic scheme is presented for this

reaction. It is shown that cannabidiols are the key intermediates in this reaction

and abnormal cannabidiol undergoes a retro-Friedel-Crafts reaction followed by

recombination to normal cannabidiol. This retroreaction of 4 is rationalized on

steric arguments. The isolation and study of products from this reaction give a

much clearer understanding of the factors which control the outcome of acidcatalyzed reactions of p-mentha-2, 8-dien-1-ol and olivetol and have provided

three new cannabinoids.

RAZDAN, R.K. and HANDRICK, G.R. Hashish. A stereospecific synthesis of

(-)-delta-1-and (-)-delta-1(6)-tetrahydrocannabinols. Journal of the American

Chemical Society 92: 6061-6062 (1970)

REGELSON, W., BUTLER. J.R., SCHULTZ, J., KIRK, T., PEEK, L. and GREEN, M.L.

Delta-9-tetrahydrocannabinol (delta-9-THC) as an effective antidepressant and

appetite stimulating agent in advanced cancer patients. Presented at the International Conference on the Pharmacology of Cannabis, National Institute on Drug

Abuse, December 3-6, 1974.

158
RICHTER, J.A. and GOLDSTEIN, A. Effects of morphine and levorphanol on brain

acetylcholine content in mice. The Journal of Pharmacology and Experimental

Therapeutics 175(3): 685-691 (1970)

A modest increase in brain acetylcholine has been demonstrated with both

morphine and levorphanol. It occurs in the “free” and “bound” fractions of acetylcholine but usually is largest and most significant in the latter. Similar increases

were found in the pooled cerebral cortex and cerebellum and in the rest of the brain

when these regions were examined separately. The inert stereoisomer dextrorphan,

at a dose equal to an effective dose of levorphanol, did not cause an increase in

brain acetylcholine. In mice made tolerant to the analgesic effect of levorphanol

by repeated injection, only a small increase in brain acetylcholine occurred.

RICHTER, J.A. and GOLDSTEIN, A. Tolerance to opioid narcotics, II. Cellular tolerance

to levorphanol in mouse brain. Proceedings of the National Academy of Sciences

66(3): 944-951 (July, 1970)

Mice were made tolerant to a large dose of levorphanol, a congener of

morphine. Then 3H-levorphanol was given. The concentration of free, unchanged levorphanol in the brain water (ultrafiltrate) was found to be much

higher than required to produce pharmacologic effects in nontolerant animals.

The resuit indicates that tolerance arises from a diminished sensitivity to the

drug at cellular or subcellular sites of drug action in the brain.

ROIZIN, L., HELPERN, M., BADEN, M.M., KAUFMAN, M. and AKAI, K. Toxosynpathies

(a multifactor pathogenic concept). Drug Abuse: Current Concepts and Research.

Edited by W. Keup. Springfield, Illinois: Charles C. Thomas, 1972. Pp. 97-11.6.

The simultaneous occurrence of multiple variable interractions intensify

the toxogenetic or pathogenetic potentialities of the independent pharmacodynamic

agent. Comparative studies of human and experimental drug toxicology have

suggested that the tissue reaction patterns (relative tissue reaction scale) are

the result of the interplay between the overall biological cofactors of the reacting organism (inherited and acquired) and the pharmacodynarnic properties

of the chemical agents with the coparticipation of accessory of secondary

cofactors (environmental, nutritional, socioecological, stressors, etc.).

ROSENBERG, H., KHANNA. K.L., TAKIDO. M. and PAUL, A.G. The biosynthesis of

mescaline in Lophophora williamsii. Lloydia 32(3): 334-338 ‘(September, 1969)

Data are presented in support of a proposed pathway of biosynthesis of

mescaline from dopamine.

ROSENGARTEN, H., MELLER, E. and FRIEDHOFF, A. J. In vitro enzymatic formation of

melatonin by human erythrocytes. Research Communications in Chemical

Pathology and Pharmacology 4(2): 457-465 (September, 1972)

An enzyme capable of forming melatonin from N-acetyl-serotonin was

identified in the red blood cells of humans. The properties of this

0-methyltransferase are described with respect to distribution in blood,

identity of the product formed and substrate specificity.

ROSENMAN, S.J. and SMITH, C.B. 14C-catecholamine synthesis in mouse brain during

morphine withdrawal. Nature 240: 153-155 (1972)

159
ROTH, R.H., WALTERS, J.R. and AGHAJANIAN, G. K. Effect of impulse flow on the

release and synthesis of dopamine in the rat striatum. Frontiers in

Catecholamine Research. Edited by E. Usdin and S.H. Synder. New York:

Pergamon Press, 1973. Pp. 567-574.

In order to gain further insight into the mechanism responsible for the

increase in dopamine (DA) produced by gamma-hydroxybutyrate (GHB), a

compound which occurs as a natural metabolite of mammalian brain, the

effect of GHB on the firing of dopaminergic neurons in the zona compacta of

the substantia nigra was investigated by means of single unit recording

techniques. These experiments revealed that GHB administered i.v. or

i.p. decreased the firing of units localized to the DA containing cells

present in the zona compacta of the substantia nigra. Cessation of impulse

flow in DA neurons was found to result in a decrease in release and

catabolism of DA and an increase in synthesis. These changes are reflected by a dramatic increase in the steady state levels of DA in the

neuronal terminals. Once this new steady state level of DA is established

the rate of synthesis returns to normal but is not inhibited as it is when

DA levels are increased by inhibition of monamine oxidase (MAO). Drugs

which are capable of stimulating DA receptors block this increase in DA

observed after inhibition of impulse flow, suggesting that DA synthesis

may in part be controlled by alterations in receptor activity.

SCHEEL-KRÜGER, J. Studies of various amphetamines, apomorphine and clonidine on

body temperature and brain 5-hydroxytryptamine metabolism in rats. Psychopharmacologia 36: 189-202 (1974)

Amphetamine and various amphetamine derivatives, phenmetrazine,

pipradrol, methylphenidate and NCA can increase the concentration of 5-HIAA in

the rat brain without changing that of 5-HT. Metamphetamine produced a decrease

in 5-HT and no effect on 5-HIAA whereas p-hydroxyamphetamine produced no

effects on 5-HT and 5-HIAA. The experiments performed at different environmental

temperatures (12-14°C. 21-22°C and 21-28-C) with simultaneous measurements of

the body temperature indicate that no simple correlation exists between the drug

induced hyperthermia and the effect on 5-HIAA. The amphetamine and phenmetrazine

effect on 5-HIAA seems to be related to hyperthermia whereas the pipradrol and

methylphenidate effect on 5-HIAA appears independent of hyperthermia. Apomorphine

(2 x 2.5 mg/kg) which activates central dopamine receptors produced a significant

increase in 5-HIAA whereas clonidine (0.5 mg/kg) which activates central noradrenaline receptors produced a significant decrease in 5-HIAA.

In conclusion, the effect of various amphetamines on 5-HT metabolism seems

very complex in mechanism of action and might be related to hyperthermia, to a

direct effect on 5-HT neurons and to the ratio between central dopamine/noradrenaline

receptor activation of these drugs.

160
SCHEEL-KRÜGER, J., BRAESTRUP, C., EPLOV. L. and NIELSEN, M. The effect

of amphetamine and reserpine on 3H-noradrenaline and its metabolites

synthesized from intraventricular injected 3H-dopamine. Acta Pharmacologica

et Toxicologica 35 (Supplement I): 50 11974)

The in vivo effect of amphetamine, reserpine, protriptyline, and pargyline

has been studied on brain 3H-noradrenaline (3H-NA) and its quantitatively major

metabolites. conjugated 3H-3-methoxy-4-hydroxyphenyleneglycol (3H-MOPEG)

and conjugated 3H-3,4-dihydroxyphenyleneglycol (3H-DOPEG) synthesized after

intraventricular (I.V.) injected 3H-dopamine (3H-DA). The present study shows

characteristic metabolic changes after the abovementioned drugs: amphetamine

produqed a strong decrease in 3H-DOPEG, whereas reserpine contrastingly

produced a strong increase in 3H-DOPEG. Both drugs decreased 3H-NA and produced

a relative increase in 3H-MOPEG. The most significant effect after protriptyline

was a decrease in 3H-DOPEG. Pargyline produced a very strong decrease in

both 3H-DOPEG and 3H-MOPEG.

The present results indicate that conjugated 3H-DOPEG formed,.from endogenous

synthesized 3H-NA is a valuable indicatbr for drugs producing release (amphetamine)

and uptake inhibition (amphetamine, protriptyline) of 3H-NA in central noradrenaline

neurons. The result with reserpine provides evidence that non-stored 3H-NA to a large

degree is metabolized (intraneuronally?) by monoamine-oxidase to 3H-DOPEG.

SCHEEL-KRÜGER. J., EPLOV. L. and NIELSEN. M. The effect. of prvtriptyline on the

metabolism of labelled dopamine and noradrenaline in the rat brain.

Psychopharmacologia 26 (Supplement): 45 (1972).

Protriptyline like other tricyclic antidepressant drugs has been shown to

block the amine-uptake mechanism at the level of the cell membrane of central

noradrenaline neurons, but not of dopamine neurons.

In order to get information on the effect of protriptyline on the metabolism

of the catecholamines male Wistar rat received 3H-L-DOPA (200 mu-C i.p.). The

biochemical analyses were performed on the accumulation in the brain of labelled

noradrenaline, the noradrenaline metabolites (NM, free & conjugated MOPEG),

dopamine and the dopamine metabolites (MT. HVA and DOPAC). Prntriptyline’

(10 mg/kg s.c.) and a peripheral decarboxylase inhibitor Ro 4-4602 (50 mg/kg

i.p.) were given 30 min. hefore 3H-L-DOPA.

Protriptyline produced a strong decrease of labelled noradrenaline and all

noradrenaline metabolites. whereas no significant effect was found on labelled

dopamine or the dopamine metabolites.

As possible explanations for this finding will be discussed: Spec.ific feedback inhibition of noradrenaline biosynthesis, blockade of the uptake of 3H-L-DOPA

in noradrenaline neurons or reuptake inhibition of released dopamine formed in

noradrenaline neurons.

SCHMIDT, M.J., HOPKINS, J.T., SCHMIDT. D.E. and ROBISON, G.A. Cyclic AMP

in the brain: Effects of amphetamine and norepinephrine assessed through the

use of microwave irradiation as a means of tissue fixation. Brain Research

42: 465-477 (1972)

SCHWEITZER, J.W. and FRIEDHOFF, A.J. The chemistry and detection of amphetamines.

International Symposium on Drug Abuse. Edited by C.D.J. Zarafonetis. New

York: Lea and Febinger, 1972. Pp. 233-241.

161
SCRAFANI, J.T. and CLOUET, D.H. The metabolic disposition of narcotic analgesic

drugs: Biotransformations. Narcotic Drugs: Biochemical Pharmacology.

Edited by D.H. Clouet. New York: Plenum Press, 1971. Pp. 137-158.

The biotransformations of narcotic drugs are analyzed. General patterns

of metabolism of narcotic drugs are discussed with reference to chemical reactions, effects of species, sex, dose, and effects of route of administration.

Sites of metabolism are described. Drugs analyzed include alpha-acetylmethadol,

anileridine, codeine, cyclazocine, dextromethorphan, dihydromorphine,

ethylmorphine, heroin, methadone, morphine, nalorphine, naloxone, normorphine, pentazocine, and propoxyphene. Metabolism in tolerant animals

is discussed.

SCRAFANI. J. T., WILLIAMS, N. and CLOUET, D.H. The subcellular distribution of

narcotic analgesics in rat brain. Committee on Problems of Drug Dependence.

Washington, D.C.,: National Academy of Sciences, National Research Council,

1972.

Narcotic analgesics were taken up into rat brain synaptosomal fraction

after both in vitro exposure and in vivo administration of the drug. Little or no

bindingto other particulate fractions was observed in the experiments described

here.

The uptake of the labeled drug into the synaptosomes of the different

brain areas seemed to reflect the total uptake of the drug into the area although

the percentage uptake varied enough to suggest that there were different

narcotic analgesic binding properties for each area.

The differences in density of the peak of the binding of labeled drug were

related to the differences in optical density.

SEGAL. D.S., KUCZENSKI, R. and MANDELL. A.J. Theoretical implications of druginduced adaptive regulation for a biogenic amine hypothesis of affective disorder.

Biological Psychiatry 9(2): 147-159 (1974)

Administration of the antidepressant tricyclic desmethylimipramine (DMI 10

mg/kg b.i.d. for 8 days) produced a significant decrease in the activity of regional

brain tyrosine hydroxylase in noradrenergic pathways and a marginal decrease

in the dopaminergic system of the rat brain. No change in the enzyme activity

was observed 24 hr after a single administration of the same drug (25 mg/kg). In

contrast, chronic reserpine treatment (0.5 mg/kg q.d. for 8 days) induced a

delayed elevation of tryrosine hydroxylase activity of varying significance in the

discrete brain regions examined. The functional significance of these apparent

drug-induced compensatory responses is discussed in the context of a neurochemical

theory of affective disorder that focuses on the role of adaptive regulatory mechanisms.

SEGELMAN, A.B., SOFIA. R.D., SEGELMAN, F.P., HARAKAL, J.J. and KNOBLOCH,

L.C. Cannabis sativa L. (marijuana)V: Pharmacological evaluation of marijuana

aqueous extract and volatile oil. Journal of Pharmaceutical Sciences 63(6):

962-964 (June, 1974)

The aqueous extract (marijuana tea) and volatile oil prepared from

marijuana were compared with (-)-trans-delta-9-tetrahydrocannabinol for

their effect on hexobarbital sleeping time and analgesic action in mice. All

three substances prolonged hexobarbital sleeping time with an order of potency

of (-)-trans-delta-9-tetrahydrocannabinol greater than aqueous extract greater

than volatile oil. Each agent produced significant analgesic activity. However,

the potencies of the aqueous extract and the volatile oil were similar to each

other but only 1/200 that of (-)-trans-delta-9-tetrahydrocannabinol.

162
SETHY, V.H. and GESSNER. P.K. Effect of methanol on chloral hydrate metabolism in

mice. The Pharmacologist 12:277 (1970)

Ethanol, when administered in combination with an equimolar amount of

chloral hydrate (CH) to mice, increases the in vivo rate of reduction of CH to

trichloroethanol (TCE) by 83% (Gesener and Cabana: Fed. Proc. 26, 568, 1967)

This led to the hypothesis that it is the faster rate of formation of the alcohol

dehydrogenase-NADH complex in ethanol treated mice that is responsible for

the faster rate of reduction of CH to TCE, the complex being a prerequisite of this

reduction. Since methanol is metabolized in mice by the catalase-peroxidase

system it should not lead to the formation of the alcohol dehydrogenase-NADH

complex. Therefore the effect of methanol coadministration on the rate of CH

disappearance provides a test of the above hypothesis. We find, upon determining

the whole body levels of CH and TCE at various times following the i.p. administration of (I) 500 mg/kg of CH or (II) 500 mg/kg of CH plus an equimolar amount of

methanol, that methanol coadministration has no significant effect on the rate of

CH disappearance from the body. This supports the above hypothesis, We find,

further that. TCH levels are higher following methanol coadministration. Analysis

of this data suggests that methanol decreases significantly the rate of TCE

disappearance.

SETHY, V.H. and WINTER, J.C. Effect of chronic treatment with mescaline upon tissue

levels of the drug. Experientia 29: 571-572 (1973)

SHANI, A. and MECHOULAM, R.A new type of cannabinoid. Synthesis of Cannabielsoic

Acid A by a novel photo-oxidative cyclisation. Chemical Communications, 1970.

London, England: The Chemical Society. 1970. P. 273.

Two tricyclic dihydrobenzofuran cannabinoids have been isolated and

one of them has been synthesized by an intramolecular photo-bxidative cyclisation

which involves attack by a phenoxy-group and molecular oxygen on a double bond.

SHANI, A. and MECHOULAM, R. Photochemical reactions of cannabidiol. Cyclization to

delta-1-THC and other transformations. Tetrahedron Letters 27: 601 (1971)

Irradiation of cannabidiol (I) in methanol gave mainly 1-methoxydihydrocannabidiol (II, both isomers). Irradiation of I in cyclohexane gave a

complicated mixture from which, in addition to starting material, the following compounds were isolated: delta-1-tetrahydrocannabinol, delta-8-

tetrahydrocannabinol. 8,9 dihydrocannabidiol (V), and 3’-cyclohexylcannabidiol

(VI).

SHASKAN. E.G., HARASZTI, J.H. and SNYDER, S.H. Polyamines: Developmental

alterations in regional disposition and metabolism in rat brain. Journal of

Neurochemistry 20: 1443-1452 (1973)

The polyamines spermidine and spermine and the activity of the polyamine

synthesizing enzyme, S-adenosyl-L-methionine (SAM) decarboxylase, were measured

in regions of adult rat brains and during postnatal development. In the adult, although

spermidine levels tended to correlate with the relative amounts of white matter in

some areas, there were striking exceptions. SAM decarboxylase activity of the

adult brain was higher than in most other mammalian tissues, although brain levels

of polyamines were among the lowest. SAM decarboxylase activity appeared to be

localized to cellular cytoplasm. Its activity increased with age in contrast to the

levels of spermine, spermidine, DNA and RNA which decreased during postnatal

development.

163
SHASKAN, E.G. and SNYDER, S.H. Kinetics of serotonin accumulation into slices from rat

brain: Relationship to catecholamine uptake. The Journal of Pharmacology and

Experimental Therapeutics 175(2): 404-418 (1970)

The accumulations of H

3

-serotonin (H3-5-HT) and H

3

-norepinephrine

(H3-NE) into rat brain slices have been compared. Regional differences in

accumulation of both amines occurred with highest uptakes for both amines in

the corpus striatum. Other areas, however, showed significant differences with

respect to amine accumulation after reserpine pretreatment and with respect to

inhibition of uptake of the two amines by a variety of antidepressant drugs.

Kinetic analyses indicated two components of 5-HT accumulation, one representing a high (uptake 1) and the other a low (uptake 2) affinity transport system.

The Kl values for the competitive inhibition of dl-H3

-NE uptake by 5-HT were

approximately equal to the Km values for uptake of 2 of 5-HT, suggesting that

the low affinity transport for 5-HT might involve uptake by the catecholamine

transport system. Further evidence supporting the notion that 5-HT can be

transported by cerebral catecholaminergic transport systems is as follows.

1) The relative potency of d- and l-NE and of dopamine in inhibiting 5-HT uptake

in the hypothalamus and striatum paralleled their affinity for the catecholamine

uptake process in these two areas. 2) Catecholamines were better inhibitors of

H

3

-5-HT uptake in the striatum when 5-HT concentration was increased to levels

at which uptake 2 should predominate. Our findings suggest that doses of 5-HT

administered into the brain in a variety of studies may enter catecholaminergic

neurons in significant quantities.

SHASKAN, E.G. and SNYDER, S.H. Polyamine turnover in different regions of rat brain.

Journal of Neurochemistry 20: 1453-1480 (1973)

The dynamics of the formation and disappearance of polyamines in rat

brain have been examined after intraventricular administration of a tracer dose

of (

3H) putrescine. After 2 days (3H) putrescine was no longer detectable in any

brain region examined. (

3H) Spermidine and (3H) spermine were formed in all

brain areas. In the midbrain, hypothalamus and cerebellum (regions which

manifested the greatest initial accumulation of tritium) the specific radioactivity

of spermidine declined with a half-life of 16-19 days. However, in areas with a

low initial accumulation of tritium (the medulla-pons. internal capsule, cerebral

cortex and corpus striatum) the specific radioactivity of spermidine changed very

little between 2 and 19 days after the putrescine administration. Levels of

(

3H) spermine increased continuously in all brain areas for a 14-day period after

the putrescine injection.

SIMON, E.J., HILLER. J.M. and EDELMAN. I. Stereospecific binding of the potent narcotic,

analgesic 3H-etorphine to rat brain homogenate. Proceedings of the National

Academy of Sciences 70: 1947 (1973)

Etorphine, the most potent narcotic analgesic known, was labeled with

tritium by catalytic exchange. This drug exhibits stereospecific, saturable binding

to rat-brain homogenate. At saturation, the stereospecific binding is 0.1-0.15

pmol/mg of protein. Specific binding is inhibited by high salt concentrations,

sulfhydryl reagents, and proteolytic enzymes, but is unaffected by phospholipases

A and C, sodium azide, sodium fluoride, and prostaglandins E and E2. Competition for binding of (

3H) etorphine correlates with agonist and antagonist potencies.

The stable, stereospecific binding of an active narcotic analgesic supports the

existence of opiate receptors.

164
SLATKIN, D.J., DOORENBOS, N.J., HARRIS, L.S.. MASOUD. A.N., QUIMBY. M.W.

and SCHIFF. P.L., JR. Chemical constituents of Cannabis sativa L. root.

Journal of Pharmaceutical Sciences 60(12): 1891-1892 (December. 1971)

An extract of Cannabis sativa L. root yielded two pentacyclic triter-penes,

friedelin and epifriedelanol, and N-(p-hydroxy-beta-phenylethyl)-p-hydroxy-transcinnamamide. Structures of the triterpenes were confirmed by preparation of

derivatives and comparison to authentic friedelin. Epifriedelanol was also

oxidized to friedelin. The amide was confirmed by synthesis.

SMITH, C.B., SHELDON, M.I., BEDNARCZYK. J.H. and VILLARREAL J.E. Morphineinduced increases in the incorporation of 14C-tyrosine into 14C-dopamine and

14C-norepinephrine in the mouse brain: Antagonism by naloxone and tolerance.

The Journal of Pharmacology and Experimental Therapeutics 180(3): 547-557

(1972)

The effects of morphine and levorphanol upon the incorporation of

14C-tyrosine into 14C-catecholamines in various tissues of the mouse were

determined. Morphine, 100 mg/kg, increased the synthesis of 14C-catecholamines

in mouse brain and adrenals but not in heart or spleen. Morphine, 100 mg/kg, had

no effect upon the free tyrosine or 14C-tyrosine content of the mouse brain.

d-Amphetamine, 10 mg/kg, did not increase the incorporation of 14C-tyrosine

into 14C-catecholamines in these four tissues. Morphine, 100 mg/kg, and

levorphanol, 10 mg/kg, nearly doubled the incorporation of 14C-tyrosine into

both 14C- dopamine and 14C-norepinephrine in the brain. Morphine-induced increases

in 14C-catecholamine synthesis occurred in the cerebral. cortex, diencephalon,

striatum, brainstem and cerebellum. After repeated administration of either

morphine, 100 mg/kg, or levorphanol, 30 mglkg, tolerance and cross-tolerance

developed to the effects of these drugs upon the synthesis of 14C-dopamine and

14C-norepinephrine. Naloxone, a specific morphine antagonist, blocked the

effects of morphine upon 14C-dopamine and 14C-norepinephrine synthesis. The

present study suggests that the catecholamines may play an important role in the

mechanisms by which narcotic analgesics produce certain specific effects.

SNYDER, S.H. Biochemically identified receptors in the design of new psychotropic

drugs. Predictiveness in Psychopharmacology - Preclinical and Clinical

Aspects. Edited by A. Sudilovsky, S. Gershon and B. Beer. New York:

Raven Press, 1974.

SNYDER, S.H. Catecholamines and serotonin. Chapter 6 of Basic Neurochemistry. New

York: Little, Brown and Company, Inc., 1972. Pp. 89-104.

The catecholamines. norepinephrine and dopamine, as well as the indoleamine, serotonin, are putative neurotransmitters in certain neuronal tracts in the

brain. They occupy a uniquely important place in neurobiology because they are

the only putative neurotransmitters whose localization in particular brain tracts has

been established and whose relationship to specific animal or human behaviors has,

at least in part, been worked out. Hence, a discussion of the neurochemistry of

these compounds can integrate findings derived from electron microscopy, histochemistry, neurophysiology, enzymology, pharmacology, psychology, and even

clinical psychiatry.

A great deal of information about catecholamines and serotonin had accumulated

prior to knowledge of which neuronal tracts contained them or even whether they

were localized in neurons at all. Nonetheless, for clarity’s sake, it might be best to

begin by presenting the histochemical observations that have delineated the neuronal

systems which contain these compounds in the brain.

165
SNYDER, S.H. Catecholamines as mediators of drug effects in schizophrenia. The Neurosciences - Third Study Program. Edited by F.O. Schmitt and F.G. Worden,

Cambridge, Massachusetts: MIT Press, 1974. Pp. 721-732.

Interactions of psychoactive drugs and neurotransmitters are a fruitful area

for correlating biochemistry and behavior, especially as related to psychiatric

illness. Ways in which psychoactive drugs influence neurotransmitters, particularly

the biogenic amines, are reviewed. Emphasis is placed on a critical assessment of

criteria for determining if a given “effect” of a drug represents its mode of action.

Possible clues that such drug effects afford to the pathophysiology of various

psychiatric disabilities in schizophrenia are evaluated.

SNYDER, S.H. Catecholamines in the brain as mediators of amphetamine psychosis.

Archives of General Psychiatry 27: 169-179 (August, 1972)

Amphetamine psychosis appears to be a fruitful experimental model

of paranoid schizophrenia or paranoid state. A variety of animal and human

studies suggest that neurochemical mediation of certain behavioral effects of

amphetamine in animals may reflect such mechanisms in human amphetamine

psychosis. Specifically, locomotor stimulation appears attributable to

central norepinephrine and stereotyped behavior to dopamine. while experiments

with amphetamine isomers in man suggest a dopamine. while experiments with

amphetamine isomers in man suggest a dopamine mediation of human

amphetamine psychosis.

Pharmacological and stereochemical evidence suggest that clinical

efficacy of phenothiazine drugs in the treatment of schizophrenia may be

related to blockade of dopamine receptors. Taken together, these findings

provoke the speculation that specific and distinct effects of amphetamines on

dopamine and norepinephrine neurons may combine to account for major

symptoms of amphetamine psychosis.

SNYDER, S.H. Neurotransmitter and drug receptors in the brain. Biochemical

Pharmacology (in press)

SNYDER, S.H. Putative neurotransmitters in the brain: Selective neuronal uptake,

subcellular localization, and interactions with centrally acting drugs.

Biological Psychiatry 2: 367-389 (1970)

This review is concerned with specific neuronal uptake systems for

different possible neurotransmitters in the brain and how advantage can be

taken of these uptake systems to label nerve terminals with their transmitter

in radioactive form. In these studies, kinetic analysis permitted a

differentiation of the properties of the uptake system of the dopamine and

norepinephrine neurons in the brain. These differences facilitated the

prediction of new therapeutic agents in Parkinson’s disease. Kinetic analysis

also revealed that exogenous serotonin can enter catecholamine as well as

serotonin neurons, and that these two uptakes can be discriminated. By

labeling nerve terminals with radioactive neurotransmitters, some with

carbon-14 and others with tritium, it was possible to develop methods to

separate synaptosomes (pinched off nerve terminals) storing different

neurotransmitters.

SNYDER, S.H. Stereoselective features of catecholamine disposition and their behavioral

implications. Journal of Psychiatric Research 11: 1-10 (1974)

166
SNYDER, S.H. and BANERJEE, S.P. Amines in schizophrenia. Frontiers in

Catecholamine Research 1133-1138 (1973)

This essay is not confined to catecholamines in schizophrenia, because

to do so would convey the impression that other amines are irrelevant to the

disease. Some drug actions suggest a role for dopamine; others implicate the

indoleamines. The ‘dopamine story’ derives from the influences of

antischizophrenic phenothiazines and butyrophenones upon the synaptic activities

of dopamine and studies of amphetamine psychosis as a model schizophrenia

mediated via brain dopamine. Aspects of indoleamines relevant to schizophrenia

are: (a) the psychotomimetic actions of indoleamine-related psychedelic drugs,

and (b) the existence of enzymes capable of methylating indoleamines to form

psychedelic drugs in the human body.

SNYDER, S.H., BANERJEE, S.P., YAMAMURA, H.I. and GREENBERG, D.

Drugs, neurotransmitters, and schizophrenia. Science 184:243-1253

(June, 1974)

Of various biochemical approaches to the study of schizophrenia, the

investigation of brain neurotransmitter interactions with psychotropic drugs

has proved most productive in recent years. Analyses of the mechanism of

the antischizophrenic activities of the phenothiazines and the ability of amphetamines to worsen schizophrenic symptoms and elicit a schizophrenialike psychosis have focused attention upon dopamine in the brain. Findings

of reduced platelet monoamine oxidase and brain dopamine beta-hydroxylase

activities in schizophrenics, represent enticing but tentative data that would be

consistent with a “dopamine hypothesis.” The ability of psychedelic drugs

to mimic the symptoms of certain early stages of schizophrenia remains a

promising lead. An enzymatic activity that utilizes the methly group of

5-methyltetrahydrofolic acid to O-methylate and N-methylate phenylethylamines

and indoleamines, thereby forming psychotomimetic drugs, is a possible

mechanism for the production of such compounds in the mammalian brain.

None of these approaches yet affords the definitive “answer” to the riddle of

schizophrenia, and roles for other neurotransmitters, such as acetylcholine

and gamma-aminobutyric acid are possible.

SNYDER, S.H., PERT, C.B. and PASTERNAK, G.W. The opiate receptor. Annals

of Internal Medicine 81 (4): 534-540 (October, 1974)

Binding of radioactive opiates and opiate antagonists to the opiate

receptor in the brain and other tissues can be shown. This binding mediates

the pharmacologic effects of the drugs. The regional distribution of the opiate

receptor in monkey and human brain parallels the motivational affective

pathways of pain perception and comprises several limbic system structures.

In subcellular fractionation experiments, the opiate receptor is localized to

synaptic membranes. The influence of sodium onreceptor binding permits

predictions of the extent to which a drug possesses opiate agonist,

antagonist, or mixed properties. The simple, sensitive, and specific opiate

receptor binding assay facilitates development of pure opiate antagonists for

treating narcotic addiction and mixed agonist-antagonist agents with potential

as nonaddicting analgesics.

167
SNYDER, S.H., YOUNG. A.B., BENNETT. J.P. and MULDER, A.H. Synaptic

biochemistry of amino acids. Federation Proceedings 32(10): 2039-2047

(October, 1973)

Neurophysiological research has suggested that certain naturally

occurring amino acids possess transmitter properties in the mammalian

central nervous system. L-glutamic and L-aspartic acids act as excitatory

agents on the postsynaptic membranes of many neurons. Gamma-amino

butyric acid and glycine mimic natural inhibitory transmitters in the

cerebral cortex, and brainstem and spinal cord, respecively. For the

transmitter candidates L-glutamic and L-aspartic acids in cerebral cortex

and spinal cord, and glycine only in the spinal cord and brainstem we found

unique, sodium-dependent, high affinity transport systems in synaptosomes.

Subcellular fractionation demonstrated unique synaptosomal populations

which accumulate these amino acids. These amino acids are selectively

released from central nervous system slices by K

+

 depolarization. For

L-proline, a previously unsuspected transmitter, we found a unique,

sodium-dependent, high affinity transport system in cerebral cortical

synaptosomes and selective release by K

+

 depolarization. Other nontransmitter

candidate amino acids possessed none of these neurochemical properties.

Strychnine, a specific postsynaptic antagonist of glycine in the central nervous

system binds to fractions rich in synaptic membranes and its binding appears

to represent an interaction with the postsynaptic glycine receptor. The

displacement of strychnine binding by glycine and glycine analogs parallels

glycinelike neurophysiological activity. The regional distribution of strychnine

binding correlates with endogenous glycine levels and with the neurophysiological

actions of glycine.

SPAULDING, T.C., FORD, R.D., DEWEY, W.L., McMILLAN, D.E. and HARRIS, L.S.

Some pharmacological effects of phenitrone and its interaction with delta-9-THC.

European Journal of Pharmacology 19: 310-317 (1972)

We have investigated the pharmacological effects of phenitrone

(3-(hexahydro-1-H-azepin-1-yl)-3’-nitropropiophenone HCl), a compound which

has been reported to block and reverse the toxic and behavioral effects of

hashish in dogs. There was no apparent blockage of cannabinoid-like activity

when phenitrone was administered prior to or concomitantly with delta-8-THC,

or the NIMH marihuana distillate in dogs and pigeons. However, phenitrone

produced bizarre behavioral effects in dogs when given at a dose of 40 mg/kg

and decreased the rate of conditioned key pecking for food at doses above 18

mg/kg in pigeons. When phenitrone and delta-9-THC were given simultaneously,

a dose-dependent inhibition of delta-9-THC-induced activity in the mouse tailflick test was observed. Phenitrone did not block hypothermia produced by

either a single injection or 5 daily injections of delta-9-THC in mice. Phenitrone

also produced a decrease in spontaneous activity and had an LD50 of 175 mg/kg

i.p. in mice.

168
SPAULDING, T.C., MINIUM, L., KOTAKE, A.N. and TAKEMORI, A.E. The

effect of diazepam on the metabolism of methadone by the liver of methadonedependent rats. Drug Metabolism and Disposition 2(5): 458-463 (1974)

The N-demethylation of methadone by 9000g supernatant fractions

of hepatic homogenates was investigated in methadone-dependent rats. In

these studies rats were administered methadone hydrochloride by allowing

free access to the drug dissolved in the drinking water (0.5 mg/ml). Rats

in the control group ingested tap water. The Vmax of N-demethylation by

liver supernatant fractions from methadone-dependent rats was 40-50%

higher than that from control animals, whereas the Km values did not

differ significantly. The increase in Vmax after chronic administration

of methadone was not reflected by alteration of’either the amount of

cytochrome P-450 or the ethyl isocyanide binding. Diazepam was found

to be a competitive inhibitor of N-demethylation of methadone with a Ki

of 1. 7 X 10-4 M when incubated with hepatic supernatant fractions from

control rats. However, diazepam was an uncompetitive inhibitor when

incubated with supernatant fractions from livers of methadonedependent rats. These data indicate that, unlike other opioid narcotics,

methadone increased its own metabolism upon chronic treatment. Further,

diazepam was shown to be a fairly effective inhibitor of the Ndemethylation of methadone which may explain in part the enhanced effect

of methadone observed in narcotic addicts when the combination is taken.

SPAULDING, T.C. and TAKEMORI, A.E. Studies on N-demethylation of

methadone in methadone-dependent rats. The Pharmacologist 16: 194 (1974)

When a methadone (M) solution (0.5 mg/ml) was substituted for

drinking water in rats, withdrawal signs could be precipitated by naloxone

after 5 days of drinking. The N-demethylation of M by 9,000 x g supernatants

of hepatic homogenates was investigated in these M-dependent rats. Vmax

was increased by 40-50% while the apparent Km remained unchanged when

compared to control values (Vmax nmoles/mg/hr; Km= 1.78 x 10-4 M).

The content of cytochrome P-450/mg microsomal protein for control and

M-dependent rats was 0.730 ± .034 and 0.732 ± .055 respectively and the ethyl

isocyanide difference spectrum for control and dependent rats was 0.431 and

0.471 ± .026 respectively. Diazepam (D) at a concentration of 5.9 x

10-5 or 1.57 x 10-4 M was found to be a competitive inhibitor of the Ndemethylation of M with a Ki of 1.71 x 10-4M. However, D became an

uncompetitive inhibitor when incubated with supernatants from livers of

M-dependent rats. Unlike other opioid narcotics, M increased its own

metabolism upon chronic treatment with no change in microsomal

P-450. D was shown to be a fairly effective inhibitor of the N-demethylation of M which may explain in part the enhanced effect of M observed

in narcotic addicts when the combination was taken.

169
STOELTING, R.K., MARTZ R.C., GARTNER, J., CREASSER, C., BROWN, D.J.

and FARNEY, R.B. Effects of delta-9-tetrahydrocannabinol on halothane

MAC in dogs. Anesthesiology 38(6): 521-524 (June, 1973)

The effects of acute and subacute administration of delta-9-

tetrahydrocannabinol (THC) on halothane requirements (MAC) in four groups

of dogs were measured. THC administered intravenously produced a doserelated alteration in MAC. THC, 0.1 mg/kg, did not alter MAC 1, 3, or 24

hours after its administration. THC, 0.5 mg/kg, decreased MAC 32 per cent

(P less than 0.05) 1 hour after injection, but MAC was not significantly different

from control after 3 and 24 hours. MAC was decreased 42, 36, and 18 per cent

(P less than 0.05) from control 1, 3, and 24 hours after 2.0 mg/kg THC. MAC

was not changed from control 24 hours after four daily injections of 0.5 mg/kg

THC.

Student Association for the Study of Hallucinogens, Inc. MDA. STASH Capsules 5(1)

(February, 1973)

Student Association for the Study of Hallucinogens, Inc. STASH fact sheet on cocaine.

Grassroots (February, 1972 supplement)

Student Association for the Study of Hallucinogens, Inc. STASH fact sheet on DOM

(“STP”). Grassroots (July, 1972 supplement)

Student Association for the Study of Hallucinogens, Inc. STASH fact sheet on methadone.

Grassroots (May, 1972 supplement)

Student Association for the Study of Hallucinogens, Inc. STASH fact sheet on opioids.

Grassroots (November, 1972 supplement)

Student Association for the Study of Hallucinogens. Inc. STASH fact sheet on psilocybin.

Grassroots (August, 1972 supplement)

Student Association for the Study of Hallcinogens, Inc. STASH notes: A mini-review of

the 1973 marijuana literature, Part I. STASH Capsules 6(2) (March-April,

1974)

Student Association for the Study of Hallucinogens, Inc. STASH notes: A mini-review of

the 1973 marijuana literature, Part II. STASH Capsules 6(3) (May-June, 1974)

Student Association for the Study of Hallucinogens, Inc. STASH notes: Methaqualone.

STASH Capsules 5(3) (May-June, 1973)

Student Association for the Study of Hallucinogens, Inc. STASH notes: Phenyclidine

(PCP). STASH Capsules 5(2) (April, 1973)

170
TAKEMORI. A.E., WARD, A., PORTOGHESE, P.A. and TELAND. V.G. Potential

nonequilibrium analgesic receptor inactivators. Further pharmacologic

studies of N-acylanileridines. Journal of Medicinal Chemistry 17(10):

1051-1054 (1974)

The antagonistic property of ethyl p-(4-ethoxycarbonyl-4-phenyl-1

piperidinoethyl) fumaranilate (5) was investigated. Compound 5 was found to

antagonize morphine analgesia in complex manner which could not be described as a simple competitive or noncompetitive type. The antagonism,

however, lasted for over 6 hr suggesting that 5 has a high affinity for the

analgesic receptors. Compound 5 appeared to possess dependence liability

in the single-dose suppression test. In the electrically stimulated isolated

guinea pig ileum, 5 acted like an agonist. No antagonistic activity of 5 was

apparent in the latter two tests.

TAKIDO, M. KHANNA, K.L. and PAUL, A.G. New synthesis of rac. anhalonidine

and rac. pellotine. Journal of Pharmaceutical Sciences 59(2): 271-273

(February, 1970)

A new synthesis of rac. anhalonidine and rac. pellotine is reported.

The procedure, a modification of the method of Bobbitt et.al. for the synthesis

of 1, 2, 3, 4-tetrahydroisoquinolines, is simpler and gives better yields than

those previously reported.

TAYLOR, J.F. Development aspects of the transport of meperidine into rat brain

in vivo. Federation Proceedings 29: 686 (1970)

The development of a blood-brain barrier to meperidme in young rats

has not been detected pharmacologically, thus it was investigated by

drug distribution studies. Meperidine (25 mg/kg) was injected into

16- and 32-day old rats which were then decapitated at 5 min. intervals up to 30

min. after drug administration. Brain and plasma, obtained at time of

sacrifice and analyzed by gas chromatography, contained maximum amounts of

the drug at 10 min. after the injection. The average concs. of meperidine in

the brain and plasma of 16-day old rats (41.5 ug/g and 4 ug/ml at 10 min.)

were significantly higher than those of 32-day old animals (25 ug/g and 2.8 ug/

ml at 10 mm.). However, the average ratios of brainplasma cones. of drug

were similar (10.4:1 and 9:1). indicating little difference between the 2 groups

with respect to meperidine transport from plasma to brain. With

gastroenemius muscle, the tissue: plasma concs. of drug were the same in

both age groups, the low values (2:1 to 3:1 at 10 mm.) indicating the much

greater ability of the brain to concentrate meperidine. In 16-day old rats whose

drug metabolizing ability was induced by phenobarbital pretreatment the conc. of

meperidine in brain 10 min. after injection was lower than in untreated animals

of the same age.

171
TAYLOR, K.M. and SNYDER, S.H. Differential effects of D-and L-amphetamine on

behavior and on catecholamine disposition in dopamine and norepinephrine

containing neurons of rat brain. Brain Research 28: 295-309 (1971)

We have compared the effects of D- and L-amphetamine on the

disposition of intraventricularly administered (

3H) norepinephrine and (3H)

dopamine and on endogenous catecholamine in various regions of the rat

brain. In behavioral experiments the effects of D- and L-amphetamine on

locomotor activity and on compulsive gnawing behavior were also compared.

In brain areas where norepinephrine is the predominant catecholamine, Damphetamine but not its L-isomer inhibited (

3H) catecholamine accumulation

and lowered endogenous norepinephrine levels. In the corpus striatum, a

dopaminergic brain region, both D- and L-amphetamine markedly reduced

accumulation of (

3H) catecholamines. D-Amphetamine was 10 times as

potent as L-amphetamine in enhancing locomotor activity. but was only

twice as active in evoking compulsive gnawing behavior. Our results suggest

that brain norepinephrine is selectively involved in mediating amphetamineinduced locomotor stimulation while a dopaminergic component may participate

in eliciting the compulsive gnawing syndrome.

TAYLOR, K.M. and SNYDER, S.H. Dynamics of the regulation of histamine levels

in mouse brain. Journal of Neurochemistry 19: 341-352 (1972)

The intraperitoneal administration of L-histidine in a dose of 1000

mg/kg increased three-fold the whole brain levels of histamine in the mouse.

This increase was evident in all brain regions except the medulla oblongatapons. The subcellular localization of histamine and histidine was the same

in mice administered L-histidine as in saline-treated animals. Cold

exposure and restraint further augmented the elevation of histamine elicited

by histidine treatment. Alpha-Hydrazino-histidine and 4-bromo-3-hydroxybenzyloxyamine (NSD-1055) but not alpha-methyl-DOPA inhibited histidine

decarboxylase (EC 4.1.1.22) activity in mouse brain homogenates and

prevented the increase in brain histamine after histidine administration.

NSD-1055 and alpha hydrazino-histidine also lowered brain levels of

histamine by 50 per cent. NSD-1055 lowered whole brain levels of histamine

rapidly, with a half-life for the depletable histamine pool of about 5 mm.

Assuming that inhibition of histidine decarboxylase accounted for the

reduction in histamine, then the rate of histamine decline reflects the rate

of histamine turnover, and our results suggest that a portion of mouse

brain histamine turns over quite rapidly. Reserpine lowered brain levels of

histamine by about 50 per cent, whereas the antihistammic agent,

dexbrompheniramine, and sodium pentobarbital elevated histamine levels.

172
TAYLOR, K.M. and SNYDER, S.H. Histamine in rat brain: Sensitive assay of endogenous levels, formation in vivo and lowering by inhibitors of histidine decarboxylase. The Journal of Pharmacology and Experimental Therapeutics 173(3):

619-633 (1971)

The sensitivity of an enzymatic isotopic method for histamine was

enhanced so that as little as 0.2 ng in tissue samples could be measured. With

this method histamine was measured in regions of the rat brain. Concentrations ranged from 177 ng/g in the hypothalamus to 22 ng/g in the cerebellum.

3H-histamine was measured reliably in the hypothalamus after the intraventricular injection of 3H-histidine. The formation of hypothalamic 3H-histamine

from 3H-histidine was inhibited by alpha-hydrazinohistidine and 4-bromo-3-

hydroxybenzyloxamine (NSD-1055) but not by alpha-methly-dopa, suggesting

that histamine is formed by the action of a specific histidine decarboxylase.

Alpha-hydrazinohistidine and NSD-1055 but not alpha-methyldopa maximally

lowered endogenous histamine in several brain regions 35 to 40%, with a halflife of depletion of about five minutes. This suggests that a portion of brain

histamine turns over at’a very rapid rate,

TELLER, D.N. and DENBER, H.C.B. Binding of psychotropic drugs to soluble proteins.

Neuro-Psychopharmacology . Edited by H. Brill. New York: Excerpta Medica

Foundation, 1967. P. 1177.

Studies of fluorescence polarization and quenching of chlorpromazine,

thioproperazine, promazine, prochlorperazine and LSD-25 indicated methods

for the measurement of drug binding to proteins. Titration of fluorescence

quenching of human serum fractions, bovine ribonuclease preparations, and

purified enzymes from various sources, can be performed with 10-9 mole or

less of the drug and protein. Results indicate that the phenothiazine drugs bind

preferentially to proteins possessing oxidative activity. Drug binding is further

enhanced in the presence of reduced pyridine nucleotide coenzymes.

Additional, non-stoichiometric and loose binding (or absorption), can be

observed and measured. Tightly coupled drug protein complexes have been prepared from polyacrylamide gel columns. In the case of LSD-human albumin,

the binding shows low dissociation at 8 mu-g LSD/mg protein. The phenothiazine

drugs bind to a greater extent than LSD, and dissociate (thioproperazine greater

than prochlorperazine greater than promazine greater than chlorpromazine) in

the oxidized state. Binding of the psychotropic drugs to particulate protein

(subcellular organelles) is several times as great as to the soluble proteins.

173
TELLER, D.N., DENBER, H.C.B. and KOPAC, M.J. Binding of chlorpromazine and

thioproperazine in vitro -- I. Results of centrifugation methods with tissue

and mitochondria from rat liver and human leukocytes. Biochemical

Pharmacology 16: 1397-1410 (1967)

Binding of two phenothiazine neuroleptics, chlorpromazine (CPZ) and

thioproperazine (TPZ) was studied with rat liver and human leukocytes as

sources of tissue and mitochondria. After 10 min of incubation at 24° in 15 or

30 mu-g CPZ/ml Hank’s solution, rat liver bound 66-88 per cent, whereas

human leukocytes bound 27-29 per cent of the drug. Eight sequential centrifugal washings of the rat liver tissue released 30 per cent of the CPZ, but under

the same conditions human leukocytes released 84-100 per cent of the bound drug.

In contrast, weobserved no difference in mitochondrial binding due to difference

between tissues. Liver and leukocyte mitochondria were centrifuged at 8°

through linear sucrose density gradients that contained a constant concentration

of 15 or 30 mu-g phenothiazine/ml. After 5 min of centrifugation through a

sucrose gradient containing 15 mu-g CPZ/ml, 3.7 mu-g CPZ/ml was bound/mg

mitochondrial protein; after 15 min. 5.3 mu-g drug/ml was bound/mg protein.

With 30 mu-g CPZ/ml in the gradient, 2.2 and 9.9 mu-g of drug/ml were bound/

mg protein after 5 and 15 min, respectively. If TPZ, at either 15 or 30 mu-g/ml,

was present in the gradient, 3.0 and 4.4 mu-g of drug/ml were bound/mg protein after 5 and 15 min. Cooperative effects on binding by the mitochondria and

the drugs were observed as a function of duration of exposure at 8°. Significant quantities of each drug, measured spectrophotofluorinetrically, were

removed from solution by the mitochondrial suspensions.

TRUITT. E.B., JR. and ANDERSON, S.M. Biogenic amine alterations produced in the

brain by tetrahydrocannabinols and their metabolites. Annals of the New York

Academy of Sciences 191: 68-73 (1971)

The involvement of biogenic amines in the brain effects of tetrahydrocannabinols has been reviewed. It appears on the basis of equilibrium-level

changes that Cannabis extracts and delta-9-tetrahydrocannabinol (delta-9-THC)

significantly elevate brain serotonin (5-HT) levels while producing a slight fall

or no significant effect on norepinephrine (NE) except at high doses, when a

rise occurs. Preliminary estimates of turnover times suggest that THC slows

both 5-HT and NE turnover. More complete studies of biogenic amine function

will be required before the final mechanisms of THC on the brain are elucidated.

TRUITT, E.B., JR, and ANDERSON, S.M. The role of biogenic amines in the central

actions of tetrahydrocannabinols and their metabolites. Acta Pharmaceutica

Suecica 8: 696-697 (1971)

Earlier studies using equilibrium levels have shown greater changes

in the whole brain content of serotonin (5-HT) rather than catecholamines,

noradrenaline (NA) and dopamine (DA). Several investigators have found an

elevation of 5-HT with one exception. In contrast, no marked changes have been

noted in whole brain levels of NA. However, the use of turnover analysis in

this investigation shows that changes occur in NA metabolism as well.

174
TURANO, P., MARCH, J.E., TURNER, W.J. and MERLIS, S. Qualitative and quantitative report on chlorpromazine and metabolites in plasma, erythrocytes and

erythrocyte washings from chronically medicated schizophrenic patients.

Journal of Medicine 3: 109-120 (1972)

Qualitative and quantitative analysis of blood plasma, of erythrocyte

washings, and of hemolysates of 22 schizophrenics under long-term chlorpromazine therapy was carried out by thin layer chromatography of dichloromethane

extracts before and after hydrolysis of samples obtained at 1.5 h after morning

medication, and again 12-15 h after evening medication. Chlorpromazine, five

nonhydroxylated and six hydroxylated metabolites, could be identified. The

major metabolites found were’chlorpromazine, Nor2chlorpromazine and their

sulfoxides in plasma and washings, while 7-hydroxychlorpromazine and its

sulfoxide appeared as glucuronides in plasma and washings, but free and associated with 7-hydroxy Nor1

- and Nor2-chlorpromazine in hemolysates. Quantitatively, plasma levels vary quite widely between individuals, but rise with

increasing dose.

TURANO, P., TURNER, W.J. and DONATO, D. Further studies of chlorpromazine

metabolism in schizophrenic men. The Phenothiazines and Structurally

Related Drugs. Edited by I.S. Forrest, C.J. Carr and E. Usdin. New York:

Raven Press, 1974.

Nonenzymatic oxidation of CPZ and 7-OH-CPZ was shown to occur at

each of the steps in preparation of biological materials for quantitation by

TLC or GC. The oxidations, in absence of Fe2+, in light or in dark, in water

or in organic solvents, led to monodesmethylation, sulfoxidation, and formation of N-S dioxides. In water, CPZ also gave rise probably to acidic derivatives. In water or diethyl ether, 3,7-dihydroxy-CPZ arose from 7-OH-CPZ.

Ascorbic acid increased sulfoxide formation but restricted further oxidation.

TURANO, P., TURNER, W.J. and MANIAN, AA. Thin-layer chromatography of

chlorpromazine metabolites. Attempt to identify each of the metabolites

appearing in blood, urine and feces of chronically medicated schizophrenics.

Journal of Chromatography 75: 277-293 (1973)

For abstract, see Section I. Methodology of Drug Research.

175
TURK, R.F., DEWEY, W.L. and HARRIS, L.S. Excretion of trans-delta-9-tetrahydrocannabinol and its metabolites in intact and bile-cannulated rats. Journal of

Pharmaceutical Sciences 62(5): 737-740 (1973)

Tritiated delta-9-tetrahydrocannabinol (I) was administered both orally

and intravenously to groups of bile duct cannulated rats and those with their

bile duct intact. From 55.8 to 66.9 percent of the total radioactivity was excreted during the 96 hr period following administration. The excretion of

radioactivity was minimal in each group beyond 48 hr after drug administration.

The major route of excretion following the intravenous administration in bile

duct-cannulated rats was by way of bile (59.4 percent; feces, 2.7 percent),

whereas more radioactivity was excreted in feces (41.5 percent) than bile

(21.5 percent) when the drug was given orally. This extract was found to contain I by thin layer chromatography (TLC) and gas liquid chromatography analysis.

After intravenous administration, the radioactivity in the feces was not extractable

in petroleum ether but appeared in ether, methanol, and water extracts. TLC

confirmed that the radioactivity in these solvents was associated with metabolites

of I. Bile contained mainly metabolites of I, as did the urine. Less than 10

percent of the radioactivity was excreted in the urine of each group of rats.

TURNER, C.E. and HADLEY, K. Constituents of Cannabis sativa L. II: Absence of

cannabidiol in an African variant. Journal of Pharmaceutical Sciences 62(2):

251-255 (February, 1973)

Cannabidiol is shown to be absent in an African variant of Cannabis

sativa L. (marijuana) grown in Mississippi. TLC, GC, and GC-mass spectrometry were used for identification. The absence of cannabidiol in a variant of

African Cannabis questions the validity of published biosyntheses of the cannabinoids.

TURNER, C.E. and HADLEY, K.W. Constituents of Cannabis sativa L. III: Clear and

discrete separation of cannabidiol and cannabichromene. Journal of

Pharmaceutical Sciences 82(7): 1083-1086 (July, 1973)

Synthetic cannabidiol and cannabichromene were discretely separated

by GLC using their trimethylsilyl ether derivatives. The mono and disilylated

derivatives of cannabidiol were identified. This procedure was utilized in the

analysis of Cannabis sativa L.

TURNER, C.E., HADLEY, K.W. and DAVIS, K.H., JR. Constituents of Cannabis sativa

L. V. Stability of an analytical sample extracted with chloroform. Acta

Pharmaceutica Jugoslavica 23(2): 89-94 (1973)

For abstract, see Section I. Methodology of Drug Research.

TURNER, C.E., HADLEY, K.W. and FETTERMAN, P.S. Constituents of Cannabis sativa

L. VI: Propyl homologs in samples of known geographical origin. Journal of

Pharmaceutical Sciences 62(10): 1739-1741 (October, 1973)

176
TURNER, C.E., HADLEY, K.W., FETTERMAN, P.S., DOORENBOS, N.J., QUIMBY,

M.W. and WALLER, C. Constituents of Cannabis sativa L. IV: Stability

of cannabinoids in stored plant material. Journal of Pharmaceutical Sciences

62(10): 1601-1605 (October, 1973).

The (-)-delta-9-trans-tetrahydrocannabinol content of Cannabis sativa

L. stored at -18, 4, and 22 ± 1

o

 decomposed at a rate of 3.83, 5.38, and 6.92%,

respectively, per year, whereas the material stored at 37 and 50° showed considerable decomposition. C. sativa L. stored in the absence of direct light at

-18, 4, and 22 ± 1

o

 was more stable than cannabis stored under nitrogen. These

data indicate that for normal research use, storage under nitrogen at 0° is not

mandatory. Cannabinol is not the only decomposition product of (-)-delta-9-transtetrahydrocannabinol. Tentative evidence supports the possible formation of

hexahydrocannabinol as a decomposition product in stored C. sativa L.

TURNER, W.J., TURANO, P.A. and MARCH, J.E. Quantitative determination of

chlorpromazine metabolites in urine. Clinical Chemistry 16(11): 916-921

(1970)

For abstract, see Section I. Methodology of Drug Research.

VALERINO, D.M., VESELL, E.S., AURORI, K.C. and JOHNSON. A.O. Effects of

various barbiturates on hepatic microsomal enzymes. A comparative study.

Drug Metabolism and Disposition 2(5): 448-457 (1974)

Six barbiturates were compared with respect to the extent that they

stimulated hepatic microsomal enzymes of mature male rats after 1, 3, 7,

and 14 days of daily ip drug administration. Phenobarbital, pentobarbital,

secobarbital, thiopental, and barbital stimulated ethylmorphine N-demethylase

and aniline hydroxylase activities and increased microsomal cytochrome P-450

content. Considerable temporal differences occurred among these barbiturates

in maximal stimulatory responses. Stimulatory responses approached or

exceeded 200% of control values after 3,7, and 14 days of daily phenobarbital

(100 mg/kg) administration. Responses exceeding 200% of control values were

elicited by barbital (150 mg/kg) during the 14-day observation period. Considerably less stimulation occurred with pentobarbital, secobarbital, and thiopental, and none with hexobarbital. Compared on a molar basis, phenobarbital

was the most potent stimulatory agent for each microsomal parameter after

three daily ip injections. Correlation coefficients between partition coefficients

for these six barbiturates and their stimulatory potencies were less than 0.45

and were considered not to be biologically significant. Oral administration of

phenobarbital (100 mg/kg), secobarbital (75 mg/kg), or hexobarbital (150 mg/kg)

for 3 consecutive days did not significantly alter the stimulatory response of an

identical ip dose of each barbiturate. An association appears to exist between

plasma half-lives of phenobarbital (10.1 hr), pentobarbital (2.3 hr), and hexobarbital (36. 2 min) and their stimulatory potencies. Hepatic radioactivity 24

hr after administration of these three barbiturates was directly related to their

stimulatory potencies.

177
VALERINO, D.M., VESELL, E.S., JOHNSON, A.O. and AURORI, K.C. Effects of

various centrally active drugs on hepatic microsomal enzymes: A comparative

study. Drug Metabolism and Disposition 1(5): 669-678 (1973)

The extent to which six centrally active drugs stimulated hepatic

microsomal enzymes of mature male rats was compared. Of the three parameters examined, diphenylhydantoin enhanced only ethylmorphine N-demethylase

activity and cytochrome P-450 content, whereas the other five drugs stimulated

aniline hydroxylase activity as well. By measuring changes in these microsomal

systems after 3, 7, and 14 days of drug administration, the stimulatory capacities of the six drugs were determined and compared. The stimulatory capacity

of each drug was related to its dose and varied considerably in the temporal

pattern exhibited. Near maximal stimulation of all three parameters occurred

very early with phenobarbital (after three daily injections), whereas chlorpromazine, diazepam, meprobamate, and diphenylhydantoin produced maximal

stimulatory responses only after 7-14 daily injections. Daily administration of

high doses of diphenylhydantoin or ethanol decreased the activity or content of

at least one of the three microsomal systems under investigation. On a molar

basis, phenobarbital was the most potent stimulatory agent after three daily

injections; at this time the other five drugs were generally similar to one another.

In the doses employed in this study, only phenobarbital produced more than

2-fold stimulation of all three microsomal parameters. After 7 days of administration, diphenylhydantoin elevated ethylmorphine N-demethylase activity 240%

above control values.

VANVUNAKIS, H., FARROW, J.T., GJIKA, H.B. and LEVINE, L. Specificity of the

antibody receptor site to D-lysergamide: Model of a physiological receptor

for lysergic acid diethylsmide. Proceedings of the National Academy of Sciences

68(7): 1483-1487 (July, 1971)

Antibodies to D-lysergic acid have been produced in rabbits and guinea

pigs and a radioimmuno-assay for the hapten was developed. The specificity of

this lysergamide-antilysergamide reaction was determined by competitive binding

with unlabeled lysergic acid diethylamide (LSD), psychotomimetic drugs, neurotransmitters, and other compounds with diverse structures. LSD and several

related ergot alkaloids were potent competitors, three to seven times more

potent than lysergic acid itself. The N, N-dimethyl derivatives of several compounds, including tryptamine, 5-hydroxytryptamine, 4-hydroxytryptamine,

5-methoxytryptamine, tyramine, and mescaline were only about ten times less

effective than lysergic acid, even though these compounds lack some of the ring

systems of lysergic acid. The pattern of inhibition by related compounds with

various substituents suggests that the antibody receptor site recognizes structural

features resembling the LSD molecule. In particular, the aromatic nucleus and

the dimethylated ethylamine side chain in phenylethylamine and tryptamine derivatives may assume in solution a conformation resembling ring A and the methylated nitrogen in ring C of LSD. Among the tryptamine derivatives, a large percentage of the most potent competitors are also psychotomimetic compounds.

WAINER, B.H., FITCH, F.W., FRIED, J. and ROTHBERG, R.M. Immunological

studies of opioids: Specificities of antibodies against codeine and hydromorphone.

Clinical Immunology and Immunopathology 3(2): 155-170 (1974)

For abstract, see Section I. Methodology of Drug Research,

178
WAINER, B.H., FITCH, F.W., FRIED, J. and ROTHBERG, R.M. Immunochemical

studies of opioids: Specifications of antibodies against codeine and

hydromorphone. Clinical Immunology and Immunopathology 3: 155 (1974)

Two new immunogenic opioid-protein conjugates were prepared.

Codeine-6-hemisuccinate was synthesized from the reaction of codeine with

succinic anhydride and hydromorphone-6-carboxymethyloxime was

synthesized from the reaction of hydromorphone with alpha-aminoxyacetic

acid. Both opioids were attached covalently to bovine serum albumin using

the mixed anhydride procedure and employed as immunogens in rabbits.

Antibody measured by the ammonium sulfate method showed increases in

titer and avidity following subsequent immunizations. The specificities of

both antisera were studied by competitively inhibiting the binding of labeled

opioid to antibody by the prior addition of increasing concentrations of

various unlabeled opioids. The ranges of immunoreactivity of both antisera

were different and corresponded closely to the structures of the respective

immunizing haptens. These observations suggest that antibodies prepared

against codeine, hydromorphone, and morphine may be used multiply for

qualitative as well as quantitative determinations of opioids in biologic fluids.

WAINER, B.H., FITCH, F.W., FRIED, J. and ROTHBERG, R.M. A measurement of

the specificities of antibodies to morphine-6-succinyl-BSA by competitive

inhibition of 14C-morphine binding. Journal of Immunology 110(3): 667-673

(March, 1973)

For abstract, see Section I. Methodology of Drug Research.

WAINER, B.H., FITCH, F.W., ROTHBERG, R.M. and FRIED, J. The structure of

morphine monohemisuccinate. Science 178: 647 (November, 1972)

WALSH, C.T., LEVINE, R.R., SQUIRES, C. and TALEVIA, L. Kinetics of C

14

-

methadone absorption from the rat cut and the influence of some

physiologic and pharmacologic factors on the absorptive process.

Federation Proceedings (in press)

Absorption of C

14-methadone as a function of both dose and time was

studied in vivo using the closed segment technique. Disappearance of methadone

from duodenal segments followed first-order kinetics, consistent with a

mechanism of passive diffusion. The half-life of duodenal absorption was 15.6

min with similar values obtained for the jejunum, ileum and cecum. In contrast,

the half-life of absorption from the stomach was 10 hr. After gastric intubation

of 100 mu-g of methadone, the disappearance of radioactivity from the stomach

also followed first-order kinetics with a half-life of 2.1 hr; stomach emptying

is therefore the rate-limiting factor in the absorption of methadone. To determine

the extent of absorption of orally administered methadone, urinary excretion of

radioactivity after administration of a 5 mg/kg dose of C

14 methadone by gastric

intubation was compared with that after s.c. injection. The cumulative urinary

excretion of radioactivity in 72 hr was 10.0 ± 3.9% after oral and 15.2 ± 2.4%

after parenteral administration, indicating 65.8% absorption by the oral route.

Absorption from duodenal segments and disappearance from the stomach following

intubation were not affected by 20-day s.c. pretreatment with methadone

(5 mg/kg to 10 mg/kg, b.i.d.).

179
WALSH, M.J., DAVIS, V.E. and YAMANAKA, Y. Tetrahydropapaveroline: An

alkaloid metabolite of dopamine in vitro. The Journal of Pharmacology

and Experimental Therapeutics 174(3): 388-400 (1970)

Tetrahydropapaveroline (THP) has been found to be a quantitatively

important metabolic product of dopamine-C14 in rat brainstem and liver

homogenates. Methods have been developed for the separation and isolation

of THP from tissue extracts. The identity of THP as a metabolite of

dopamine in tissue homogenates has been confirmed by thin layer and gasliquid chromatography and by infrared spectrophotometry. The relative

formation of THP in vitro was greatly dependent upon the substrate

concentration and upon the amount of nicotinamide adenine dinucleotide

available for further oxidation of 3,4-dihydroxyphenylacetaldehyde to 3,

4-dihydroxyphenylacetic acid. THP was the major metabolite of dopamine

in the absence of exogenous coenzymes with both liver orbrainstem

homogenates. Incorporation of nicotinamide adenine dinucleotide or

reduced nicotinamide adenine dinucleotide into incubation mixtures of liver

homogenates essentially abolished THP production and markedly enhanced

the formation of the acid or neutral metabolites. However, THP remained

the major catabolite of the intermediate aldehyde in brain under all conditions.

Consequently, the relative amount of dopamine diverted to THP assumed

appreciable importance under conditions limiting the oxidation or reduction

of 3,4-dihydroxyphenylacetaldehyde. Since THP is known to be

pharmacologically active, formation of this alkaloid may be of functional

importance.

WAY, E.L., Brain neurohormones in morphine tolerance and dependence. Pharmacology

and the Future of Man. Proceedings of the 5th International Congress on

Pharmacology, Vol. I. San Francisco, California: Karger, Basel, 1973. Pp. 77-94.

WAY, E.L., HO, I.K. and LOH, H.H. Brain 5-hydroxytryptamine and cyclic AMP in

morphine tolerance and dependence. Advances in Biochemical

Psychopharmacology Vol. 10. Edited by E. Costa, G.L. Gessa and M.

Sandler. New York: Raven Press, 1974. Pp. 219-229.

WAY, E.L. and SETTLE, A. Cholinergic-dopaminergic interaction during morphine

abstinence. Presented at the 9th International Congress on

Neuropsychopharmacology, Paris, France, July, 1974.

180
WEI, E., LOH, H.H. and WAY, E.L. Brain sites of precipitated abstinence in

morphine-dependent rats. The Journal of Pharmacology and Experimental

Therapeutics 185 (1): 108-115 (1973)

The brains of morphine-dependent rats were explored for areas

sensitive to naloxone-precipitated withdrawal. Stainless-steel guide

cannulas were implanted into different brain areas of male albino rats.

One to five days after cannula implantation, physical dependence on

morphine was induced by s.c. implantation of a pellet containing 75 mg

of morphine base. Naloxone hydrochloride crystals were intracerebraily

applied 70 to 76 hours after morphine pellet implantation. After application

of naloxone, the abstinence signs of wet shakes and escape behavior were

most frequently elicited in the medial thalamus and in medial areas of the

diencephalic mesencephalic junctures. Neocortical, hippocampal.

hypothalamic, tegmental, lateral thalamic and striatal areas of the brain

were less sensitive to naloxone-precipitated withdrawal. The neuroanatomical

pathways related to opioid dependence are discussed.

WILLIAMS, N.W. and CLOUET, D.H. The effect of morphine on the uptake and

release of neurotransmitters, by isolated synaptosomes. Proceedings of

the Fifth International Congress on Pharmacology, San Francisco.

California, 1972. P. 253.

WILSON, H.A., PASTERNAK, G.W. and SNYDER, S.H. Differentiation of opiate

agonist and antagonist receptor binding by protein modifying reagents.

Nature (in press)

WINTER, B.A. and GOLDSTEIN, A. A photochemical affinity-labelling reagent for

the opiate receptor(s). Molecular Pharmacology 6: 601-611 (1972)

A radioactive analogue of levorphanol. (

3H) N-beta-( p-azidophenyl)

ethylnorlevorphanol compound (6), has been synthesized as a photochemical

affinity label for the opiate receptor site(s). It has potent opiate-like

pharmacological activity in whole mice and isolated intact guinea pig ileum.

Upon photolysis of the analogue in the presence of bovine serum albumin

as a test protein. radioactivity is incorporated into the protein. Photolysis

of the analogue in the presence of total particulate matter from whole mouse

brain results in incorporation of radioactivity into a pellet insoluble in water

and organic solvent. This incorporation is significantly but incompletely

blocked by both levorphanol and destrorphan. Incorporation into guinea pig

ileum longitudinal muscle strips is also observed but is not significantly

blocked by levorphanol or dextrorphan. The implications of the results are

discussed.

181
WINTER, J.C. Tolerance to a behavioral effect of lysergic acid diethylamide and crosstolerance to mescaline in the rat: Absence of a metabolic component. The

Journal of Pharmacology and Experimental Therapeutics 178(3): 625-630

(1971)

This investigation examined tolerance to lysergic acid diethylamide

(LSD) after the administration of LSD or mescaline in rats responding on a

fixed ratio schedule of positive reinforcement. After the requisite conditions

were established for the development of tolerance in the behavioral situation,

the same schedule of drug administration was applied to untrained animals

and the levels of LSD in brain and liver were determined. In this way the

metabolic component of tolerance was assessed. Pretreatment with either

LSD or mescaline for two days preceding the administration of LSD caused a

diminution of the rate-depressant effect of LSD. This demonstration of

tolerance to LSD and cross-tolerance to mescaline was in agreement with the

results of other workers. Determination of the total amount and concentration

of LSD in brain and Liver revealed no significant differences between rats

which received LSD for the first time and those pretreated with LSD or mescaline,

These results indicate that there is no gross alteration in brain and liver levels

of LSD concomitant with the development of tolerance to LSD or cross-tolerance

of LSD to mescaline in the particular behavioral task studied.

WURSCH, M.S., OTIS, L.S., GREEN, D.E. and FORREST, I.S. 3H-delta-9-THC

metabolism in rhesus and squirrel monkeys. Proceedings of the Western

Pharmacological Society 15:68 (1972)

Our study was designed to find a suitable primate model for in vivo

metabolism of delta-9-THC on which the biotransformations could be studied

and suitable methodology for the assay of its metabolites could be developed.

YAGEN, B. and MECHOULAM. R. Stereospecific cyclizations and isomerizations of

cannabichromene and related cannabinoids. Tetrahedron Letters

60: 5353 (1969)

YARBROUGH, G.G., BUXBAUM, D.M. and SANDERS-BUSH, E. Biogenic amines and

narcotic effects: II. Serotonin turnover in the rat following acute and chronic

morphine administration. The Journal of Pharmacology and Experimental

Therapeutics (in press)

YARYURA-TOBIAS. J.A., DIAMOND, B. and MERLIS, S. Psychiatric manifestations

of levodopa. Canadian Psychiatric Association Journal 17: SS-123 - SS-128

(1972)

182
YARYURA-TOBIAS, J.A., DIAMOND, B., and MERLIS, S. The action of L-dopa on

schizophrenic patients (a preliminary report). Current Therapeutic Research

12(8): 528-531 (August, 1970)

YARYURA-TOBIAS, J.A.. WOLPERT, A., WHITE, L, AGOLA, P. and MERLIS. S.

A clinical evaluation of clopenthixol. Current Therapeutic Research 12(5):

271-279 (May, 1970)

YEH. S.Y. and MITCHELL, C.L. Effect of monoamine oxidase inhibitors on

formation of morphine glucuronide. Biochemical Pharmacology 21:

571-578 (1972)

The inhibition of the formation of morphine glucuronide in vitro by

five monoamine oxidase inhibitors is described. Pargyline and phenelzine

at 1.0 and 5.0 X 10-4M concentration and tranylcypromine at 5 and 10X

10-4M concentration were competitive inhibitors of morphine glucuronidation,

while isocarboxazide was a mixed-type inhibitor. Nialamide, in the

concentrations studied, did not significantly inhibit the formation of morphine

glucuronide.

YOUNG, A.B. and SNYDER, S.H. A sensitive specific enzymatic-fluorometric

assay for homocarnosine. Journal of Neurochemistry 21: 387-396 (1973)

We have developed a sensitive and specific assay for homocarnosine

in tissues. Homocarnosine is separated from GABA by ion exchange

chromatography. After hydrolysis of homocarnosine with swine kidney

carnosinase, the evolved GABA is measured by an enzymatic-fluorometric

procedure. As little as 0.1 nmol of tissue homocarnosine can be detected

by this procedure. Homoanserine, which would be detected by this assay,

can be separated from homocarnosine by thin layer chromatography. No

homoanserine could be detected in any tissue examined. There are marked

regional variations in levels of homocarnosine in guinea-pig brain that do

not correspond to regional differences in GABA levels.

YU, J.H. and SMITH, C.B. Noncompetitive inhibition by cocaine of uptake and binding

of 3H-serotonin by rat brain slices. Presented at the Fifth International

Congress on Pharmacology, San Francisco, California, July 23-28, 1972.

ZIMMERMANN, E., GISPEN, W.H., MARKS, B.H. and de WIED, D., editors.

Drug Effects on Neuroendocrine Regulation. Progress in Brain Research,

Vol. 39. New York: American Elsevier Publishing Company, Inc., 1973.

183
ZITKO, B.A., HOWES, J.F., RAZDAN, R.K., DALZELL. B.C., DALZELL, H.C.,

SHEEHAN, J.C., PARS, H.G., DEWEY, W.L. and HARRIS, L.S. Water

soluble derivatives of delta-1-tetrahydrocannabinol. Science 177: 442-

444 (1972)

Delta-1-tetrahydrocannabinol, which is resinous and insoluble in

water and therefore difficult to study pharmacologically, can be converted

to a water soluble derivative without loss of its biological activity. This

has been achieved by preparing esters bearing a nitrogen moiety with the

use of carbodiimide as a condensing agent. The availability of such watersoluble derivatives will allow the evaluation of delta-1-tetrahydrocannabinol

in self-administration studies in monkeys for its addiction liability potential

in man. This technique of water solubization is also applicable to other

compounds of chemical and biological significance.

184
III

Mechanisms

of Action

of Different Drugs

ABEL, E.L., editor. Behavioral and Social Effects of Marijuana. New York:

MSS Information Corporation, 1973.

For abstract, see Section II. Drug Chemistry and Metabolism.

ABEL, E.L., McMILLAN, D. E. and HARRIS, L.S. Tolerance to the behavioral and

hypothermic effects of 1-delta-9-tetrahydrocannabinol in neonatal chicks.

Experientia 28: 1188-1189 (1972)

The development of tolerance to the behavioral effects of

marihuana and to its principle active ingredient, 1-delta-9-

tetrahydrocannabinol (delta-9-THC) has been demonstrated in various

species of adult animals including rats, mice, pigeons, and monkeys.

Our experiments with chicks show that tolerance develops not only

to the behavioral effects of delta-9-THC but to its physiological

effects as well, and that this is also observable in neonatal

animals.

ABEL, E.L., McMILLAN, D.E. and HARRIS, L.S. Tolerance to. the hypothermic

effects of delta-9-THC as a function of age in the chicken. British Journal

of Pharmacology (in press)

ADAMS, M.D., DEWEY, W.L. and HARRIS, L.S. Cardiovascular effects of

delta-8- and delta-9-tetrahydrocannabinol in rats. The Pharmacologist

44: 394 (1974)

Intravenous administration (0.1-3.0 mg/kg) of delta-8- or

delta-9-tetrahydrocannabinol (THC; solubilized in a mixture of

polyoxyethylated vegetable oil, ethanol and saline) produced transient

increases in blood pressure in rats followed by a sustained bradycardia

and decrease in blood pressure. Tachyphylaxis to the depressor phase

limited the number of injections that could be administered to a single

animal. Intraarterial injections of delta-8- and delta-S-THC (0.1 mg/kg,

0.3 mg/kg, 1.0 mg/kg and 3.0 mg/kg) produced vasoconstriction in the

perfused hindquarters of rats. Dose-response curves indicate that delta-8-

and delta-9-THC have equal potency with regard to this vasoconstrictor

action. No tachyphylaxis to the vasoconstrictor effect was observed.

The hindquarter vasoconstrictor response to delta-9-THC (0.3 mg/kg,

or 1.0 mg/kg) was not altered by treatment with phenoxybenzamine

100 mu-g/kg). Constrictor responses to delta-S-THC (0.1 mg/kg,

0.3 mg/kg and 1.0 mg/kg) were also measured before and after

185
phentolamine (1.0 mg/kg). Phentolamine caused slight reductions

in responses to 0.1 mg/kg and 0.3 mg/kg delta-9-THC and a significant

reduction in response to 1.0 mg/kg delta-9-THC. These data illustrate

that delta-8- and delta-9-THC may have vasoconstrictor actions in

certain vascular beds which may be independent of stimulation of alpha

adrenergic receptors.

ADAMS, W. J., LORENS, S.A. and MITCHELL, C.L. Morphine enhances hypothalamic

self-administration in the rat. Proceedings of the Society for Experimental

Biology and Medicine 140: 770-771 (1972)

Morphine sulfate (10 mg/kg subcutaneously) suppressed selfstimulation 1-2 hr after injection but augmented it 5-6 hr postadministration.

Complete tolerance to the depressant effect was developed after three

daily injections. The excitatory effect, however, tended to increase

throughout the 5 day testing period.

ADLER, M. W., BENDOTTI, L., GHEZZI, D., SAMANIN, R. and VALZELLI, L.

Dependence to morphine in differentially housed rats. Psychopharmacologia

(in press)

ADLER, M. W., KOSTOWSKI, W., RECCHIA, V. and SAMANIN. R. Anatomical

specificity as the critical determinant of the effect of raphe lesions on

morphine analgesia. European Journal of Pharmacology (in press)

ADLEP, M.W., LIN, C., SMITH, K.P., TRESKY, R. and GILDENBERG,. P.L.

Lowered seizure threshold as a part of the narcotic abstinence syndrome

in rats. Psychopharmacologia 35: 243-247 (1974)

For abstract, see Section I. Methodology of Drug Research.

AGHAJANIAN, G. K. LSD and CNS transmission. Annual Review of Pharmacology

12: 157 (1972)

The research conducted on the effects of D-lysergic acid

diethylamide (LSD) and CNS transmission is reviewed to determine its

mode and site of action. Much evidence exists to support the assumption

that LSD produces its effects by altering synaptic transmission. Moreover,

the fact that serotonin containing neurons of the raphe nuclei are selectively

sensitive to small parenteral doses of LSD suggests that the drug has its

primary effects on specific neurons and synapses linked to the raphe

neuronal system rather than on synaptic transmission in general. It is

thought that LSD either blocks or mimics serotonin, and there is evidence

to support both modes of action. Two-brom-LSD is a potent blocker of

serotonin, more so than LSD; however, it has little psychotomimetic

activity. On the other hand, LSD but not 2-brom-LSD tends to have a

selrotonin like effect at low doses and is inhibitory only at high doses. In

any event, the elucidation of the mechanism of action of LSD will require

more than isolated obdsertrations on the effects of LSD or serotonin on raphe

or other individual neurons. Ultimately it will be necessary to integrate data

from the unit level with knowledge about the interconnections and physiological

role of the neuronal systems within which these units function.

186
AGHAJANIAN, G.K. and BUNNEY, B.S. Central dopaminergic neurons:

Neurophysiological identification and responses to drugs. Frontiers in

Catecholamine Research. Edited by E. Usdin and S.H; Snyder. New York:

Pergamon Press, 1973. Pp. 643-648.

For abstract, see Section I. Methodology of Drug Research.

AGHAJANIAN, G.K., BUNNEY, B.S. and KUHAR, M.J. Use of single unit

recording in correlating transmitter turnover with impulse flow

in monoamine neurons. New Concepts in Neurotransmitter Regulation.

Edited by A. J. Mandell. New York: Plenum Press, 1973.

The rate of firing of monoaminergic neurons was recorded

to investigate the relationship between monoamine turnover and impulse

flow within monoaminergic systems. Recordings from 5-hydroxytryptamine

(5-HT) and catecholamine (CA) containing neurons indicate 2 mechanisms

of action. One involves a direct effect on monoamine synthesis or

degradation in which the rate of firing of monoamine neurons is secondary

to the biochemical changes. The second mechanism involves a metabolic

change which is secondary to an effect on neuronal firing rate. Mechanisms

for other drugs tested are also discussed.

AGHAJANIAN, G.K. and FREEDMAN, D.X. Biochemical and morphological aspects of

LSD pharmacology. Psychopharmacology: A Review of Progress, 1957-1967.

Edited by D. Efron, J. Cole, J. Levine and J.R. Wittenborn. Washington. D.C.

U.S. Government Printing Office, 1968. Pp. 1185-1193.

For abstract, see Section II. Drug Chemistry and Metabolism.

AGHAJANIAN, G. K., HAIGLER, H.J. and BLOOM, F.E. Lysergic acid diethylamide

and serotonin: Direction actions on serotonin-containing neurons in rat

brain. Life Sciences 11(13): 615-622 (1972)

A study was made of the effects of lysergic acid diethylamide

(LSD) and serotonin (5HT) on serotonin-containing neurons in rat

brain. LSD and 5HT were applied directly by microiontophoresis to

5HT-containing neurons in the midbrain raphe nuclei. The firing of

these neurons was markedly inhibited by both LSD and 5HT. The effects

of LSD given systematically and microionophoretically were similar. This

suggests that the inhibition of raphe neurons which occurs after the systemic

administration of LSD could be due to a direct action of the drug.

ALPERT, M., ANGRIST, B., DIAMOND, F. and FRIEDHOFF, A.J. Effects of high

doses of amphetamine on digital tremor in volunteers pretreated with

agents which alter biogenic amines. Committee on the Problems of Drug.

Dependence. Washington, D.C.: National Academy of Sciences, National

Research Council, 1971.

In biochemical studies these workers found that the 1 and d

stereoisomers of amphetamine are differentially effective in inhibiting

catecholamine uptake into striatal and hypothalamic synaptosoines.

Using 3H-dopamine and tissue derived from rat corpus striatum it

was found that d and 1 amphetamine were equally effective in blocking

uptake. Using 3H norepinephrine and tissue derived from rat hypothalamus

it was found that d-amphetamine was ten times more potent in preventing

uptake of norepinephrine than l-amphetamine.

187
ALTSHULER, H. L. and BURCH, N.R. The electroencephalographic effects of cocaine

and d-amphetamine in the rhesus monkey as described by period analysis.

Proceedings of the Society for Neurosciences 3: 343 (1973)

The electroencephalographic (EEG) descriptors of cocaine are poorly

characterized and their mechanisms poorly understood. The effects of

cocaine and d-amphetamine on the period analytic descriptors of the

electroencephalogram of the monkey, Macaca mulatta, were evaluated when

the animal was seated in a primate chair. Each animal served as his own

control, and control studies were performed using intravenous (IV) saline

injections. IV doses of cocaine (0.05-5.0 mg/kg) and d-amphetamine

(0.05-5.0 mg/kg) were administered to each animal in accordance with a

randomized experimental design and the EEG continuously recorded for 2

hours after each dose. Periods of photic stimulation (3-30 Hz) were

interspersed with periods of spontaneous EEG. A number of changes were

observed in the period analytic descriptors. The major period (zero

crossings) count was dramatically increased for 5 or more min post-dose.

Intermediate period (first derivative) and minor period (second derivative)

counts were more variable in their changes, although differences between

the drugs were seen at all points of the dose-response curve, in most

frequency bands and in responses to photic driving. Reserpine (0.5 mg/kg/day)

and 1 DOPA (100 mg/kg/day) were administered chronically to naive monkeys

and those previously studied, and the acute effects of cocaine and d-amphetamine

evaluated electrographically. Differences in the acute responses to the

stimulants were seen in the pretreated animals when compared to the nonpretreated ones. These results implicate central biogenic amines in the

actions of d-amphetamine and cocaine on the EEG.

ALTSHULER, H.L., and BURCH, N.R. Period analysis of the electroencephalogram

of subhuman primates. Behavior and Brain Electrical Activity. Edited by

N.R. Burch and H. L. Altshuler. New York: Plenum Press, 1974.

For abstract, see Section I. Methodology of Drug Research.

A LTSHULER, H.L., BURCH, N.R. and DOSSETT, R.G. The effects of cocaine and

d-amphetamine on the spontaneous and photically driven occipital

electroencephalogram of the monkey. Federation Proceedings 33(3):

293 (March, 1974)

Some aspects of the mechanisms of central stimulation by

cocaine (C) and d-amphetamine (A) were examined. The spontaneous and

photically-driven (3-30 Hz) EEG of 3.5-6 kg M. mulatta monkeys

was analyzed by period analysis. This technique provides the major period

(MAP, baseline cross count), intermediate period (IMP, first derivative)

and minor period (MIP, second derivative) descriptors of the spontaneous

EEG, and pre- and post-stimulus descriptors of the photically-driven EEG.

The occipital area was most effected by both drugs. Following C

spontaneous MAP counts change only slightly, while IMP and MIP counts

increase dramatically. All three occipital area period descriptors increase

following A. The photically-driven EEG was profoundly altered by both

drugs, especially shifts in dominant driving frequencies. These

alterations, as well as spontaneous changes, were modified by chronic

daily treatment with reserpine (0. 5 mg/kg) or l-DOPA (100 mg/kg).

Data obtained from parallel experiments without interspersed photic

driving suggest that photic stimulation may contribute to the changes

seen in the spontaneous, non-stimulated, occipital EEG. The central

amine manipulations in this study demonstrate the key role of the biogenic

amines in the electrophysiological effects of C and A.

188
ALTSHULER, H.L., BURCH, N.R.. PHILLIPS, P.E. and DOSSETT, R.G. The

effects of cocaine and d-amphetamine on simian electroencephalographic

responses to photic driving. Proceedings of the Society for Neurosciences

4: 117 (1974)

Cocaine (C) and d-amphetamine (A) were previously demonstrated to

produce pronounced changes in the period analytic descriptors of the

spontaneous occipital electroencephalogram (EEG) of the monkey, which

were unrelated to photic responses. The current study reports EEG

responses to photic stimulation at frequencies of 3-30 Hz following C

and A. Experiments were done in which intravenous doses of saline,

C (0.5 mg/kg - 5.0 mg/kg) and A (0.25 mg/kg - 2.5 mg/kg) were

administered to rhesus monkeys during 90 minute experiments composed

of both spontaneous and photically driven EEG recordings. Both drugs

caused profound changes in the EEG responses to photic stimulation.

Photic driving responses were uniformly inhibited at the stimulation

frequency following 2.5 mg/kg of C and 0.5 mg/kg of A, but the

responses were shifted to other frequencies often in proximity to the

driving frequency. The shift in response frequency was not observed.

as shifts to harmonic frequencies, nor were there clear dose-related aspects

to the response shifts. The extreme potency of these compounds in

altering EEG responses to photic stimulation demonstrates further the profound

effects of C and A on the primate visual system.

AMAROSE, A.P., SCHUSTER, C.R. and MULLER, T.P. An animal model for the

evaluation of drug induced chromosome damage. Oncology 27: 550-562

(1973)

Cytogenetic analyses of cells subjected to psychotropic drugs are

important but restrictive when man is the study subject. An experimental

animal system, using the rabbit, was established to ascertain whether a

relationship exists between in vivo administration of drugs of abuse and

chromosome damage. This report describes the cytogenetic data after

acute and/or chronic intravenous administration of d-methamphetamineHCl, LSD-25, and mitomycin C. The hyperthermia data of LSD-25

were analyzed during the experiments with this drug. A positive

control was established with mitomycin C and sterile injectable saline

was used for the negative controls. Pre and post chromosome complements

failed to show any statistical association between chromosome damage and

LSD or methamphetamine. The hyperthermia engendered after the injection

of LSD was statistically significant and residual in nature.

ANDERSON, T. and SCHANBERG, S.M. Effect of thyroxine and cortisol on brain

ornithine decarboxylase activity and swimming behavior in developing rat.

Biochemical Pharmacology (in press)

ANDERSON, T.R. and SLOTKIN, T. Effects of morphine on the rat adrenal medulla.

Biochemical Pharmacology (in press)

189
ANDERSON, T.R. and SLOTKIN, T.A. Maturation of the adrenal medulla - IV.

Effects of morphine. Biochemical Pharmacology (in press)

Chronic morphine administration in adult rats results in

neurogenic secretion of adrenal catecholamines and compensatory

‘increases in basal catecholamine levels, in activities of catecholamine

biosynthetic enzymes (tyrosine hydroxylase and dopamine beta-hydroxylase)

and in the number of storage vesicles in the tissue. Perinatally addicted

developing rats demonstrated changes completely different from those seen

in adults: catecholamine levels and dopamine beta-hydroxylase activity were

reduced compared to controls and no induction of tyrosine hydroxylase was

observed. The time course of adrenomedullary maturation was delayed through

the first 10-20 days of age, with reduced numbers of storage vesicles and

larger proportions of partially filled vesicles. On exposure to morphine,

continued until weaning, perinatally addicted rats did not display any of the

changes in catecholamine synthesis or vesicular uptake seen in adult rats.

Developing rats treated only in utero or only postnatally demonstrated

different types of biochemical deficits which appeared at different times

during development. The effects of morphine in developing rats vs. adult

rats can be partly explained by the absence of functional innervation of the

neonatal adrenal medulla; however other factors may also operate.

ARNFRED, T. and RANDRUP. A. Cholinergic mechanism in brain inhibiting

amphetamine-induced stereotyped behaviour. Acta Pharmacologia et

Toxicologia 26: 384-394 (1968)

In previous papers we have presented evidence indicating that

amphetamine produces stereotyped behaviour continuous sniffing-lickingbiting in rats) by activating a dopaminergic mechanism in the corpus

striatum (RANDRUP & MUNKVAD 1968. review). This view, however,

does not exclude the possibility, that the stereotyped behaviour can be

influenced ‘inhibited or enhanced) by other transmitter systems in the

brain, and published evidence shows that it is prolonged when amphetamine

is combined with anticholinergic drugs (SCHELKUNOV 1964).

Thus it is possible that there is a cholinergic mechanism or system in

the brain, which antagonizes the stereotyped behaviour. This possibility

has been investigated by experiments reported in the present paper,

ASTON, R. Mechanisms contributing to barbiturate intolerance in rats. British

Journal of Pharmacology 49: 527 (1973)

Female rats, 3 weeks after pretreatment with 200 or 400 (mg/kg)/

day barbitone for 2 or 30 days, exhibited a prolonged sleeping time and a

reduced awakening barbiturate brain level when challenged with either barbitone

or pentobarbitone. After 3 additional weeks, the latter responses had

returned, or were returning to, control values.

Barbitone pretreatment schedules had no residual effect upon in vitro

hepatic pentobarbitone-metabolizing activity measured 3 or 6 weeks later,

except in one instance, when hepatic enzyme activity was significantly enhanced

3 weeks after 30 daily doses of 200 mg/kg barbitone. In this case, however,

an enhanced barbiturate sleeping time, together with a reduced awakening

barbiturate brain level, were observed.

190
Aston, R. continued

It is concluded that barbitone administered intraperitoneally in

doses of 200 to 400 (mg/kg)/day for 2 or 30 days induces a non-hepatogenic

intolerance to barbiturates, related to an increased sensitivity of the central

nervous system to these drugs. This central intolerance is seen 3 weeks, but

not 6 weeks, after pretreatment. Furthermore, this central intolernace has

been observed to co-exist with an hepatic tolerance, a situation which could

result in a reduced LD50 coupled with an increase in ED50.

ASTON, R. and HIBBELN, P. Induced hypersensitivity to barbital in the female rat.

Science 157(3795): 1463-1464 (September, 1967)

Female rats, treated with two daily anesthetic doses of barbital, exhibit

1 month later a significant increase in sleeping time over that of control animals.

Hypersensitive animals, as compared to controls, show no alteration in liver

weight (as percentage of body weight), but they manifest a significant shortening

of time for induction of anesthesia. Induced hypersensitivity to barbiturates is

apparently not the result of alterations in the metabolism of these agents, but

it may be related to enhanced susceptibility of the central nervous system to

these drugs.

AYHAN, I.H. Daily susceptibility variations. to the morphine-induced hyperactivity

of rats. Journal of Pharmacy and Pharmacology 26: 76-78 (1974)

AYHAN, I.H. and RANDRUP, A. Inhibitory effects of amphetamine, L-DOPA and

apomorphine on morphine-induced behavioural excitation of rats. Archives

internationales de Pharmacodynamie et de Therapie 204(2): 283-292 (August, 1973)

The influence of amphetamine, L-DOPA and apomorphine on morphineinduced hyperactivity was studied in rats. A small dose of morphine (2 mg/kg)

produced stimulation of locomotion, rearing and grooming. By combined

administration, amphetamine, L-DOPA and apomorphine potentiated each

other with respect to behavioural effects. In contrast, these three drugs strongly

inhibited the occurrence of morphine-induced behavioural excitation. These

results support the idea that the mechanism of morphine-induced hyperactivity

differs from that of amphetamine, L-DOPA and apomorphine and stimulation

of rats’ behaviour by morphine is probably not due to the activation of. dopaminergic

systems in the brain.

AYHAN, I.H. and RANDRUP, A. Role of brain noradrenaline in morphine-induced

stereotyped behavior. Psychopharmacologia 27: 203-212 (1972)

The injections of morphine into rats which had been made tolerant to

morphine produced stereotyped sniffing, licking and biting reminiscent of

amphetamine-stereotypy. Pretreatment with drugs acting on the brain

catecholamines such as reserpine, H 44/68. FLA-63 and receptor blockers could

inhibit this behaviour. Comparison between morphine and amphetamine

stereotypy indicated that brain noradrenaline plays a more important role

than dopamine in morphine induced stereotyped behaviour, in contrast to

amphetamine stereotypy where dopamine is the most important brain amine.

The result of experiments with intraventricular injections of noradrenaline supported

this conclusion. because the noradrenaline suppressed the blocking action of

FLA-63 on morphine-induced stereotypy.

191
BABBINI, M. and DAVIS, W.M. Time-dose relationships for locomotor activity

effects of morphine after acute or repeated treatment. British Journal of

Pharmacology 46(2): 213 (October, 1972)

Effects of morphine sulphate (1.25, 2.5, 5, 10, 20 and 40 mg/kg i. p.)

on locomotor activity of male rats were observed for 8 h after single doses

in non-tolerant rats. The lower three doses had only an excitatory effect,

whereas the higher three doses caused initial depression followed by a delayed

excitatory effect.

The same doses of morphine were administered daily for 30 days.

No tolerance developed within this time to the excitatory effect. The locomotor

excitatory effect of the higher three doses of morphine became progressively

more pronounced over treatment periods of 30 days (and 48 days for 20 mg/kg),

while the latency to peak activity decreased.

An explanation of these results is suggested on the basis of two

different central drug-receptor interactions affecting motility.

BAILEY, D.N. and JATLOW, P.I. Chemical analysis of massive crystalluria

following primidone overdose. American Journal of Clinical Pathology

58(5): 583-589 (November, 1972)

For abstract, see Section II. Drug Chemistry and Metabolism,

BAKER, W.W. Excitatory responses following intracaudate injection of

N-methyl-dl-aspartic acid. Archives internationales de Pharmacodynamie

et de Therapie 196: 226-234 (1972)

In chronic cats, unanesthetized and anesthetized, intracaudate

microinjections of N-methyl-dl-aspartic acid (NMA) produced a broad

spectrum of excitatory responses which included: rage (only unanesthetized

preparation), tremors and gross body movements, mydriasis and salivation.

‘In the anesthetized preparations, intracaudate NMA also exerted an analeptic

action in that it activated the cortex (abolished spindling activity), roused

the animal with opening of eyelids, involuntary movements. vocalization.

increased respiration and accelerated heart rate. These actions were

transient and the animal lapsed back into an anesthetic state. However, upon

supplemental injections of NMA analeptic effects were repeatable without any

evidence of cumulative action or tachyphylaxis. Caudate-mediated NMA excitatory

responses were not blocked by pretreatment with either local scopolamine (in

contrast to carbachol) or tetracaine. It is concluded that the caudate participates

directly in modulating motor, behavioral and electrocortical activities, and

that the depolarizing action of local NMA disrupts inhibitory control in the

caudate to produce extensive excitation of the C.N.S.

192
BAKER, W.W. and BENEDICT, F. Analysis of local discharges induced by

intrahippocampal microinjection of carbachol or diisopropylfluorophosphate (DFP).

International Journal of Neuropharmacology 7: 135 -147 (1968)

Following intrahippocampal injections, carbachol and diisopropylfluorophosphate (DFP) each were highly effective in producing hippocampal discharges;

electrographically, both types of discharges resembled one another. Our data

indicate that these discharges are both of cholinergic origin and result from

an action on local “muscarinic” receptors. However, the build-up and persistence

of endogenously released acetylcholine precede the DFP discharges. These

cholinergic discharges were readily suppressed by intrahippocampal scopolamine,

a potent muscarinic antagonist. In contrast, nicotinic blocking agents were

ineffective. This coupled with the unresponsiveness of the hippocampus to

nicotine and pharmacologically related agonists strongly suggests an absence of

“nicotinic” receptors in this area. Of the other antagonists, tetracaine was

almost as effective as scopolamine in abolishing cholinergic discharges: whereas,

pyridine-2-aldoxime methiodide (2-PAM) was specific only against the DFP

discharges since it reversed in situ the inhibition of cholinesterase by DFP.

Antagonism of carbachol effects by 2-PAM was negligible. It appears that the

levels of acetylcholine and its actions on “muscarinic” receptors are critical

in influencing hippocampal function. These local cholinergic systems in the

hippocampus might then be expected to assume special significance in normal and

abnormal brain activities.

BAKER, W.W. and BENEDICT, F. Differential responses of hippocampal repetitive

discharges to scopolamine and pentobarbital. Experimental Neurology

21: 187-200 (1968)

The hippocampus responded to microinjected drugs by producing two’

well-defined patterns of repetitive activities, firing either intermittently or

continuously. The intermittent discharges, established after intrahippocampal

picrotoxin or d-tubocurarine (dTC), developed as discrete foci which fired

cyclically as spike-waves with an interposed afterdischarge; the continuous

discharges, established after microinjected carbachol or diisopropylfluorophosphate

(DFP), fired as sustained, uninterrupted spikes of uniform amplitude. These

patterned discharges were further contrasted by their differential susceptibilities

to intravenous pentobarbital or scopolamine. The afterdischarge components of

both the dTC and picrotoxin foci were differentially suppressed by small doses

of pentobarbital (1-5 mg/kg); whereas, the continuous discharge activity due

to either carbachol or DFP, was selectively abolished by scopolamine (0.1 mg/kg).

The afterdischarges eliminated by pentobarbital were readily restored, but the

cholinergic discharges abolished by scopolamine were difficult to reestablish,

Significantly, both the spike-wave of the foci and the uninterrupted spike

discharges were considerably more resistant to pentobarbital. According to

our interpretations, the afterdischarges are related to lowering of presynaptic

inhibition which pentobarbital antagonizes by either directly or indirectly

increasing local inhibition, thus raising the local threshold of excitability.

By contrast, the continuous discharges are attributed to actions at presynaptic and postsynaptic cholinergic receptors; scopolamine is more effective

against this activity by virtue of its direct and selective interference with these

local cholinergic excitatory mechanisms. Our findings call attention to some of

the critical interactions of local excitatory and inhibitory processes in the

hippocampus, and demonstrate their importance not only in generating local

discharges, but also in the patterning of the type of repetitive activity.

193
BAKER, W.W. and BENEDICT, F. Increased local cholinergic activity on hippocampal

foci. Federation Proceedings 28: 775 (1969)

Hippocampal foci each with a characteristic pattern of firing were

developed acutely in cats by microinjecting focogenic agents intrahippocampally

(I.H.). Cholinergic activity was increased at the focus site by supplementary

microinjections of carbachol or an anticholinesterase. Carbachol (5 mu-g I.H.)

stimulated foci with increased firing rates. lengthened afterdischarges and

intermittent seizures. These effects were antagonized by I. H. scopolamine

(10-30 mu-g). Initially, diisopropylfluorophosphate (DFP) and physostigmine

accelerated firing rates of foci but then markedly depressed their excitability.

Depressed activity, however, was restored by small doses of I. H. acetylcholine

(ACh). Excitation by neostigmine paralleled that by carbachol. Because of

their quaternary structure and limited lipid solubilities, excitation by carbachol

and neostigmine are attributed to actions on superficial cholinergic sites.

Inhibition by DFP and physostigmine (build-up of endogenous ACh) are ascribed

to actions on less accessible “Interior” ChE stores (and ACh receptors): these

sites are bounded by a lipid barrier. Our results suggest a potential role of these

local cholinoceptive mechanisms in determining the fate of hippocampal foci.

BAKER, W.W. and BENEDICT, F. Local electrographic responses to intrahippocampal

d-tubocurarine and related neuromuscular blocking agents. Proceedings of the

Society for Experimental Biology and Medicine 124: 607-611 (1967)

Our research was primarily structured to analyze the local electrographic

patterns of excitation induced by dTC microinjected into the hippocampus.

To characterize this activity further, the study was expanded to include other

neuromuscular blocking agents. We hoped also to characterize the local

mechanisms associated with hippocampal effects of dTC and if possible, to

relate these to the cholinergic receptor mechanisms which have been defined

pharmacologically at the neuromuscular junction.

BAKER, W.W. and BENEDICT, F. Selective effects of i.v. pentobarbital and scopolamine

on chemically-induced repetitive discharges in the hippocampus. Federation

Proceedings 27:571 (1968)

BAKER, W.W. and CONNOR, J.D. Production of tremor by intracaudate cholinergic

agents and its suppression by locally administered catecholamines. Excerpta

Medica, International Congress Series, No. 154. Amsterdam, the Netherlands:

Excerpta Medica Foundation, 1967. P. 32.

Of a series of cholinergic muscarinic agents microinjected into the caudate

nucleus, carbachol (anafog of acetylcholine) was the most potent in producing limb

tremors in cats. Tremors similarly developed after intracaudate anticholinesterases

which potentiated the acetylcholine released endogenously. In contrast, cholinergic

nicotinic agents were totally inactive. Muscarinic blocking agents (belladonna

alkaloids), administered locally suppressed carbachol-induced tremors; nicotine

blocking agents were ineffective. These findings indicate that cholinergic agents

act specifically on “muscarinic” receptors in the caudate to produce involuntary

movements.

194
Baker, W.W. and Connor, J.D. continued

Tremors induced by carbachol were readily suppressed also by intracaudate catecholamines, but not by other sympathomimetics which are noncatecholamines. Antitremor potencies of the catecholamines paralleled their

order of beta-receptor activity as defined by Ahlquist. Intracaudate pretreatment with beta-adrenergic blocking drugs, however, prevented this inhibition of

cholinergic tremors: locally injected alpha-adrenergic blocking agents under

comparable conditions were ineffective. These results coupled with our finding

that microinjected adenosine triphosphate (ATP) also abolished tremors suggest

that suppression of the carbachol tremors by the catecholamines is mediated by

a “metabolic” effect involving beta-adrenergic receptors.

Since in the caudate increased cholinergic activity elicited tremor,

whereas the catecholamines suppressed this activity, we feel justified in concluding that the level of these. neurotransmitters are critically balanced and

thus participate dynamically in the regulation of involuntary motor activity.

BAKER, W.W., CONNOR, J.D., ROSSI, G.V. and LALLEY, P.M. Production of

tremor by intracaudate cholinergic agents and its suppression by locally

administered catecholamines. Progress in Neuro-Genetics, Vol, 1.

Edited by A. Barbeau and J. R. Brunette. Amsterdam, the Netherlands:

Excerpta Medica Foundation, 1969. Pp. 390-403.

BAKER W.W. and KRATKY, M. Changes in local excitability produced by intrahippocampal

injections of thiosemicarbazide and GABA. Archives internationales de Pharmacodynamie et de Therapie 170: 81-92 (1967)

Cholinergic agents microinjected into the caudate nucleus produced tremor

by a selective and persistent action on local muscarinic acetylcholine receptors.

Carbachol (an analog of acetylcholine resistant to hydrolysis by cholinesterase),

the most potent of these, acted directly on the receptors. The anticholinesterases,

also tremorogenic, exerted their primary effects by inhibiting cholinesterase

and thus permitted a piling up of endogenous acetylcholine to interact with the muscarinic

receptors. Sustained tremor activity, which required the persistent receptor

action of carbachol or acetylcholine was readily abolished by intracaudate

injection of muscarinic blocking agents.

Tremor was also suppressed by intracaudate catecholamines, epinephrine

and dopamine, and by adenosine triphosphate (ATP). Evidence based on the

effectiveness of beta-adrenergic antagonists in blocking this suppression by catecholamines Indicates that this tremor inhibition is mediated specifically by beta-adrenergic

receptors in the caudate. Anti-tremor effects of both the catecholamines and ATP

are interpreted as linked together in a metabolic schema in which both are capable

of accelerating the enzymatic conversion of glycogen to glucose. In this proposal

additional glucose is needed to offset the increased requirements associated with the

cholinergic mechanisms contributing to tremor.

Our study substantiates a hypothesis that acetylcholine-dopamine levels

are critically balanced in the caudate and ‘by their action on specific receptors these

neurotransmitters comprise an important local tremor regulatory mechanism.

The results suggest that reduced cholinesterase functioning also merits attention

as a contributory local factor in tremorogenesis.

195
BAKER. W.W. and KRATKY, M. Differential suppression of spontaneous and evoked

hippocampal electrical activities by local tetracaine. Archives internationales

de Pharmacodynamie et de Therapie 173: 395-410 (1968)

When microinjected, tetracaine suppressed spontaneous electrical

activity as well as various types of locally induced electrical discharges at

the hippocampal injection site. The evoked activities anlyzed were representative of local responses of neuronal population in the hippocampus to

microinjected drugs and included: 1) sustained cholinergic discharges related

to local action of carbachol or diisopropylfluorophosphate, and 2) intermittent

focal discharges produced by intrahippocampal d-tubocurarine (dTC). Tetracaine was most effective in abolishing spontaneous background electrogram

and the cholinergic discharges, but was significantly less active against dTC

spike-wave. After tetracaine suppression, spontaneous and discharge

activities could be partially restored with supplemental microinjections of

cholinergic agents but not with calcium. Excitability of partially suppressed

dTC foci was enhanced by increasing local cholinergic activity. Although the

differential suppression of neuronal activity by tetracaine has been meaningfully interpreted as due to a specific interference with local cholinergic

mechanisms, other less specific actions also warrant serious consideration.

From this emphasis on cholinergic mechanisms, our findings further suggest

that the levels of acetylcholine are critical in regulating local excitability

in the hippocampus and as such are directly involved in normal and abnormal

functioning of this brain area.

BAKER, W.W., ZIVANOVIC, D. and MALSEED, R.T. Contrasting local effects of MAO

inhibitors on caudate tremor activities. European Journal of Pharmacology

(in press)

BAKER, W.W., ZIVANOVIC, D., MALSEED, R.T. and MAHONEY, R. Differential effects

of MAO inhibitors on caudate tremorgenic activity. Federation Proceedings

31: 290 (1972)

Tremor responses were elicited in chronic cats by intracaudate

microinjections of the MAO inhibitors tranylcypromine (TRAN) and harmaline

(HARM), but not pargyline (PARG). This tremorgenesis may involve alterations in functional levels of monoamines (NE, DA, 5-HT) in the caudate

following blockade of their metabolic deamination. Characteristics (latency,

amplitude, frequency) of TRAN (160-360 mu-g) and HARM (130-380 mu-g)

tremors were similar, differing principally in their duration of tremor (5

days with TRAN; 1 hr with HARM). TRAN tremor appeared to involve cholinergic intervention since it was suppressed by 120 mu-g of hemicholinium (HC-3).

an inhibitor of ACh synthesis. Following suppression by HC-3, increased

sensitivity to ACh was apparent since tremor activity was transiently reestablished at doses of ACh (25 mu-g) usually ineffective in initiating tremor.

Conversely, HARM tremor was resistant to suppression by HC-3. Endogenous

cholinergic (PHYSO) tremors were readily abolished by local injections of

PARG (120-200 mu-g); however, TRAN (200 mu-g) required a substantially

longer latency to effect tremor suppression. Our results indicate differential

effects of MAO inhibitors on tremorgenic mechanisms in the caudate which we

attribute to differences in their ability selectively to inhibit MAO, as well as

to alter the balance of neurotransmitters locally.

BANERJEE, S.P., and SNYDER, S.H. Cannabinoids: Influence on neurotransmitter

uptake in rat brain synaptosomes. The Journal of Pharmacology and Experimental Therapeutics (in press)

196
BARRY, H. Classification of drugs according to their discriminable effects in rats.

Federation Proceedings 33(7): 1814-1824 (July, 1974)

For abstract, see Section I. Methodology of Drug Research.

BECKER, F., ROSSMAN, T., REISS, B. and SIMON. E.J. The effect of levorphanol

tartrate on ribonucleic acid synthesis in normal and regenerating rat liver.

Research Communications in Chemical Pathology and Pharmacology 3(1): 105

(1972)

The ability of levorphanol. a synthetic analogue of morphine. to inhibit

the synthesis of RNA in normal and regenerating liver has been studied. Hepatocytes were fractionated in a manner which permitted examination of the synthesis

of ribosomal and non-ribosomal RNA from the cytoplasm and nucleus. The

synthesis of every fraction of RNA of the normal hepatocyte was almost totally

inhibited by this agent at the indicated dose. Seventy-percent hepatectomy

induced an enormous increase in the synthesis of most of the RNA fractions

examined. Levorphanol severely inhibited the synthesis of all ribosomal RNA

components in regenerating rat liver. A less severe but significant depression

of the synthesis of non-ribosomal components also occurred. These results

suggest that levorphanol inhibits the synthesis of all classes of hepatocyte RNA,

though the effect is somewhat more pronounced on the synthesis of ribosomal

RNA components.

BENNETT, J.L. and AGHAJANIAN. G.K. Stereospecific binding of D-LSD and

physiological response to serotonergic neurons. Federation Proceedings

33(3, part I): 256 (1974)

D-lysergic acid diethylamide (D-LSD) in low doses (10 midrograms/kg)

inhibits the firing of serotonergic neurons in rat brain: to explore the possibility that this action may be mediated by a high-affinity receptor, the binding

of D-LSD to rat brain homogenates was studied. A high-affinity binding site

was detected; reduction in binding occurred when homogenates were preheated

(80 degrees C) when the incubation was at 4 degrees C instead of 37 degrees C,

or when serotonin was present. L-LSD competed with the binding of D-LSD in

a low but not high-affinity range, indicating only the latter is stereospecific.

High-affinity binding was found in cerebral cortex, striatum, and midbrain, but

not in cerebellum. The concentration of D-LSD in brain after I.V. injections

which just inhibit serotonergic neurons was in the same range as the above

high-affinity binding. L-LSD had no effect on the firing rate of serotonergic

neurons even at 100 times the dose of D-LSD. These results suggest a correlation between the physiological action of D-LSD on serotonergic neurons and

the high-affinity binding of D-LSD to brain homogenates: both are sterospecific

and occur in the same low concentration range.

BEN-ZVI, Z., MECHOULAM, R. and BURSTEIN, S. Identification through synthesis of

an active delta-1(6)-tetrahydrocannabinol metabolite. Journal of the American

Chemical Society 92: 3468 (1970)

BEN-ZVI, Z., MECHOULAM, R., EDERY, H. and PORATH, G. 6-beta-delta-l-tetrahydrocannabinol. Synthesis and biological activity. Science 174: 951 (1971)

For abstract, see Section II. Drug Chemistry and Metabolism.

197
BEYER, J.R. and ELLIOTT, H.W. A comparative study of the analgesic and

respiratory effects of N-allylnorcodeine (nalodine), nalorphine, codeine

and morphine. The Journal of Pharmacology and Experimental Therapeutics

(in press)

BHARGAVA, H.N., AFIFI, A-H. and WAY, E.L. Effect of chemical sympathectomy

on morphine antinocicgption and tolerance development. Biochemical Pharmacology 22: 2769-2772 (1973)

BHARGAVA, H.N. and WAY, E.L. Brain acetylcholine (ACh) and choline (Ch) changes

during acute and chronic morphinization and during abrupt and naloxone precipitated withdrawal in morphine tolerant-dependent mice and rats.

Proceedings of the Western Pharmacological Society 17: 173-177 (1974)

BHARGAVA, H.N. and WAY, E.L. Morphine tolerance, dependence and withdrawal

and brain acetylcholine (ACh). The Pharmacologist 16(2): 270 (1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

BIANCHINE. J.R. and EADE, N.R. The effect of 5-hydroxytryptamine on the cotton

pellet local inflammatory response in the rat. Journal of Experimental

Medicine 125: 501-510 (1967)

The cotton pellet technique was used to evaluate the effect of 5-HT

and certain related compounds on granuloma formation in the rat. 5-HT

(10 mg/kg) significantly decreased granuloma formation, significantly increased adrenal weight, and significantly decreased thymus weight in normal

rats, and significantly decreased granuloma formation and thymus weight in

sham-operated rats. On the other hand, 5-HT (10 mg/kg) significantly increased granuloma weight in adrenalectomized rats.

Methysergide (1 mg/kg) blocked the inhibitory effect of 5-HT on

granuloma formation as well as the changes in weight of adrenal and thymus

glands.

5-HIAA (11 mg/kg) and 5-HTP (13 mg/kg) failed to alter granuloma

formation.

BICHER, J.L. and MECHOULAM, R. Pharmacological effects of two active constituents of marihuana. Archives internationales de Pharmacodynamie

et de Therapie 172: 24-30 (1968)

For abstract, see Section II. Drug Chemistry and Metabolism.

198
BLUMBERG, J.B., TAYLOR, R.E. and SULSER, F. Modification by antipsychotic

drugs of the cyclic 3',5'-AMP (cAMP) response to d-LSD in rat brain following microwave irradiation. Federation Proceedings 32: 496 (1973)

It has previously been reported that d-LSD raises the concentration

of AMP in brain and that trifluoperazine prevented this effect (Uzunov and

Weiss, Pharmacologist 13, 257, 1971). In the present experiments. amounts

of AMP were estimated in discrete areas of the brain after exposure of rats

to microwave irradiation to eliminate artifacts produced by decapitation.

d-LSD (0.5 mg/kg i.p.) rapidly and significantly increased the concentfatioh

of AMP in cortex and midbrain with the maximum increase occurring at 20

minutes (160-20%). No significant increase was noted in cerebellum and

brainstem. BOL (0.5-2.0 mg/kg i.p.) was without effect. Chlorpromazine

(10 mg/kg i.p.), haloperidol (5 mg/kg i.p.) and pimozide (5 mg/kg i.p.) did not

change the basal levels of AMP-in any brain area except the cortex but

effectively inhibited the LSD induced increase in AMP in cortex and brainstem. Regardless of the molecular mechanism involved, these and earlier.

findings (Palmer et al., Psychopharmacologia 23, 201, 1972) suggest that the

AMP system in brain may be implicated in the pharmacological activity of

antipsychotic drugs.

BOISSE, N.R. and OKAMOTO, M. Comparison of barbital and pentobarbital physical

dependence in the cat. The Pharmacologist 16: 247 (1974)

Despite the failure of long-acting barbiturates to result in severe

physical dependence in man, barbital has long been the choice for the experimental production of dependence. To effectively compare the abstinence

characteristics of short and long-acting barbiturates, cats were treated 5

weeks with barbital (B) or pentobarbital (P) intra-gastrically in maximally

tolerable doses at intervals allowing equi-effective recovery to provide an

equiv. chronic CNS depression. Kinetic analysis of blood levels shows the

fractional change in blood conc. of B and P to be the same reinforcing treatment equivalency. P abstinence is most severe culminating in a 10%

incidence of convulsions and 30% death. In contrast, all cats survived B

abstinence and seizures were usually absent. Results of substitution

expts, wherein B replaced P or P replaced B following chronic treatment

suggest an important role for elimination kinetics (t ) in abstinence. To

exclusively manipulate t , a schedule of 1st. -order dose reduction was

developed to extend P t to that of B. These findings confirm the important role of t in the overt expression of an underlying dependence. Also,

this study permits a comparison of effectiveness of B and P to induce dependence.

BOLT, A.G. and FORREST. I.S. In vivo and in vitro interactions of chlorpromazine

and melanin. Chapter 4 of Recent Advances in Biological Psychiatry, Vol.

X. New York: Plenum Press, 1968. Pp. 20-28.

For abstract, see Section II. Drug Chemistry and Metabolism.

199
BONNET, K.A. and ROGERS, J. Regional studies of the consequences of acute and

chronic intracerebral morphine injection. Presented at the Fourth Annual Meeting

of the Society for Neuroscience, St. Louis, Missouri, October 20-24, 1974.

Fisher rats were implanted with bilateral fine guage cannulae for injection

of morphine into discrete brain structures. Footshock sensitivity was determined

for four motoric responses and vocalization by a modified jump-flinch procedure.

Bilateral injections of saline one week postoperatively revealed significant group

differences in shock sensitivity. Bilateral 1 or 10 mu-g morphine injections

produced different response category profiles for each implant group. Caudate

animals became hypersensitive in most response categories. Center median

animals were dramatically analgesic in the vocalisation response. Only

substantia nigra animals resembled the response profiles of animals given

systemic morphine. Repeated 10 mu-g injections resulted in tolerance on all

response categories for substantia nigra, and loss of hyperalgesia in the caudate

animals. Posterior hypothalamus showed increasing analgesia with successive

injections and no indications of tolerance development. Subsequent systemic

morphine injection (5 mg/kg) was reduced in analgesic effects only in animals

given repeated morphine injections into the posterior hypothalamus.

BORGEN, L.A. and DAVIS, M. Cannabidiol interaction with delta-9-tetrahydrocannabinol.

Research Communications in Chemical Pathology and Pharmacology 7(4): 663

(1974)

Two experiments were conducted in rats and rabbits concerning the

effects of cannabidiol (CBD). a supposedly inactive marihuana constituent, on

several actions of delta-9-tetrahydrocannabinol (delta-9-THC). In rats, 25

mg/kg of CBD given i.p. 30 min. prior to 10 mg/kg delta-9-THC reduced the

magnitude and duration of the hypothermic effects of delta-9-THC, while CBD

alone had no effect on body temperature. CBD (25 mg/kg. i.v.) given 1 hr.

before delta-9-THC (3 mg/kg, i.v.) to unanesthetized rabbits caused a significant attenuation of the depressant effects of delta-9-THC on heart rate,

respiration and rectal temperature. These data suggest that although CBD is

relatively inactive compared to delta-9-THC. it may be a potential competitive

antagonist of the effects of delta-9-THC.

BORGEN, L.A. and DAVIS, W.M. Cannabidiol (CBD) attenuation of effects of delta9-THC. The Pharmacologist 15(2): 201 (1973)

Studies were conducted in 3 species concerning the effects of CBD on

various actions of delta-9-THC. In the rat and pigeon, CBD pretreatment

(25-50 mg/kg, 1 hr. prior) reduced the operant depressant effects of delta-gTHC (1-3 mg/kg) on V160'' or F160'' schedules of food-reinforced performance.

CBD alone had no effect at these dosages. Similarly, CBD (25 mg/kg, i.p.)

given prior to 10 mg/kg delta-9-THC reduced both the magnitude and duration

of hypothermic effects of delta-9-THC, while having no effect on body temp.

when given alone. CBD and delta-9-THC, individually and in combination,

were administered i.v. to unanesthetized rabbits equipped for recording of

body temp., EKG, and respiration. Delta-9-THC (3 mg/kg), produced a

3.5-4.3°C drop in temp. and a 40-50% drop in heart and respiration rate.

effects which were maximal at 2-3 hr. post-injection. CBD (25 mg/kg i.v.)

had no effect on body temp., but produced a 10-20% drop in heart and

respiration rate which lasted 30-45 min. CBD (25 mg/kg) 1 hr. before delta9-THC (3 mg/kg) caused an attenuation of delta-9-THC effects on all 3

parameters, both in magnitude and duration. Thus, although CBD is relatively

inactive compared to delta-9-THC, it may be a potential competitive antagonist of delta-9-THC effects.

200
BORGEN, L.A., LOTT, G.C. and DAVIS, W.M. Cannabis-induced hypothermia: ,A

dose-effect comparison of crude marihuana extract and synthetic delta-gtetrahydrocannabinol in male and female rats. Research Communications in

Chemical Pathology and Pharmacology 5(3): 621 (May, 1973)

Synthetic delta-9-THC was found to produce a greater hypothermic

effect in rats than a crude marihuana extract containing a larger delta-9-THC

dosage. Additionally, female rats showed a more pronounced hypothermic

response than males to both delta-9-THC and the marihuana extract.

BOWERS, M.B., JR. Acute psychosis induced by psychotomimetic drug abuse. II.

Neurochemical findings. Archives of General Psychiatry 27: 440-442

(October, 1972)

For abstract, see Section II. Drug Chemistry and Metabolism.

BOWERS, M.B., JR. Cerebrospinal fluid 5-hydroxyindoleacetic acid (5HIAA) and

homovanillic acid (HVA) following probenecid in unipolar depressives treated

with amitriptyline. Psychopharmacologia 23: 26-30 (1972)

Lumbar cerebrospinal fluid 5-HIAA, HVA, and the ratio 5-HIAA/

HVA were measured followed probenecid administration in eleven patients

with unipolar depression before and during treatment with amitriptyline

(AMI). Control values were obtained from a group of inmate volunteers.

Prior to treatment CSF 5HIAA formation in the depressives was not different

from controls. During treatment with AMI, CSF 5-HIAA formation decreased.

One patient with psychotic symptoms prior to AMI and two patients who developed psychotic reactions on AMI showed relatively low CSF 5HIAA formation prior to antidepressant therapy. Compared to controls CSF HVA

values were higher in the depressives prior to AMI therapy.

BOWERS, M.B., JR. 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA)

following probenecid in acute psychotic patients treated with phenothiazines.

Psychopharmacologia 28: 309-318 (1973)

Lumbar CSF 5HIAA and HVA were measured following probenecid

administration in acute psychotic patients before and during treatment with

phenothiazines. Patients with more classical schizophrenic symptoms had

higher values for 5HIAA/HVA than other psychotics. depressives, and inmate volunteers. Prior to treatment CSF 5HIAA, but not HVA, correlated

significantly with several clinical items related to psychotic disorganization.

Phenothiazine treatment produced significant increases in CSF HVA which

could not be correlated with the dose of antipsychotic or antiparkinson drugs.

291
BOYD. E.S., BOYD, E.H. and BROWN, L.E. The effects of some drugs on an evoked

response sensitive to tetrahydrocannabinols. The Journal of Pharmacology and

Experimental Therapeutics 189(3): 748 (1974)

The effects of several drugs were compared with those of delta-gtetrahydrocannabinol (delta-9-THC) on responses evoked in frontal lobe polysensory areas, ipsi- and contralateral to the stimulus site in primary

somatosensory cortex, in squirrel monkeys with postmesencephalic or high

spinal sections. Delta-9-THC augmented both the early evoked response and

the late evoked response, which occurs 150 to 200 msec after the stimulus.

It also frequently augmented or induced repetitive synchronous activity after

the late response. In contrast, pentobarbital, ethanol and diethyl ether depressed both early and late responses, while chlorpromazine and chloralose

depressed late responses without consistently affecting early responses; none

of these drugs induced late repetitive activity. Mescaline had effects similar

to those of delta-9-THC on late responses. but its effect on early responses

was much less. Lysergic acid diethylamide had little effect on early responses

but depressed late responses at high doses. Phencyclidine also had little effect

on early responses. It facilitated late responses at low doses and depressed

them at high doses. Picrotoxin and pentylenetetrazol had effects similar to,

but greater than, those of delta-9-THC. Strychnine had variable, and mostly

small, effects on evoked responses. Gallamine, atropine, amphetamine,

levarterenol and methoxamine were essentially without effect on the responses

studied. It is concluded that the effects of delta-9-THC and mescaline on these

responses in polysensory cortex are similar to those of certain convulsants but

are unlike those of depressants or of amphetamine, levarterenol, lysergic acid

diethylamide, phencyclidine or strychnine.

BOYD, E.S., BOYD, E.H. and BROWN, L.E. Effects of tetrahydrocannabinols on

evoked responses in polysensory cortex. Annals of the New York Academy

of Sciences 191: 100-127 (1971)

Graded doses of delta-8- and delta-9-THC’s were given to the

encephale isole squirrel monkey and the effects compared to those of pentobarbital and ethanol on early and late responses evoked in the postarcuate

polysensory area. an area of cerebral cortex where sensory integration has

been postulated to occur. The early and late responses. which were evoked

by stimulation of primary somatosensory cortex, were found to be locally

generated at the recording site, to have the same pattern of cortical distribution, and to interact with each other in a complex fashion that included the

resetting of the late responses by a second early response. Tetrahydrocannabinols increased the amplitudes of the early responses; low doses of

pentobarbital and ethanol had variable effects on them, whereas high doses

depressed them. An even more striking differential effect of the THC’s was

observed on the late responses. They caused a dose-dependent increase in

the late responses, followed by rhythmic activity, whereas all doses of pentobarbital and ethanol tested depressed the late responses. It is suggested that

these differential effects of THC’s may underlie the distortions of sensory

perception or of time sense in humans caused by marijuana and THC’s, or

they may underlie the hyperreactivity to sensory stimuli reported in experimental animals.

202
cerveau isole squirrel monkey and recording the responses in frontal lobe

polysensory areas ipsi- and contralateral to the stimulus, and in the contralateral parietal lobe primary somatosensory area, homotopic to the stimulus.

Low doses of both THC’s increased the amplitudes of the responses and higher

doses generally decreased them. Low doses of pentobarbital also produced

increases in amplitude and higher doses decreased or abolished the responses.

The THC’s only slightly decreased the facilitation seen in control recovery

cycles, but even low doses of pentobarbital markedly reduced or abolished it.

Pentobarbital had its usual effects on the electrocorticogram, i.e., a dosedependent’flatte’ning with spindling at intermediate doses, but the THC’s caused

spiking and, at high doses, occasionally a spike and wave pattern. It is

suggested that the increased responsiveness of cortical areas produced by the

THC’s without the concomitant decrease of recovery produced by pentobarbital

may be related to the changes in sensory perception produced by the THC’s.

BOYD, E.S., BOYD, E.H., MUCHMORE, J.S. and BROWN, L.E. Effects of two

tetrahydrocannabinols and of pentobarbital on cortico-cortical evoked responses

in the squirrel monkey. The Journal of Pharmacology and Experimental

Therapeutics 176: 480 (1970)

The effects of two tetrahydrocannabinols (delta-8-THC and delta-gTHC) were studied by stimulating primary somatosensory cortex in the

BRAESTRUP, C. Effect of phenoxybenzamine, aceperone arid clonidine on the level of

3-methoxy-4-hydroxyphenylglycol (MOPEG) in rat brain. Journal of Pharmacy

and Pharmacology 26: 139-141 (1974)

BRAESTRUP, C. Effects of clonidine (catapressan) on synthesis and mettibolism of

noradrenaline in the central nervous system of rats. Acta Pharmacologica et

Toxicologica 35 (Supplement I): 22 (1974)

For abstract, see Section II: Drug Chemistry and Metabolism.

BRAESTRUP, C. Effects of phenoxybenzamine, aceporone and clonidine on the level of

3-methoxy-4-hydroxyphenylglycol (MOPEG) in rat brain. Journal of Pharmacy

and Pharmacology 26 (2): 139-141 (February, 1974)

BRAESTRUP, C. Gas chromatographic evidence for the presence of 3-methoxy-4-hydroxyphenylethanol in rat brain. Biochemical Pharmacology 21: 1775-1776 (1972)

BRAESTRUP, C., NIELSEN, M. and SCHEEL-KRÜGER, J. Feed back mechanisms

in central noradrenergic neurones in vivo, investigated through changes in

noradrenaline metabolism. Journal de Pharmacologie 5 (Supplement II):

11 (1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

203
BR ASE, D.A., TSENG. L., LOH, H.H. and WAY, E.L. Cholinergic modification of

naloxone-induced jumping in morphine dependent mice. European Journal of

Pharmacology 26: 1-8 (1974)

The effects of several i.p. administered, centrally active cholinergic

agonists and antagonists on the naloxone-induced jumping behavior of morphine

tolerant and dependent mice were studied in an effort to differentiate muscarinic

and nicotinic modification of the withdrawal jumping behavior. Nicotine,

tremorine, oxotremorine, arecoline and physostigmine significantly inhibited

jumping, whereas atropine, benzotropine, pempidine and mecamylamine

significantly potentiated jumping. Quaternary cholinergic drugs did not

modify jumping. These drug effects were obtained generally without an alteration of the amount of naloxone or morphine in the brain. Cholinergic

drugs also modified the jumping incidence in mice undergoing abrupt morphine

abstinence. It is concluded that the inhibition of withdrawal jumping in morphine dependent mice by both muscarinic and nicotinic agonists and its

enhancement by muscarinic and nicotinic antagonists reflect cholinergic modifications of the jumping response by a central mechanism(s).

BRAUDE, M.C., MANSAERT, R. and TRUITT, E.G., JR. Some pharmacologic

correlates to marihuana use. Seminars in Drug Treatment 1(3): 229-246

(December, 1971)

BREESE, G.R., COOPER, B.R. and MUELLER, R.A. Evidence for involvement of

5-hydroxytryptamine in the actions of amphetamine. British Journal of

Pharmacology 52: 307-314 (1974)

Pargyline treatment, 1 h before (+)-amphetamine (1 mg/kg), reduced

amphetamine-stimulated motor activity. This inhibition was reversed in

animals pretreated with p-chlorophenylalanine (PCPA).

Following treatment with PCPA or 5,6-dihydroxytryptamine (5,6-

DHT), amphetamine-induced locomotor activity was significantly potentiated.

The increased response to amphetamine in PCPA-treated rats was reversed

in animals pretreated with 5-hydroxytryptophan.

The inhibition of amphetamine-stimulated locomotor activity by treatment with 6-hydroxydopamine was not reversed by PCPA treatment.

Stereotypies produced by amphetamine were not found to be altered by

depletion of 5-hydroxytryptamine.

Induction of adrenal tyrosine hydroxylase activity produced by chronic

amphetamine administration was significantly potentiated by PCPA, emphasizing the involvement of a 5-hydroxytryptamine inhibitory system in more than

one action of amphetamine.

204
BREESE. G.R., COOPER, B.R. and SMITH. R.D. Biochemical and behavioural alterations

following 6-hydroxydopamine administration into brain. Frontiers in Catacholamine

Research. Edited by E. Usdin and S. H. Snyder. New York: Pergamon Press, 1973.

Adult and neonatal rats treated with 6-OHDA to reduce NE, DA or both

catecholamines have been used to examine the role of brain catecholamines in

several behaviours. The data implicated DA-containing fibres in the maintenance of several diverse functions including consummatory behaviour, active

avoidance responding and self-stimulation of brain. Motor activity and

stereotypies induced by amphetamine also appear to be dependent upon brain

DA. Table 1 shows that brain NE at this time has been associated only with

temperature control. Present findings are consistent with proposals (Everett

and Wiegand, 1962; Seiden and Carlsson, 1963) suggesting alternative roles for

DA not clearly related to its usual association with extrapyramidal function.

BRIDGE, T.P. and ELLINWOOD, E.H., JR. Quaalude alley: A one-way street.

American Journal of Psychiatry 130(2): 217 (1972)

BRISTER. C.C. and DAVIS, W.M. Antagonism of acute lethality of narcotic

analgesics in aggregated and isolated mice by the central cholinomimetic

action of pilocarpine. Archives internationales de Pharmacodynamie et de

Therapie 210(2): 298-305 (August, 1974)

The central cholinomimetic action of pilocarpine hydrochloride, in

combination with the peripherally-acting anticholinergic methylatropine bromide (1.0 mg/kg i.p.), was tested for ability to protect mice against acute

toxicity of 5 analgesics. Pilocarpine (10-30 mg/kg i.p.) pretreatment reduced

lethality after morphine, meperidine, levorphanol, methadone and pentazocine

in aggregated mice, but failed to antagonize lethality after d-amphetamine. In

isolated mice the effect of pilocarpine was comparable to that for aggregated

mice for the latter 3 analgesics. However, a higher dose was required to

antagonize mortality of isolated mice after meperidine, which caused the most

prominent excitation among the analgesics. Moreover, no protection was found

against morphine, but instead a toxic synergism. Symptomatic observations

suggested both central depressant and excitatory effects of pilocarpine which

seemed to interact with similarly mixed central effects of the analgesics in a

complex fashion, varying among the several analgesics. Observations that

atropine sulfate (3.0 mg/kg i.p.) completely prevented the protective action

of pilocarpine. while methacholine chloride (10 mg/kg i.p.) plus methylatropine (1.0 mg/kg) failed to afford protection, substantiate a central site for the

action of pilocarpine.

BROWN, D.J., MILLER, F.N., LONGNECKER, D.E., GREENWALD, E.K., HARRIS.

P.D. and FORNEY, R.B. The influence of delta-9-tetrahydrocannabinol on

cardiovascular and subcutaneous microcirculatory systems in the bat.

The Journal of Pharmacology and Experimental Therapeutics 188(3): 624-629

(1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

205
BUNNEY, B.S. and AGHAJANIAN, G.K. A comparison of the effects of chlorpromazine,

7-hydroxychlorpromazine and chlorpromazine sulfoxide on the activity of central

dopaminergic neurons. Life Sciences 15(2): 309 (July, 1974)

Using single unit recording techniques, chlorpromazine (CPZ) and

two of its naturally occurring metabolites in man, 7-hydroxychlorpromazine

and CPZ sulfoxide. were tested for their ability to reverse amphetamine induced depression of rat dopaminergic ventral tegmental neurons. Small

equivalent doses of CPZ and 7-hydroxychlorpromazine were found to readily

reverse amphetamine induced depression of these cells. CPZ sulfoxide was

found to be 50-100 times less potent in this regard. On the basis of this and

other evidence, it is suggested that 7-hydroxychlorpromazine may be a good

antipsychotic agent.

BUNNEY, B.S. and AGHAJANIAN, G.K. Electrophysiological effects of amphetamine

on dopaminergic neurons. Frontiers in Catecholamine Research. Edited by

E. Usdin and S. Snyder. New York: Pergamon Press, 1973.

D-amphetamine (D-AMP) administered intravenously in low doses

markedly depresses the firing rate of dopaminergic neurons. This effect

of D-AMP appears dependent upon the presence of ongoing synthesis as it is

abolished by alpha-methyl-P-tyrosine (AMPT) (a tyrosine hydroxylase inhibitor) and by high doses of R04-4602 (a decarboxylase inhibitor). The

previously proposed hypothesis that D-AMP depresses DA cell firing rate indirectly via a postsynaptic nondopaminergic feedback pathway was confirmed.

This conclusion is based on the following findings: 1) as predicted, D-AMP

selectively depresses the firing rate of dopaminergic neurons in the substantia nigra zona compacta and adjacent ventral tegmental; 2) the direct

effect of D-AMP on DA cell activity when applied iontophoretically, even with

high ejection currents, is weak and transient as compared to its marked depressant effect when applied with low currents in the vicinity of postsynaptic

neurons (i. e. neurons receiving a dopaminergic input): and 3) transaction

between the substantia nigra and striatum abolishes the depressant effect on

DA cell firing rate of systemically administered D-AMP. The latter result

strongly suggests the existence of a neuronal feedback pathway although its

precise anatomical location has yet to be determined.

BUNNEY, B.S. and AGHAJANIAN, G.K. Electrophysiological effects of amphetamine

on dopaminergic neurons. Life Sciences 13(4): 14 (1973)

The electrophysiological effects of amphetamine on dopaminergic

neurons was examined in the rat. To evaluate the proposed suggestion that

amphetamine, by increasing the concentration of dopamine (DA) postsynaptically,

may initiate a neuronal feedback inhibition of DA cells, its effect on the firing

rate of dopaminergic neurons was determined by single unit recordings. Recordings were made from the DA containing cells in the zona compacta of the

substantia nigra and adjacent ventral tegmental area of the rat midbrain.

D-amphetamine was potent in decreasing the spontaneous activity of DA

neurons. Pretreatment with alpha-methyl-paratyrosine blocked this depressant

effect and reversed it when given after amphetamine. Haloperidol and

cholorpromazine both prevented and reversed the amphetamine induced depression of the firing rate. It is assumed that ongoing synthesis of DA is

necessary for D-amphetamine to exert its effect and that DA receptors may

be involved in amphetamine’s ability to depress DA neurons. Tests were made

to rule out the possibility that amphetamine might have a direct effect on

dopaminergic cells. The hypothesis that amphetamine releases newly synthesized DA which in turn affects DA cell firing via a postsynaptic feedback pathway was supported.

206
BURKS, T. Mediation by 5-hydroxytryptamine of morphine stimulant actions in dog

intestine. The Journal of Pharmacology and Experimental Therapeutics

185(3): 530 (1973)

Intestinal contractor effects of morphine, 5-hydroxytryptamine (5-HT)

and cholinergic agonists were investigated in sections of dog small intestine

perfused in vitro with Krebs’ solution. Morphine and 5-HT produced similar

patterns of intestinal hypermotility characterized by initial tonic increases in

intraluminal pressure and pronounced secondary phasic contractions. The

morphine-induced hypermotility could not have resulted from extrinsic influences on the isolated segments of bowel. Cholinergic agonists generally.

produced only brief tonic contractions of the intestinal smooth muscle. Treat-,

ment of dogs with reserpine to deplete local stores of 5-HT selectively reduced

intestinal responses to morphine. This indicated that release of endogenous

5-HT initiates the spasmogenic response to the narcotic. The contractor effects

of 5-HT and morphine were diminished by tetrodotoxin, nicotine depolarization

and atropine but not by tetraethylammonium. These data demonstrate that a

significant portion of the stimulatory action of the 5-HT released by morphine

results from activation of intramural cholinergic nerve elements which differ

from those activated by conventional ganglionic stimulants. Experiments with

the 5-HT receptor blocking drugs, cinanserin and cyproheptadine, indicate that

the 5-HT mobilized by morphine also exerts direct stimulatory actions on smooth

muscle 5-HT receptors. The hypermotility of the dog bowel induced by morphine thus appears to result from release of local intestinal 5-HT. The 5-HT

liberated by morphine exerts both direct and indirect exitatory smooth muscle

effects. The indirect component of 5-HT action is mediated by cholinergic

nerve elements in the wall of the intestine:

The Journal of Pharmacology and Experimental Therapeutics 191: 518 (1974)

BURKS. T.F. and GRUBB. M.N. Sites, of acute morphine tolerance in intestine.

Experiments were performed to differentiate between neurotransmitter receptors and narcotic receptors as sites for acute narcotic tolerance

in dog intestine. Intestinal motor responses to bolus intra-arterial injections

of morphine, 5-hydroxytryptamine (5-HT), bethanechol and dimethylphenylpiperazinium were measured in isolated small bowel segments. The vasculature of the isolated segments was perfused with Krebs-bicarbonate ‘solution

(control) or with Krebs’ solution containing morphine, levorphanol, naloxone

or 5-HT. During perfusion of gut segments with morphine (2 mu-g/ml), intestinal motor responses to bolus doses of morphine were significantly reduced (acute tolerance). Responses to 5-HT, bethanechol and dimethylphenylpiperazinium were not reduced., Perfusion of segments with levorphanol (0.2 mu-g/ml) reduced responses to 5-HT slightly and reduced

responses to morphine considerably. Levorphanbl did not alter responses to

bethanechol and dimethylphenylpiperazinium. Naloxone (2 mu-g/ml) ‘perfusion, like morphine perfusion, reduced responses to morphine selectively,

Responses to both morphine and 5-HT were reduced during perfusion of

bowel segments with 5-HT (20 mu-g/ml). Previous studies have indicated

that both 5-HT and cholinergic receptors are involved in the intestinal stimulatory response to morphine (Burke, T. F. J. Pharmacol. Exp. Ther.

185: 530-539, 1973). Acute tolerance of tachyphylaxis to the narcotics, however, did not prevent responses to 5-HT, and the cholinergic agonists., These

observations thus suggest that acute tolerance to morphine results from events

expressed at the level of the narcotic receptor. Reduced responsiveness to

morphine occurs during, tachyphylaxis to 5-HT apparently because morphine’s

stimulatory effects are mediated in part by 5-HT.

207
BURKS, T.F., JAQUETTE. D.L. and GRUBB, M.N. Development of tolerance to the

stimulatory effect of morphine in dog intestine.

25: 302-307 (1974)

European Journal of Pharmacology

Intestinal motor responses to morphine and 5-hydroxytryptamine (5-HT)

were measured in dogs injected daily for 16 days with morphine (stabilized at

30 mg/kg i.v.) and compared to responses obtained in control animals. Intestinal contractions produced by 10 and 20 mu-g/kg morphine were reduced in the

morphine-treated animals. Responses to 5-HT did not differ between the two

groups. The contractor dose-response curve for morphine, but not for 5-HT or

bethanechol, was shifted markedly to the right in intestinal segments isolated

from morphine-treated dogs. It is concluded that tolerance to the intestinal

stimulatory effect of morphine occurs in the dog.

BURSTEIN, S., LEWIS, E. and VARANELLI. C. Prostaglandins and cannabis - II:

Inhibition of biosynthesis by the naturally occurring cannabinoids. Biochemical

Pharmacology 22: 2905-2910 (1973)

A series of the naturally occurring cannabinoids were tested for possible

effects on the biosynthesis of prostaglandins. Most of the substances examined

were able to inhibit in varying degrees the conversion of 8,11,14-eicosatrienoic

acid to prostaglandin E1 (PGE1) when incubated with bovine seminal vesicle

microsomes. The order of activity starting with the most potent was cannabinol, cannabidioIic acid, delta-6-tetrahydrocannabinol (delta-6-THC), cannabidiol,

bichromene and delta-1-THC; cannabicyclol showed almost no inhibitory activity.

It is suggested that certain of the pharmacological actions of some of these

cannabinoids may be explained by a similar effect in vivo. Olivetol, which represents a partial structure for all of the compounds tested, showed high activity,

indicating that the inhibitory power of the cannabinoids resides in the aromatic

portion of the molecule.

BURSTEIN, S. and MECHOULAM. R. Stereospecifically labelled delta-1(6)-tetrahydrocannabinol. Journal of the American Chemical Society 90: 2420 (1968)

BURSTEIN, S.H., MENEZES, F., WILLIAMSON, E. and MECHOULAM, R.

Metabolism of delta-1(6)-tetrahydrocannabinol, an active marihuana constituent.

Nature 225: 87-88 (1970)

BURSTEIN, S. and RAZ, A. Inhibition of prostaglandin E2 biosynthesis by delta-1-

tetrahydrocannabinol. Prostaglandins 2(5): 369 (1972)

Psychopharmacologia 25: 275-280 (1972)

BUXBAUM, D.M. Analgesic activity of delta-9-tetrahydrocannabinol in the rat and mouse.

An analysis of the analgesic activity of delta-9-tetrahydrocannabinol

(delta-9-THC) was carried out in rats and mice using both the hot plate and

tail flick tests. In the rat, the dose-effect curve of delta-9-THC was comparable to that of morphine in both tests. In the mouse, however, the THC

dose-effect curves were more variable and less steep than the morphine

dose-effect curves. THC was less potent than morphine in both tests in mice.

THC analgesia reached its peak at one hour and had a longer duration of action

than morphine.

208
BUXBAUM, D.M., BUSHING, J.A., CARTER, M.E. and SANDERS-BUSH, E. Longterm effects of p-chloroamphetamine (PCA) on cerebral serotonic (5HT) and

morphine (M)-induced locomotor activity in the rat. Presented at the Fifth

International Congress on Pharmacology, San Francisco, California, 1972.

BUXBAUM, D. and SCHMIDT, D.E. Modification of motor induced motor effects by

cholinergic antagonists and effects of morphine on regional ACH utilization in

rat. Federation Proceedings, (in press)

CARINO, M.A. and HORITA, A. The monoamine oxidase activity of the hamster gastrointestinal tract. Proceedings of the Western Pharmacological Society 12: 25 (1969)

CAVERO, I., BUCKLEY, J.P. and JANDHYALA, B.S. Hemodynamic and myocardial

effects of (-)-delta-9-trans-tetrahydrocannabinol in anesthetized dogs.

European Journal of Pharmacology 24: 243-251 (1973)

(-)-Delta-9-trans-tetrahydrocannabinol (delta-9-THC) (39 mu-g-2.5 mg/kg, i.v.)

decreased blood pressure, heart rate, cardiac output and right ventricular contractile

force in a dose-related manner in intact dogs under pentobarbital anesthesia. The

delta-9-THC-induced hypotension appeared to result mainly from a consistent and

reproducible attenuation of cardiac output since no marked alteration in total

peripheral resistance occurred. In these animals the decrease in cardiac output

appeared to be related to the bradycardia since there was no change in stroke

volume following delta-9-THC. However, when the change in heart rate was prevented

by atria1 pacing or cardiac denervation, a less but significant reduction in cardiac

output was induced by delta-9-THC. Under these experimental conditions delta-9-THC

also significantly attenuated stroke volume. In contrast, delta-9-THC did not induce any

significant changes in cardiac output, blood pressure, and heart rate of dogs pretreated

with a ganglionic blocker.

Delta-9-THC appeared to be devoid of any measurable direct effect on

the myocardium since the compound neither significantly altered right ventricular

contractile force of the denervated or ganglionic blocker-pretreated hearts nor

interfered with the positive inotropic responses to i.v. calcium and isoproterenol.

In the major vessel occlusion preparation administration of delta-9-THC

was followed by a reduction in venous tone. Furthermore, measurements of blood

and plasma volume excluded an effect of delta-9-THC in these parameters.

From these findings it is suggested that the reduction in cardiac output

induced by delta-9-THC is the result of the action of this compound on cardiac rate

as well as venous return; no evidence could be documented for a direct effect of

this compound on the myocardlum.

CAVERO, I., BUCKLEY, J.P. and JANDHYALA, G.S. Parasympatholytic activity of

(-)-delta-9-trans-tetrahydrocannabinol in mongrel dogs. European Journal of

Pharmacology 19(2): 301-304 (1972)

The compound (-)-delta-9-trans-tetrahydrocannabinol (delta-9-THC)

(0,312-5 mg/kg) shifted the frequency - response curves of vagal stimulation

to the right and attenuated salivation induced, by chorda tympani stimulation in

dogs. This parasympatholytic activity of delta-9-THC was neither atropine like

nor due to ganglionic blockage. It is postulated. that delta-9-THC may interfere,

with the release of acetylcholine.

209
CAVERO, I., ERTEL, R., BUCKLEY, J.P. and JANDHYALA, B.S. Effects of (-)-delta9-trans-tetrahydrocannabinol on regional blood flow in anesthetized dogs, European

Journal of Pharmacology 20: 373-376 (1972)

Distribution of cardiac output to various organs was studied utilizing Sr-labelled

microspheres in dogs. In the group receiving delta-9-THC, 2.5 mg/kg, i.v., there

was a significant reduction in the fractional blood flow accompanied by an increase

in resistance in the splanchnic vasculature. Net total peripheral resistance was

unchanged.

CAVERO, I., KUBENA, R.K., DZIAK, J., BUCKLEY, J.P. and JANDHYALA, B.S.

Certain observations on interrelationships between respiratory and cardiovascular

effects of (-)-delta-9-trans-tetrahydrocannabinol. Research Communications in

Chemical Pathology and Pharmacology 3(3): 483-492 (May, 1972)

- -

The effects of (-)-delta-9-trans-tetrahydrocannabinol (delta-9-THC), a

pharmacologically active constituent of marihuana, on the cardiovascular and

respiratory system was investigated in mongrel dogs under pentobarbital

anesthesia. Delta-9-THC (5 mg/kg, i.v.) caused a transient hypernea and

hypoxic hypoxia in spontaneously breathing animals; however, no alterations in

the blood gas parameters were observed in artificially ventilated animals. The

delta-9-THC induced hypotension reached its maximum within 15 minutes in

animals maintained at a constant arterial pO2, but this effect was significantly

attenuated during the hypoxemic state in the spontaneously breathing animals.

The present data suggest that the full hypotensive activity of delta-9-THC may

be prevented by hypoxic hypoxia, however, the bradycardic effect of this

compound was profound and independent of any alterations on blood gas

parameters.

CAVERO, I., LOKHANDWALA, M.F., BUCKLEY, J.P. and JANDHYALA, B.S. The

effect of (-)-delta-9-trans-tetrahydrocannabinol on myocardial contractility and

venous return in anesthetized dogs. European Journal of Pharmacology

23: 74-82 (1974)

Administration of (-)-delta-9-trans-tetrahydrocannabinol (delta-9-THC, 2.5

mg/kg i.v.) to pentobarbital-anesthetized dogs in which heart rate was maintained

constant by electrical pacing, decreased aortic blood pressure, cardiac output,

left ventricular, peak pressure and left ventricular end diastolic pressure and dP/dt.

However, the contractility index (max. dp/dt)/I.P. was not altered by the compound,

Furthermore, it was shown that the decrease in cardiac output due to delta-9-THC

could be restored to original levels by an infusion of saline-dextran in quantities

sufficient to elevate the left ventricular end diastolic pressure to pre-delta-9-THC

level.

In dogs in which cardiac output was maintained constant by a right heart bypass

procedure delta-9-THC decreased blood pressure and total peripheral resistance

and‘augmented intravascular blood volume. This increase in intravascular blood

volume was significantly less (74%) in animals in which the splanchnic (superior, inferior,

and celiac) arteries were ligated prior to the administration of delta-9-THC. On

the other hand, in spinal dogs delta-9-THC was devoid of any measurable cardiovascular effects.

These observations clearly support the hypothesis that the diminution of cardiac

output induced by delta-9-THC in animals with constant cardiac rate is primarily

due to dominished venous return to the heart and not to an impaired ability of

the myocardium.

210
CAVERO, I., SOLOMON, T., BUCKLEY, J. P. and JANDHYALA, G.S. Studies on the

bradycardia induced by (-)-delta-9-trans-tetrahydrocannabinol in anesthetized

dogs. European Journal of Pharmacology 22(3): 263 (1973)

Decreased heart rate resulted from (-)-delta-9-trans-tetrahydrocannabinol (delta-9-THC) in a dose related manner in dogs under pentobarbital anesthesia. This cardiac effect of delta-9-THC was neither due to an impairment

of transmission across the sympathetic ganglia nor to a specific stimulation of

parasympathetic ganglia. Selective blockade of either parasympathetic (atropine, bilateral vagotomy) or sympathetic (propranolol, spinal section at C2-C4)

neurogenic activity to the heart partially ‘prevented the negative chronotropic

effect of THC. However, the bradycardic effect of delta-9-THC was completely

abolished in animals in which the autonomic pathways to the heart were pharmacologically or surgically inactivated. Administration of delta- 9-THC into the

vascularly isolated, neurally intact cross-perfused head of dogs significantly

slowed the. heart rate in intact as well as debuffered recipients. This bradycardia was reduced in recipients in which the trunk was atropinized prior to

cerebral administration of delta-9-THC. Injection of delta-9-THC into the

femorai vein of the recipient in the dog cross circulation preparation also

caused a significant decrease in heart rate which was essentially abolished

either by bilateral vagotomy or by atropinization of the recipients. These results

are compatible with the hypothesis that the negative chronotropic effects of delta9-THC in dogs under pentobarbital anesthesia is of central origin and involves

both a direct and reflexogenic alteration of central autonomic outflow regulating

the heart rate.

CHAPEL, J.L. and TAYLOR, D.W. Drugs for kicks. Crime and Delinquency 16(1):

1-35. (1970)

This paper is a review of drugs that are being used by children and

adolescents. In discussing the sniffing of glue, gasoline, thinners, and lighter

fluid, the use of narcotics, hallucinogenic drugs, and rare and exotic hallucinogens, topics such as general information, effects, techniques of administration, habit description, clinical findings, association with crime, and others

are discussed. Inhaling noxious vapors may result in acute brain syndrome

resembling alcohol intoxication plus hallucinations and delusions. The resulting

deterioration of judgment sometimes leads to serious accidents and possible

fatal consequences. More serious is the problem of the adolescent narcotic

addict who is under severe compulsion to obtain drugs, often illegally, to feed

his physical and psychic craving. Lysergic acid diethylamide (LSD) and marihuana are the most commonly abused hallucinogens. Although neither has been

shown to be addictive, both produce physiologic and psychic manifestations that

can be severe, and both can precipitate psychotic breaks. LSD has been shown

to cause chromosomal breaks in the cells of users and their offsprings. Other

drugs such as morning glory seeds, nutmeg, and peyote are used less frequently

but give the same reactions. The paper conjectures that the use of LSD, 2, 5-

dimethoxy-4-methylamphetamine (STP), and other psychedelic drugs, but not

marihuana, will eventually decrease but that other modes of getting kicks will

spring up to take their place.

211
CHAU, T.T., DEWEY, W.L. and HARRIS, L.S. Mechanism of the synergistic

lethality between pentazocine and vasopressin in the rat. The Journal of

Pharmacology and Experimental Therapeutics 186(2): 288 (1973)

Findings in a study of the mechanism of the synergistic lethality

between pentozocine and vasopressin show that pentazocine injected immediately

before vasopressin caused a significantly greater mortality in rats than when

either compound was given alone. This effect was not observed in either mice

or dogs. There was no alteration of the lethality of pentazocine in mice when injections of vasopressin were given immediately after the narcotic - antagonist

analgesic. Vasopressin reduced the magnitude and duration of the behavioral

effects of pentazocine in dogs. Oxytocin did not potentiate the lethality of

prntazocine in rats. Pentazocine and vasopressin caused cardiac and respiratory

depression leading to death in anesthetized rats but not in anesthetized dogs. The

synergistic lethality of these compounds in rats was not blocked by prior injections

of tripelennamine or atropine. Vagotomy did not block the synergistic lethality

in the anesthetized rats. Vasopressin significantly increased the level of pentazocine in rat brain and heart, but not in mice. Oxytocin which did not increase

the lethality of pentazocine, also did not alter the level of pentazocine in rat

brain tissue.

CHENEY, D.L. and GOLDSTEIN, A. The effect of rho-chlorophenylalanine on opiateinduced running, analgesia, tolerance and physical dependence in mice.

The Journal of Pharmacology and Experimental Therapeutics 177(1): 309-315

(1971)

For abstract. see Section II. Drug Chemistry and Metabolism.

CHENEY, D.L. and GOLDSTEIN, A. Tolerance to opioid narcotics, III. Time course

and reversibility of physical dependence in mice. Nature 232: 477 (1971)

CHENEY, D.L., GOLDSTEIN, A., ALGERI, S. and COSTA, E. Narcotic tolerance and

dependence: Lack of relationship with brain serotonin turnover. Science 171:

1169 (1971)

For abstract, see Section II. Drug Chemistry and Metabolism.

CHENEY, D.L., GOLDSTEIN, A. and SHEEHAN, P. Rate of development and reversibility of brain tolerance and physical dependence in mice treated with opiates.

Federation 29(2): 685 (March-April, 1970)

For abstract. see Section II. Drug Chemistry and Metabolism.

212
CHENEY, D.L., JUDSON, B. A. and GOLDSTEIN, A. Failure of an opiate to protect

mice against naloxone-precipitated withdrawal. The Journal of Pharmacology

and Experimental Therapeutics 182(2): 189-194 (1972)

Mice were made dependent upon the opiate narcotic. levorphanol, by

repeated injections of a fixed dose at a four- or eight-hour interval. The degree

of dependence was measured by determining the ED50 of naloxone for eliciting

jumping activity. After dependence was established. on either schedule, the

greatly increased plasma and brain levels of the agonist (levorphanol) after an

injection did not cause any increase in the ED50 of the antagonist (naloxone).

The behavior of antagonists in blocking primary opiate effects is competitive.

In contrast, the results reported here indicate that even a large increase of

levorphanol concentration in brain does not protect against naloxone precipitated

withdrawal.

CHIPKIN, R.E., DEWEY, W.L. and HARRIS, L.S. The effect of propanolol on the

antinociceptive and opiate withdrawal characteristics of morphine in mice.

The Pharmacologist (in press)

Reports have implicated the beta-adrenergic system in the actions of

morphine (M) and suggested blocking this system might be usefulin alleviating

opiate withdrawal in man. In this study, male albino mice weighing between 16

and 30 g were used. All injections were given i.p. Propranolol (P), at a dose

(10 mg/kg) which did not alter tail flick latency by itself, did not alter the ED50

of M when given 10 minutes prior to the narcotic (ED50 for M = 9.2 mg/kg and

for P + M = 9.8 mg/kg). The s.c. implantation of a 75 mg M pellet caused

physical dependence in mice as evidenced by the naloxone (N) induced jumping

test. Propranolol at doses of 10 and 25 mg/kg given 10 mins. prior to N

challenge did not significantly alter’either the frequency of N induced, jumping

or the ED50 of N in the chronic morphinized mice (ED50 for N = 0.029 mg/kg

and for P + N = 0.035 mg/kg). N caused hypoactivity in mice when administered 72 hours after M pellet implantation. An injection of 10 or 25 mg/kg P

10 mins. prior to N caused greater hypoactivity rather than reversing the

effects of N. These data suggest that the beta-adrenergic blocking agent, P,

does not alter the antinociceptive activity or lessen the withdrawal syndrome

of M in mice.

CHOULIS. N.H. and PAPADOPOULOS. H. Long acting methadone. Journal of Pharmaceutical Science (in press)

CHRISTENSEN, C., BEST, J.F. and HERIN, R.A. Changes seen in the electroencephalogram and heart rate in the rat after administration of marihuana

intravenously. Federation Proceedings 30(2): 375 (1971)

The intravenous administration of marihuana red oil affected septal

activity in the rat and altered septal - hippocampal activity. Both the dorsal

septum and hippocampal frequencies decreased and the power spectrums increased, but these changes were more pronounced in the dorsal septum.

213
CICERO, T.J. and MEYER, E.R. Morphine pellet implantation in rats: Quantitative

assessment of tolerance and dependence. The Journal of Pharmacology and

Experimental Therapeutics 184(2): 404-408 (1973)

For abstract, see Section I. Methodology of Drug Research.

CICERO, T.J., MEYER, E.R., BELL, R.D. and WIEST, W.G. Effects of morphine

on the secondary sex organs and plasma testosterone levels of rats. Research

Communications in Chemical Pathology and Pharmaco1ogy 7(1): 17-24

(January, 1974)

A 3 day period of morphine pellet implantation produced a marked reduction in the wet and dry weights of the seminal vesicles and prostate glands of

the rat. In the seminal vesicles, there was also a marked decrease in secretory

activity. The apparent atrophic changes in these important accessory sex organs

appears to be related to a pronounced morphine induced lowering of plasma testosterone levels.

CICERO, T.J., MEYER. E.R. and SMITHLOFF, B.R. Alpha adrenergic blocking agents:

Antinociceptive activity and enhancement of morphine-induced analgesia. The

Journal of Pharmacology and Experimental Therapeutics 189(1): 72-82 (April, 1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

CICERO, T.J., SHARPE, L.G., WILCOX, C.E. and SMITHLOFF, B.R. Effects of

morphine in vivo and in vitro on tyrosine hydroxylase activity in rat brain.

The Journal of Pharmacology and Experimental Therapeutics (in press)

CICERO, T.J., WILCOX, C.E., SMITHLOFF, B.R.. MEYER, E.R. and SHARPE, L.G.

Effects of morphine, in vitro and in vivo, on tyrosine hydroxylase activity in rat

brain., Biochemical Pharmacology 22(24): 3237-3246 (December, 1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

CLINESCHMIDT, V. and HORITA, A. Auto-potentiation by inhibition of monoamine

oxidase of the sympathomimetic action of phenelzine and pheniprazine.

British Journal of Pharmacology and Chemotherapy 30: 67-77 (1967)

CLONINGER, C.R., PACKMAN, P.M., CICERO, T.J., BOSHANS, R.L. and

ROBINS, E. Morphine dependence and enzyme activity in the hypothalamus.

Biochemical Pharmacology 23(5): 983-988 (March. 1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

214
CLOUET, D.H. The alteration of brain metabolism by narcotic analgesic drugs. Handbook

of Neurochemistry, Vol. 6. Edited by A. Lajtha, New York: Plenum Press, 1970.

Pp. 479-508.

The administration of narcotic analgesic drugs to experimental animals

has a profound effect on metabolism in the central nervous system. Alterations

have been observed in protein, nucleic acid, lipid, and energy metabolism. In

addition, the biogenic amines and the pituitary -adrenal hormonal mechanisms

are implicated in the biochemical response to narcotic drugs. Because all of the

metabolic systems in brain are in a delicate equilibrium, responsive to the

slightest change in chemical environment, it is likely that most of the observed

effects are secondary shifts consequent to the initial biochemical lesion. Such

factors as the competition between acetylcholine and morphine for hydrolysis and

transport, the release in vivo of serotonin and norepinephrine by morphine,

the inhibition of proteinmbonucleic acid synthesis by narcotic drugs, the

effects of the drugs on membrane phospholipids and on the loss of ATP in single

cells, all suggest possible sites of action for the drugs. The possibility that there

is more than one biochemical site of action should be considered, both because

of the many responses to drug administration in biochemical and pharmacological

parameters, and because of the structural similarities between narcotic analgesic

drugs and tissue components such as steroid hormones and the biogenic amines.

Whatever the site of the biochemical lesion in the central nervous system

produced by a single injection of a narcotic drug, it is apparent that there are

two general responses to chronic drug administration: (1) less response, or the

‘absence of any response during chronic drug treatment in a system which shows change

after a single dose, or (2) an increased-response to chronic treatment. In the first

category of responses are the effects on K

+

brain slices, the release of Ca2+ in the brain in vivo, the release of hypothalamic

-stimulated oxygen and glucose uptake by

pituitary-hormone-releasing factors, trophic hormones from the pituitary and the

changes in biogenic amines in the central nervous system. These may be considered

adaptive responses related to pharmacological tolerance since the effect of the

initial injection is reversed by chronic drug use. In the second category of response

are the effects on the synthesis of brain proteins and of biogenic amines, which

show larger changes with chronic drug administration. An attractive hypothesis,

for which the evidence is not conclusive, is that these metabolic systems are

part of the control mechanism for attaining new equilibria in the biochemical

systems of the first category, i.e., the mechanism for the development of

tolerance.

An important question remains unanswered: whether the sum total of

the biochemical responses in the central nervous system to the administration

of narcotic drugs represent a major disturbance of brain metabolism, or instead,

a minor transient effect qualitatively, and quantitatively, similar to events occurring

often in the CNS as a result of other modes of stimulation.

CLOUET, D.H. Cellular biochemistry of narcotic analgesic drugs in the central nervous

system of the rat. Psychiatric Quarterly 46(3): 384-392 (1972)

For abstract, see Section II. Drug Chemistry and Metabolism.

215
CLOUET, D.H. The effects of drugs on protein synthesis in the nervous system. Protein

Metabolism of the Nervous System. Edited by A. Lajtha. New York: Plenum

Press, 1970. Pp. 699-713.

For abstract, see Section II. Drug Chemistry and Metabolism.

CLOUET, D.H. Effects of narcotic analgesics on brain function. Biolopy of Brain

Dysfunction, Vol. II. Edited by G. Guall. New York: Plenum Press, 1973.

Pp; 115-149.

The ubiquitous role played by narcotic analgesics in altering metabolism

in single cells; in inhibiting simple polysynaptic reflexes in the spinal dog, in

affecting the regulation of body temperature in the decorticate dog, and in

modulating behavior in intact animals and man may be attributed to a wide

distribution of receptor sites for drug activity in both the central and peripheral

nervous systems. Because the narcotic drugs are large ionizable organic

molecules, they enter the nervous system readily and are distributed throughout the brain and in peripheral nerve. The localization of the drugs in gross

anatomical or subcellular areas of the CNS seems to be more dependent on

physicochemical characteristics of each drug than on the relative pharmacological action of the drug. In homologous series of drugs, correlations have

‘been made between narcotic activity and one or more physicochemical characteristics,

such as partition coefficients or dimensions of lipophilic sites. Comparisons of the

“analgesic receptor(s)“ as defined by structural modifications in various families

of narcotics suggest that the “receptor” may exist in more than one conformation

with varying numbers of binding sites. This suggestion would offer a chemical

basis for the varying pharmacological effects produced by administration of the

various types of narcotic analgesics.

On the subcellular level, the localization of radiolabeled narcotic drugs

after administration in active doses to animals in the nerve-ending fractions

isolated from the CNS, and especially in the membranes obtained from reptured

nerve-endings. may offer a clue to the localization of the “receptor.” If the

synaptic membrane is the site of drug action, and synaptic transmission is the

function which is disturbed, then secondary effects arising from these primary

lesions could involve the biogenic amines and acetylcholine in the CNS and elsewhere and the hypothalamic-pituitary-adrenal system, which in turn would produce

alterations in the neurohormonal modulation of the CNS. This progression would lead

to’s new equilibrium in neuronal functioning established to counter the drug effects.

It is possible to include most physiological and biochemical responses to drug

administration in this scheme of events. The development of tolerance to and

dependence on chronic drug use could then be considered as adaptive responses to the

effects of the drug through mechanisms as yet unknown.

CLOUET, D.H. Role of catecholamines in action of narcotic drugs. Catecholamines

and Behavior. Edited by A. Friedhoff. New York: Plenum Press, 1974.

CLOUET, D.H. Theoretical biochemical mechanisms for drug dependence. Chemical

and Biological Aspects of Drug Dependence. Edited by S.J. Mule and H. Brill.

Cleveland, Ohio: Chemical Rubber Company Press, 1972. Pp. 545-551.

216
CLOUET, D.H., JOHNSON, J.C., RATNER, M., WILLIAMS, N. and GOLD. G. J.

The effect of morphine on rat brain catecholamines: Turnover in vivo

and uptake in isolated synaptosomes. Frontiers in Catecholamine Research.

Edited by E. Usdin and S. H. Snyder. New York: Pergamon Press, 1973.

CLOUET, D.H. and NEIDLE. A. The effect of morphine on the transport and metabolism

of intracisternally-injected leucine in the rat. Journal of Neurochemistry 17:

1069-1074 (July, 1970)

For abstract, see Section II. Drug Chemistry and Metabolism.

CLOUET, D.H. and RATNER, M. The biosynthesis of catecholamines in the brains of

morphine treated rats. Committee on Problems of Drug Dependence. Washington,

D.C.: National Academy of Sciences, National Research Council, 1970. P. 7025.

CLOUET, D.H. and RATNER, M. Catecholamine biosynthesis in the brains of morphinetreated rats. Science 168: 854-856 (May, 1970)

For abstract, see Section II. Drug Chemistry and Metabolism.

CLOUET, D.H. and RATNER, M. Effect of morphine on brain tyrosine hydroxylase

activity. Federation Proceedings 30: 501 (1971)

For abstract, see Section II. Drug Chemistry and Metabolism.

CLOUET, D.H. and WILLIAMS, N. The effect of narcotic analgesic drugs on the uptake

and release of neurotransmitters in isolated syniptosomes. The Journal of

Pharmacology and Experimental Therapeutics 188(2): 419-428 (February, 1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

COCHIN, J. Factors influencing tolerance to and, dependence on narcotic analgesics.

Opiate Addiction: Origins and Treatment. Edited by S. Fisher and A. Freedman.

Washington, D. C.: V. H. Winston and Sons, Inc., 1974.

COCHIN, J. Possible mechanisms in the development of tolerance. Federation Proceedings

29(1): 19-27 (1970)

COCHIN, J. Tolerance to the narcotic analgesics: A long term phenomenon,

Proceedings of the Symposia held at the VIII Congress of the Collegium

lnternationale Neuro-Psychopharmacologicum, Copenhagen, Denmark; August, 1972.

COCHIN, J. and FEINBERG, M.P. Inhibition of development of tolerance to morphine

by cycloheximide. Biochemical Pharmacology 21: 3082 (1972)

COCHIN, J. and KORNETSKY, C. Factors in blood of morphine-tolerant animals that

attenuate or enhance effects of morphine in nontolerant animals. The Addictive

States, Vol. XLVI. Association for Research in Nervous and Mental Disease.

Baltimore; Maryland: The Williams and Wilkins Company, 1968.

217
COHEN, A.H. and BOWERS, M.B., JR. 5-hydroxyindoleacetic acid in rat forebrain and

cerebrospinal fluid following dorsal and median midbrain raphe lesions. Brain

Research 39: 519-522 (1972)

COHEN, S., DITMAN, K.S. and HAYMAN, M., editors. Symptoms and signs of drug

abuse: Continuing. Drug Abuse and Alcoholism Newsletter 1(10): 1-4

(December, 1972)

As part of a continuing report on the organic side effects of drug misuse, cardiovascular, gastrointestinal, hematopoietic. musculoskeletal,

neurological, and psychiatric drug induced dysfunctions are described.

COHN, M.L. Acute behavioral changes induced in the rat by the intracerebroventricular

administration of thyrotropin releasing factor (TRF) and somatostatin.

Proceedings of the Society of Toxicology, Williamsburg, Virginia, March 9-13,

1975.

COHN, M.L. Cyclic AMP, thyrotropin releasing factor (TRF) and somatostatin - key

factors in the regulation of the. duration of narcosis. Molecular Mechanisms

of Anesthesia. Edited by B.R. Fink. New York: Raven Press, 1975.

COHN, M.L. Dibutyryl cyclic AMP - an antidote to hypnotic, sedative and tranquilizer

overdosage in the rat. Toxicology and Applied Pharmacology 25: 439 (1973)

We have previously reported that N

6

, O

2

'-dibutyryl adenosine 3':5'-cyclic

monophosphate (db cyclic AMP) administered intracerebroventricularly (icv) in the

rat, shortened amobar bital-induced sleeping time in a dose-related manner. Five

neuropharmacologic agents, which included the aliphatic hypnotics chloral hydrate

and paraldehyde, the tranquilizer diazepan, the phencyclidine derivative ketamine,

and the inhalation agent halothane, were also tested. Dbcyclic AMP shortened, in a

dose-related manner, the duration of narcosis of each of the structurally unrelated

central nervous system depressants. The purpose of the present research was to

determine if db cyclic AMP administered icv protected rats treated with a toxic

dose, of each of these drugs. Male Sprague-Dawley rats weighing 80-100 g were

weighed and one of the central nervous system depressants was injected ip according

to the following dose schedules: amobarbital. 175 mg/kg; chloral hydrate (Noctec),

500 mg/kg (diluted 1:1 in sterile saline). diazepam, 70 mg/kg, and paraldehyde, 1.5

ml/kg. Immediately after the loss of righting reflex 225 mu-g of cyclic AMP in

15 mu-l of 0. 001 m potassium phosphate buffer solution, pH 7.5, was administered

icv. Our data showed that db cyclic AMP significantly reduced the mortality of

amobarbital from LD50 to LD3, chloral hydrate from LD50 to LD17, and paraldehyde

from LD67 to LD17. Repetitive icv doses of db cyclic AMP were required to decrease

the mortality due to ketamine and diazepam. Whereas higher doses of db cyclic

AMP (300 mu-g) given to rats treated with toxic doses of diazepam and ketamine

resulted in shortening of the sleeping time, no reduction of the LD50 was observed.

Analeptic drugs (methamphetamine, picrotoxin, doxapram, caffeine, theophylline.

and strychnine) administered icv did not shorten the sleeping time or reduce the

mortality of any of the central nervous system depressants used in this study.

218
COHN. M.L. The influence on amobarbital-induced sleeping time in rats by drugs

affecting cyclic AMP. Prostaglandins and Cyclic AMP. Biological Actions and

Clinical Applications. Edited by R.H. Kahn and W.E. M. Lands. New York:

Academic Press, 1971. Pp. 73-74.

In previous studies we have shown that dibutyryl cyclic AMP in

pharmacologic doses administered intracerebroventricularly (ICV) shortened

amobarbital-induced sleeping time in a dose-related manner in rats. The

duration of narcosis of structurally different anesthetic and tranquilizer agents

(chloral hydrate, diazepam, paraldehyde, ketamine and halothane) was also

shortened in a dose-related manner by the ICV administration of db cyclic AMP

These studies suggested that cyclic AMP in vivo has a regulatory

action on the duration of narcosis.

The purpose of this research was to determine the effects on the

duration of amobarbital-induced narcosis by the ICV administration of neuropharmacologic

agents known to increase levels of cyclic AMP in the brain.

COHN, M.L. and COHN, M. Antianesthetic effects of cyclic AMP and analeptic drugs as

determined by reversal of amobarbital-induced narcosis. Proceedings of the

Society for Toxicology, Washington, D.C., March 10-14, 1974.

COHN, M.L. and COHN, M. “Barrel rotation” induced by intracerebroventricular

injection of somatostatin in the nonlesioned rat. Proceedings of the American

Society of Pharmacology and Experimental Therapeutics, Atlantic City,

New Jersey, April 13-18. 1975.

COHN, M.L. and COHN, M. Phentolamine - an antagonist of cyclic AMP regulation of

narcosis. Proceedings of the Society for Neurosciences, San Diego, California,

November 7-10, 1973.

COHN, M.L. and COHN, M. The role of thyrotropin releasing factor and cyclic AMP

in the duration of amobarbital-induced narcosis. Proceedings of the Society for

Neurosciences, St. Louis, Missouri, October 20-23, 1974.

COHN, M.L. and COHN, M. Thermoregulatory control in the rat anesthetized with

amobarbital. Role of thyrotropin releasing factor. Proceedings of the American

Society of Anesthesiologists, Washington, D.C., October 12-16, 1974.

219
COHN, M.L., COHN, M. and TAYLOR, F.H. Norepinephrine - an antagonist of dibutyryl

cyclic AMP in the regulation of narcosis in the rat. Research Communications in

Chemical Patholopy and Pharmacology 7: 687-699 (1974)

Norepinephrine (NE) (25-300 mu-g) administered centrally to rats anesthetized with amobarbital prolonged narcosis. The higher doses of NE (150-300 mu-g/

rat) induced severe toxic symptoms followed by death. The addition of varying

doses of dibutyryl adenosine 3', 5'-monophosphate (db cyclic AMP) to NE (150 mu-g)

reduced the duration of narcosis potentiated by the latter but did not alter the toxic

symptoms of the higher doses. In the regulation of the duration of narcosis, the

lack of analogy between the behavioral effects of exogenously administered NE and db

cyclic AMP challenges the concept that the action of NE is mediated in the brain

uniquely through a second messenger system.

COHN, M.L., KRAYNACK, B., COHN, M. and SCATTAREGIA, F. Interaction of cyclic

AMP with neuropharmacologic depressant agents. Federation Proceedings 32:680

(1973)

The purpose of this study was to determine which categories of CNS depressant

were antagonized by db cyclic AMP (db CAMP). Previous findings showed that

dibutyryl surrogate of cyclic AMP administered intracerebroventricularly (ICV)

regulated in a dose-related manner the duration of amobarbital-induced narcosis

(Neuropharm. in press). Structurally different neuropharmacologic depressant

agents (the aliphatic hypnotics, chloral hydrate and paraldehyde, the tranquilizer,

diazepam, the phencyclidine derivative, ketamine, and the inhalation agent,

halothane) were similarly antagonized. Sprague-Dawley male rats weighing

80-125 g were given intraperitoneal injections of one of the CNS depressant agents

in the following dose schedule: ethanol 4.86 g/kg; methanol 11.34 g/kg; meperidine 80 mg/kg; lidocaine 160 mg/kg. Each rat was given an ICV injection of db

CAMP in varying concentrations (90 mu-g to 225 mu-g). Ethanol and methanol

sleeping time and overdosage were antagonized in a manner similar to amobarbital.

In contrast, the ICV administration of db CAMP to meperidine and lidocainetreated rats augmented the toxic effects and increased the mortality. The data

suggests that there are two general groups of neuropharmacologic CNS depressant

agents. They may be classified according to their response to exogenously

administered db CAMP. Further work is necessary to explain the diametrically

different actions of db CAMP.

COHN, M.L., TAYLOR, F., COHN M. and YAMAOKA, H. Dibutyryl cyclic AMP - an

effective antidote against lethal amounts of amobarbital in the rat. Research

Communications in Chemical Pathology and Pharmacology 6: 435-446 (1973)

Dibutyryl cyclic AMP is a potent antianesthetic agent to amobarbitalinduced narcosis in the rat. Our evidence demonstrates that without other supportive therapy centrally administered dibutyryl cyclic AMP also reverses

barbiturate poisoning by selectively antagonizing barbiturate-induced depression

without producing generalized stimulation. Such findings suggest the properties

of a true antidote to the barbiturate. Furthermore, reversal of overdosage is not

limited to barbiturates; dibutyryl cyclic AMP seems to reverse toxic levels of

all central nervous system depressants that induce narcosis.

220
COHN. M.L., YAMAOKA, H., TAYLOR, F.H. and KARYNACK, B. Action of intracerebroventricular dibutyryl cyclic AMP on amobarbital anesthesia in rats

Neuropharmacology 12: 481-495 (1973).

COHN R.A., BARRATT, E.S. and PIRCH, J.H. Marijuana responses in rats:

Influence of castration or testosterone. Proceedings of the Society for Experimental

Biology and Medicine 146: 109-113 (1974)

The ability of intracerebroventricular exogenous administration of N

6

,O2'-

dibutyryl analog of adenosine 3':5'-cyclic monophosphate (db clycic AMP) to shorten

the duration of amobarbital anaesthesia in a dose-related manner has been shown in

the rat. Alteration of the duration of sleeping time (ST) appeared to be specific to

db cyclic AMP since neither adenosine nor guanosine nucleotides administered

intracerebroventricularly produced any appreciable effects. Similarly, intracerebroventricular injected succinate or pyruvate did not alter amobarbital-induced

ST. None of the behavioral symptoms observed following the intracerebroventricular

injection of db cyclic AMP in the unanaesthetized conscious rat were evident in

the amobarbital-anaesthetized rat.

Female rats show a significantly greater behavioral response than male rats

to marijuana extract. This difference in response was partially aboiished through

castration of males or testosterone pretreatment of females. Since castration and

testosterone pretreatment may affect drug metabolism, we also studied the effects

of liver microsomal enzyme induction and inhibition on responses of rats to

marijuana. While enzyme inhibition increased the responses of rats to marijuana,

enzyme induction did not alter behavioral responses to marijuana.

COLASANTI, B. and KHAZAN, N. Agonistic properties of narcotic analgesics and

antagonists on the electroencephalogram and behavior in the rat and their reversal

by naloxone. Neuropharmacology 12: 619-627 (19.73)

Adult female Sprague-Dawley rats were prepared with chronic cortical and

temporalis muscle electrodes for recording of the electroencephalogram (EEG) and

the electromyogram (EMG). Acute i.p. administration of the narcotic analgesics

morphine. methadone, meperidine, or codeine was followed by the induction of

high-voltage slow activity in the EEG during behavioral stupor of the rat, the duration

of which was dose-related. Administration of the narcotic antagonists nalorphine,

pentazocine, or cyclazocine resulted in similar EEG and behavioral changes. This

initial period of EEG slow activity and behavioral stupor was uniformly succeeded

by a secondary phase of EEG desynchrony and behavioral arousal, the duration of

which depended upon the individual narcotic and antagonist agents. The narcotic

antagonist naloxone, however, was devoid of such effects. Nalorphine administered

at the dose ratios of 1 : 4 or 1 : 8 five min before morphine significantly reduced

the duration of the morphine response. Administration of naloxone at a dose ratio

of 1 : 5 five min before morphine, however, resulted in a complete reversal of the

entire morphine effect. These results suggest that the induction of EEG slow

activity in association with stuporous behavior of the rat is an agonistic property

of narcotics and antagonist-analgesics which is reversed by “pure” narcotic antagonists.

221
COLASANTI, B. and KHAZAN, N. Antagonism of the acute electroencephalographic and

behavioral effects of morphine in the rat by depletion of brain biogenic amines.

Neuropharmacology 12: 463-469 (1973)

Adult female Sprague-Dawley rats were prepared with chronically implanted

cortical and temporalis muscle electrodes for recording of the electroencephalogram (EEG) and the electromyogram (EMG). Morphine injections of 10 mg/kg

given i.p. to saline-treated rats were followed almost immediately by the appearance

of high voltage EEG slow bursts associated with stuporous behavior, which prevailed

for 60-90 min. This phase was superseded by the prevalence of EEG and behavioral

arousal over an additional period of 60-90 min. after which EEG and behavioral sleep

appeared. Administration of a 10 mg/kg dose of morphine to rats pretreated with

(±)-alpha-methyl-para-tyrosine (alpha-MPT) was followed by a slight but significant

shortening of the period of EEG slow bursts and the behavioral stupor as well as

by a reduction in the duration of the entire morphine effect. In contrast, rats pretreated with para-chlorophenylalanine (p-CPA) responded to morphine by an almost

immediate and continuous EEG and behavioral arousal, with only a few intervening

episodes of behavioral stupor associated with EEG slow bursts. This effect of p-CPA

was completely reversed by the administration of 5-hydroxytryptophan (5-HTP) prior

to the morphine injection. Pretreatment of the rats with both p-CPA and alpha-MPT

likewise resulted in an attenuation of the period of morphine-induced EEG and

behavioral stupor concomitant with a prolongation of the period of behavioral arousal.

The effects of this treatment, however, were less pronounced than those occurring

after p-CPA alone. These results suggest that the relative amounts of all three

monoamines norepinephrine, dopamine, and 5-hydroxytryptamine in the brain, rather

than the absolute levels of any one amine, are important in the mediation of the

central effects of morphine.

COLASANTI, B. and KHAZAN, N. Changes in EEG voltage output of the sleep-awake cycle

in response to tetrahydrocannabinols in the rat. The Pharmacologist 12: 246

(1971)

Marihuana and the active delta-8- and delta-9-trans-tetrahydrocannabinol (delta8-and delta-9-THC) derivatives are generally regarded as psychotomimetics with

sedative properties. Since the sympathomimetic hallucinogens have been reported

to cause a reduction in the mean voltage output of the EEG and its coefficient of

variation, the present study was undertaken to determine whether a similar change

would follow the administration of THC. Adult female Sprague-Dawley rats with

chronic cortical and temporal muscle electrodes were used. Administration of

delta-8-THC i.p. at doses ranging from 2.5 to 10.0 mg/kg was followed by a

dose-related decrease in the voltage output of the awake state EEG. The Bleep

and REM sleep states were relatively less affected. Polyspike discharges,

reported previously to occur after the administration of marihuana extract of

delta-8-THC (Masur and Khazan, Life Sci. 9:1275, 1970), were superimposed on

the low voltage EEG awake tracings. Administration of delta-9-THC resulted in

similar EEG changes. The reduction in the voltage output of the EEG in conjunction with the occurrence of the polyspike discharges, unique to this group of

psychotomimetics, is presumed to correlate with a state of CNS arousal during

which the rat appears behaviorally sedated.

COLASANTI, B. and KHAZAN, N. Effects of delta-8-tetrahydrocannabinol on the voltage

output of the EEG in the rat. Committee on the Problems of Drug Dependence.

Washington, D.C.: National Academy of Sciences, National Research Council,

1971.

222
COLASANTI, B. and KHAZAN, N. Imipramine-induced changes

sleep rebound and wet dog shakes of morphine-abstinent

(in press)

in the rapid eye movement

rats. Neuropharmacology

COLASANTI, B. and KHAZAN, N. Interactions of narcotic analgesics and antagonists on

the electroencephalogram (EEG) and behavior of the rat. Federation Proceedings

31: 304 (1972)

The induction by morphine of high voltage EEG slow bursts has been reported

to occur both in experimental animals and in man. The present study has been

undertaken to explore the specificity of this effect in relation to other narcotic

analgesics as well as the narcotic antagonists. Adult female Sprague-Dawley rats

were prepared with chronic cortical and temporalis muscle electrodes. Acute i.p.

injection of the narcotic analgesics morphine, methadone, meperidine. and codeine

was followed by the induction of high voltage slow activity in the EEG. The appearance of EEG slow bursts was accompanied by stuporous behavior of the rat. These

effects were dose-related and paralleled the relative potencies of the narcotic

agents. The narcotic antagonists nalorphine and naloxone, administered i.p., were

effective in blocking the appearance of slow bursts in the EEG. Administration of

nalorphine alone, however, was followed by similar EEG changes. These results

suggest that the induction of EEG slow bursts in association with stuporous behavior

of the rat is an agonistic property of narcotics and antagonist-analgesics which is

blocked by narcotic antagonists.

COLLINS, P.I., WEI, E. and WAY, E.L. The central site of morphine analgesia in

rats. Proceedings of the Western Pharmacological Society 17: 164-167 (1974).

COLLINS, P.I., WEI, E. and WAY, E.L. Central sites of morphine analgesia.

Proceedings of the Western Pharmacological Society 17: 164 (1974)

No chemical agent has yet been developed which surpasses morphine or

morphine-like drugs in the clinical relief of pain; An understanding of the sites

and mechanisms underlying the antinociceptive action of morphine may therefore

be useful in developing new approaches to pain relief. The central sites of

morphine analagesia have been ascribed to the areas surrounding the third (1) and

fourth ventricle (2), the periventricular and periaqueductal grey of the brain stem (3),

the anterior medial thalamus (4) and the posterior hypothalamus (5). In this investigation, we determined the brain areas where localized application of crystalline

naloxine, an opioid antagonist, reversed the analgesia induced by morphine

administered systemically.

223
COCK, J.D. and SCHANBERG, S.M. The effects of methamphetamine on behavior and

on the uptake, release and metabolism of norepinephrine. Biochemical Pharmacology 19: 1165-1179 (1970)

The use of different dose-response schedules may be responsible for conflicting reports between changes in behavior and norepinephrine metabolism in

brain following the administration of amphetamine. Therefore, the effects of

methamphetamine on the levels of endogenous norepinephrine and on the metabolism

of tritiated (

3H) norepinephrine in brain were studied after different dose regimens

and post. medication intervals. Various time intervals after the intraperitoneal

injection of methamphetamine (5 mg/kg) norepinephrine-3H was injected into the

criteria magna of rats. Five min later, the brains were removed and assayed for

endogenous norepinephrine, tritiated norepinephrine and its metabolites (normetanephrine, deaminated catechols and -methylated deaminated catechols). Uptake of

norepinephrine-3H was inhibited at 0.5 and 1•0 hr, returned to control levels at 2

hr and exceeded these levels at 5 hr. Both tritiated deaminated catechol and

methylated deaminated metabolite levels were decreased at 0•5 and 1 hr but approached

control levels when determined 5 hr post methamphetamine administration. Normeta’nephrine- 3H levels were highest (220 per cent of control) at 0•5 hr, then

decreased at each successive test time to 130 percent control level at 7 hr. Endogenous levels of norepinephrine were increased for the first hour and then fell to

85 per cent of control levels at 3 hr. When norepinephrine-3H was injected prior

to methamphetamine administration, no significant release of the labeled amine

occurred until 7 hr after the administration of the drug. In these release studies,

as was seen in the uptake studies, decreased levels of deaminated catechol-3H and

increased normetanephrine-3H levels occurred although norepinephrine-3H levels

were not significantly lowered. This supports the hypothesis that methamphetamine

interferes with the deamination of norepinephrine by monoamine oxidase. Changes

in behavioral ratings had a time course similar to alterations in norepinephrine-3H

uptake and metabolism. A high correlation was found between the changes in

behavior and normetanephrine-3H levels.

It is clear from these data that to properly evaluate interrelationships

between drug effects on metabolism and behavior, it is essential to compare several

dose-response schedules rather than using a single arbitrary regimen.

COOPER, B.R. and BREESE, G.R. Relationship of dopamine neural systems to the

behavioral alterations produced by 6-hydroxydopamine administration into

brain. Neuropsychopharmacology of Monoamines and Their Regulatory Enzymes.

Edited by E. Usdin. New York: Raven Press, 1974.

COOPER, B.R., COTT, J.M. and BREESE, G.R. Effects of catecholamine-depleting drugs

and amphetamine on self-stimulation of brain following various 6-hydroxydopamine

treatments. Psychopharmacologia 37: 235-248 (1974)

Changes in electrical self-stimulation responding were examined in rats with

electrodes implanted in the lateral hypothalamus following 6-hydroxydopamine treatments which depleted brain dopamine, norepinephrine or both of these catecholamines.

Acute depression of self-stimulation occurred after treatments which reduced brain

dopamine, but did not occur in rats treated to deplete just brain norepinephrine. A

chronic deficit in self-stimulation responding occurred in rats treated with 6-hydroxydopamine in combination with pargyline to reduce both brain amines, while responding

of animals in which brain dopsmine was reduced returned to levels observed prior to

6-hydroxydopamine treatment. A dose of alpha-methyltyrosine (25 mg/kg), which did

not affect responding of control rats, caused a significant reduction in responding of

rats depleted of brain dopamine. This treatment did not affect responding of rats

depleted of brain norepinephrine. Administration of the dopamine-beta-hydroxylase

inhibitor, U-14624, failed to affect self-stimulation in spite of an additional 70%

224
Cooper, B.R., Cott, J.M. and Breese, G.R. continued

reduction of brain norepinephrine content. The response to a dose of damphetamine (0.25 mg/kg), that increased self-stimulation of control rats, was

significantly reduced in rats with brain dopamine selectively depleted. Rats in

which norepinephrine was depleted responded to d-amphetamine like the control

group. Alpha-methyltyrosine antagonized the increased self-stimulation responding

following administration of d-amphetamine (1 mg/kgl to reserpinized rats, while

U-14624 did not. Results support the hypothesis that central dopaminergie fibers

have an important involvement in the maintenance of self-stimulation of brain.

COUSENS, K. and DiMASCIO, A. (-)-Delta-9-THC as an hypnotic. Psychopharmacologia 33: 355-364 (1973)

(-)-Delta-9-THC was found to significantly decrease the time it takes to fall

asleep in physically healthy insomniacs. Once asleep, interruptions of sleep were

not significantly altered over the whole night. The (-)-delta-9-THC tended to be

associated with some decrease in awakenings in the first half of the night.

The primary side effect experienced by the subjects at all dose levels in the

Pre-Sleep phase was temporal disorganization and mood alterations. There was an

increase in intensity of side effects and number of subjects affected with increasing

dosage.

The most significant side effect, however, was a “hangover” phenomenon, or

continued “high” the next day, with some residual of temporal disorganization. It

increased in intensity and duration with increase in dosage. This “hangover” seems

severe enough to eliminate the consideration of the 30 mg dose range, of (-)-delta-9-

THC for clinical use as an hypnotic.

CROFFORD, M. and SMITH, A.A. Growth retardation in young mice treated with dlmethadone. Science 181: 947-949 (September, 1973)

Newborn mice injected daily for 6 weeks with dl-methadone in dosages of 2

to 8 milligrams per ‘kilogram grew significantly more slowly than their salinetreated littermates. Litters given d-methadone, 4 milligrams per kilogram,

grew normally. Concomitant treatment with naloxone, 10 milligrams per kilogram,

prevented growth inhibition. A weight deficit persisted in mice observed 6 weeks

after cessation of methadone treatment.

CROMBIE, L., PONSFORD, R., SHANI, A., YAGNITINSKY, B. and MECHOULAM, R.

Photochemical production of cannabicyclol from cannabichromene. Tetrahedron

Letters 55: 5771-5772 (1968)

CROWDER, W.F., SMITH, S.G., DAVIS, W.M., NOEL, J.T. and COUSSENS, W.R.

Effect of morphine dose size on the conditioned reinforcing potency of stimuli paired

with morphine. The Psychological Record 22: 441-448 (1972)

After an initial operant level period, 22 rats were given non-contingent pairing

of a buzzer with intravenous injections of morphine solution in doses of 0.0032 mg/kg,

and 0.032mg/kg. The buzzer plus a saline infusion were then presented contingently

on bar-pressing behavior. The results of this test indicated that buzzer plus saline

infusion had acquired secondary reinforcing properties, the magnitude of which

increased with increasing dosage of morphine. The results may be attributed to

conditioned positive reinforcement, since no physical dependence was evident. The

present findings also suggest that a stimulus can become a secondary reinforcer

without being a discriminative stimulus for an operant.

225
CUMMINS, J.T. and MORIN, A.M. The effect of reserpine and morphine on the release

of endogenous primary amines from isolated brain tissues. Proceedings of the

Western Pharmacological Society (in press)

CUSHMAN, P., JR. Growth hormone in narcotic addition. Journal of Clinical Endocrinolopy 35: 352 (1972)

Growth hormone (GH) levels were measured in normals, methadone-treated,

former heroin addicts and actively addicted male patients during and after insulin

hypoglycemia. Normal GH response to adequate hypoglycemia was observed in the

controls and the abstinent former addicts. Although most heroin-addicted and

methadone-maintained patients also responded normally, some in each category

had suboptimal responses. Some of these GH hyporesponders also had subnormal

cortisol responses to hypoglycemia. Serum LH, T-4, T-3 and PBI’s usually were

normal in both heroin addicted and methadone maintained patients regardless of the

magnitude of their GH responses. There was no correlation of GH responsiveness

with duration of addiction. daily average cost of addiction, dose of methadone

or duration. of methadone maintenance. There were no clinical stigmata

of hypopituitarism in any patient. The evidence suggests a mild

subtle hypothalamic-pituitary dysfunction may be present in some patients characterized

principally by subnormal GH and cortisol responses to insulin hypoglycemia.

CUSHMAN, P., JR. Persistent increased immunoglobulin M in treated narcotic addiction.

Journal of Allergy and Clinical Immunology 52(2): 122-128 (August, 1973)

The increased serum IgM in treated narcotic addiction was studied using

quantitative radial diffusion techniques. Seventy per cent of 68 untreated heroin

addicts had serum IgM levels above 280 mg. per deciliter, the upper limit of normal.

Only 7 per cent of 15 abstinent patients had high serum IgM, while 36 or 33 per cent

of 109 patients maintained on methadone for at least one year had high serum IgM

levels. Fourteen of these 36 had known heroin use and 10 others abused other drugs

including alcohol, whereas only 2 of the 73 methadone-maintained patients with

normal serum IgM had known drug abuse. The association between positive urine

spots for morphine and elevated serum IgM levels was significant (p less than 0.01).

There was a significant relationship between laboratory evidence of liver disease

and increased serum IgM levels. Increased serum alkaline phosphate correlated

better (p less than 0.01) than the serum glutamic oxaloacetic transaminase (SCOT)

(p less than 0. 05) with high serum IgM levels in methadone-maintained patients,

High serum IgM levels in treated addicts are associated with continuing drug abuse

and/or with laboratory evidence of continuing mild liver disease.

CUSHMAN, P., JR. and KREEK, J.J. Some endocrinologic observations in narcotic

addicts. Narcotics and the Hypothalamus. Edited by E. Zimmermann and R.

George. New York: Raven Press, 1974.

DAVIS, J.M., JANOWSKY, D.S., EL-YOUSEF, M.K., and SEKERKE. H.J. Drug Interactions

Involving Drugs of Abuse. Washington, D.C.: U.S. Government Printing Office, 1973.

DAVIS, M. and SHEARD, M.H. Biphasic dose-response effects of n-n-dimethyltryptamine

on the rat startle reflex. Pharmacology, Biochemistry and Behavior 2: 827-829 (1974)

The startle reflex was measured in 4 groups of 10 rats each after intraperitoneal

injection of saline or 0.12. 0.25, 0. 50 or 4. 00 mg/kg N-N-dimethyltryptamine (DMT).

Low doses (0.25 and 0.50) of DMT augmented startle but the high dose (4.0) depressed

startle. This biphasic dose-response relationship is consistent with the hypothesis

that startle is enhanced when midbrain raphe neurons are inhibited but depressed when

cells post-synaptic to raphe neurons are also inhibited.

226
DAVIS, M. and SHEARD, M.H. Effects of lysergic acid diethylamide (LSD) on habituation and sensitization of the startle response in the rat. Pharmacology, Biochemistry and Behavior 2: 675 (1974)

In 4 experiments the effect of d-lysergic acid diethylamide (LSD) on the

acoustic startle response in rats was measured. A low dose (20 mu-g/kg) facilitated startle but a high dose (160 mu-g/kg) at first facilitated but then depressed

startle somewhat relative to an intermediate dose (40 mu-g/kg). 2-brom LSD

(199 mu-g/kg) had no detectable effect and 40 mu-g/kg LSD did not change startle

in raphe-lesioned rats. LSD appeared to augment sensitization rather than acting

on the startle circuit directly since it did not increase startle unless given in

conjunction with either background noise or repetitive tones.

between session habituation.

LSD did not prevent

Relationships between habituation, sensitization,

and the midbrain raphe nuclei were discussed.

DAVIS, P.W. and HORITA, A. Chronotropic responses to catecholamines as a function

of monoamine oxidase activity in the isolated perfused rat heart. Archives

internationales de Pharmacodynamie et de Therapie 173(2): 386 (June, 1968).

There has been considerable recent interest in the possible role of

monoamine oxidase (MAO) in the termination of pharmacological responses to

exogenously administered catecholamines and agents which act indirectly by

the release of norepinephrine. The purpose of the present study was to investigate

the chronotropic responses to catecholamines as a possible function of MAO activity

in the isolated perfused rat heart. Dopamine, a directly-acting amine and good MAO

substrate, and alpha-methyldopamine, a directly- and indirectly-acting amine and

non-substrate for MAO, were selected for study.

DAVIS, V.E., CASHAW, J.L., McLAUGHLIN, B.R. and HAMLIN, T.A. Alteration of

norepinephrine metabolism by barbiturates. Biochemical Pharmacology 23:

1877-1889 (1974)

Competitive inhibition of NAD-linked aldehyde dehydrogenase by acetaldehyde,

the primary metabolite of ethanol, enhances the formation in vitro of tetrahydropapaveroline (THP), a tetrahydroisoquinoline (THIQ) alkaloid derived from the

condensation of dopamine (DA) with 3,4-dihydroxyphenylacetaldehyde. Unlike the

DA-derived aldehyde, the aldehyde derivative of norepinephrine (NE) is not appreciably oxidized in brain tissue to the corresponding acid by brain aldehyde dehydrogenase, but is primarily reduced to the glycol, 3,4-dihydroxyphenylglycol

(DHPG), by an NADPH-dependent aldehyde reductase. Since it has been demonstrated

that this partially purified aldehyde reductase from bovine brain is inhibited by

barbiturates, an investigation was conducted to define the effects of barbiturates on

the over-all metabolism of 14C-NE and its aldehyde by rat brainstem homogenates.

In the absence of exogenous NAD or NADPH, the major metabolite of deaminated

NE was found in a fraction that would contain the THIQ alkaloids. A smaller portion

of the deaminated NE was isolated as the DHPG and the 3,4-dihydroxymandelic acid

(DHMA) metabolites. A substantial amount of the deaminated NE was also accounted

for as the free aldehyde. Adding NADPH markedly increased DHPG formation while

decreasing alkaloid synthesis. Incorporating barbiturates into incubation mixtures

containing NADPH. or a mixture of NAD and NADPH. appreciably inhibited DHPG

production, thereby enhancing free glycolaldehyde levels and augmenting alkaloid

formation. Thus, barbiturates - like ethanol, as mediated by acetaldehyde - markedly

modify neuroamine-derived aldehyde metabolism.

227
DAVIS, W.M., BABBINI, M., COUSSENS, W.R., SMITH, S.G. and CROWDER, W.F.

Antagonism of behavioral effects of morphine by alpha-methyltyrosine (AMT).

The Pharmacologist 13(2): 280 (1971)

Many studies have attempted to relate brain catecholamines and/or serotonin

to the analgesic action and to the mechanisms of tolerance and physical dependence

associated with morphine sulfate (MS). Other actions of MS have been little investigated in this regard. We used 50 mg/kg (i.p.) doses of 1-AMT given 4-5 hr. prior

to the expected peak of MS effect on locomotor activity of the rat. The immediate

enhancement of motility following 5.0 mg/kg (i.p.) MS, and the delayed stimulation

after 20 mg/kg both were blocked. Also, the enhanced stimulatory response to

10, 20, or 40 mg/kg MS after daily administration for 18 days was suppressed by

AMT pretreatment on day 19. Bar-pressing which delivered 0.32 mg/kg doses of

MS via a chronic indwelling jugular catheter on a CRF schedule was quickly elevated

above operant response levels (many rats pressing several hundred times on 1st

day). Such self-injection behavior also was suppressed by 50 mg/kg i.p. dl-AMT.

Thus, it appears that both behaviors are dependent upon the functional pool of brain

catecholamines.

DAVIS, W.M., BABBINI, M. and KHALSA, J.H. Antagonism by alpha-methyltyrosine of

morphine induced motility in non-tolerant and tolerant rats. Research Communications in Chemical Pathology and Pharmacology 4(2): 267-279 (1972)

The immediate locomotor stimulation induced by a 5.0 mg/kg i.p. dose of

morphine sulfate, and the delayed stimulation after a 20 mg/kg dose both were

blocked by pretreatment with 50 mg/kg (i.p.) of L-alpha-methyl-p-tyrosine (AMT).

Similarly, the enhanced locomotor response to 10. 20 and 40 mg/kg doses of

morphine after their daily administration for 18 days was antagonized by AMT pretreatment given on the 19th day. AMT had little or no effect on activity levels in

control groups receiving no morphine, but it reduced brain catecholamine levels by

about 50% at the time of activity testing. Pretreatment with L-DOPA (160 mg/kg)

alone did not reverse the effect of AMT. but the morphine effect was restored by

L-DOPA plus reserpine (3.2 mg/kg). It is evident that morphine-induced locomotor

stimulation was dependent upon normal availability of brain catecholamines.

DAVIS, W.M. and BORGEN, L.A. Tolerance development to the effects of delta-9-THC

on conditioned behavior: Role of treatment interval and influence of microsomal

metabolism. Archives internationaIes de Pharmacodynamie et de Therapie (in press)

DAVIS, W.M. and KHALSA, J.H. Morphine lethality in rats: Effects of inhibitors of

brain catecholamine synthesis and methylation. Research Communications in

Chemical Pathology and Pharmacology 6(3): 867-872 (1973)

Tropolone, an inhibitor of catecholamine-O-methyltransferase, alpha-methyltyrosine (AMT), an inhibitor of tyrosine hydroxylase, and U-14,624, an inhibitor

of dopamine-beta-hydroxylase were tested for an ability to alter the acute lethal

toxicity of morphine sulfate. Tropolone (50 mg/kg. i.p.) reduced the 24-hr i.p.

LD50 of morphine in male Holtzman rats from 292 to 54 mg/kg. The other two agents

both elevated the LD50 significantly. It is suggested that the potentiation of morphine

by tropolone resulted from a reduced inactivation of brain catecholamines released

by the action of morphine, while the protection afforded by AMT and U-14,624

pretreatment was a result of their inhibition of brain catecholamine synthesis.

228
DAVIS, W.M. and KHALSA, J.H. Some determinants of aggressive behavior induced by

morphine withdrawal. Psychonomic Science 24(1): 13-15 (1971)

Male and female rats of Sprague-Dawley and Long Evans strains were given

daily intraperitoneal injections of morphine sulfate in increasing dosages over a 15-day

period to a terminal dose of 405 mg/kg/day. During withdrawal, fighting behavior

occurred equally among older male rats (60 days at start of experiment) of both

strains, housed in groups of six, but not at all in younger ones (30 days). A

strain difference found earlier in 45-day-old rats was confirmed. Females of either

strain or age, showed no aggressive behavior during withdrawal. Decreasing

available cage space increased the number of aggressive encounters, despite a

reduction of group size to four. Saline-injected males of either strain rarely

displayed aggression. A circadian rhythmicity of such behavior was not found.

There was evidence for a seasonal variation in frequency of morphene-withdrawalinduced aggression, levels being higher in summer than in winter.

DAVIS, W.M., LOGSTON, D.G. and HICKENBOTTOM, J.P. Antagonism of acute amphetamine intoxication by hatoperidol and propranolol. Toxicology and Applied Pharmacology

29: 397-403 (1974)

The antidotal effects of a butyrophenone neuroleptic, haloperidol (HAL), and

a beta-adrenergic blocking agent, propranolol HCl(PRO), against the acute toxicity

of d -amphetamine sulfate (AS) were determined. Alteration by such treatments of 2

biochemical changes implicated in the lethal mechanism(s) of AS also ‘were examined.

Male Sprague-Dawley rats (130-160 g) were injected ip with 64.8 mg/kg (1.5 x LD50)

of AS. At 5 or 15 min after AS, SC injections of either PRO (10 or 20 mg/kg), HAL

(0. 5 or 1.0 mg/kg), or a combination of PRO (20) and HAL (1.0) were given. Both

doses of PRO and of HAL afforded considerable protection against AS lethality compared to saline posttreated controls. However, the combination did not protect as well

as did the more effective single agent, HAL. Hypoglycemia at 25 min after AS was

prevented only by HAL (0.5 mg/kg) injection at 15 min post-AS. The 4-6-fold elevation

of plasma lactate at 25 min after AS was prevented by posttreatment with PRO (20

mg/kg), but not by the HAL doses, which greatly reduced lethality. The data do not

indicate that prevention of these biochemical effects of AS was critical to reduction

of mortality. It is suggested that HAL and PRO deserve consideration as useful

alternative or supplemental antidotes to those presently recommended for human

acute intoxications from amphetamine-like drugs.

DAVIS, W.M. and SMITH, S.G. Alpha-methyltyrosine to prevent self-administration of

morphine and amphetamine. Current Therapeutic Research 14(12): 814-819

(1972)

Rats equipped with jugular cannulas were given opportunity to self-administer

intravenous doses of morphine sulfate (32 mcg/kg) or d-amphetamine sulfate (15 mcg/-

kg) by means of a bar-press response which activated an injection device. Pretreatment with L-alpha-methyltyrosine (3 intraperitoneal doses of 75 mg/kg during an

8 hr. period prior to the experimental session) blocked the development of selfadministration behavior toward both drugs. This result is interpreted as a blockade

of the mechanism by which these agents act as primary positive reinforcers. Because

of this property, it is suggested that alpha-methyltyrosine may be applicable in procedures designed to produce extinction of drug-seeking behavior in persons abusihg

opiates and/or amphetamine.

DAVIS, W.M. and SMITH, S.G. Blocking effect of alpha-methyltyrosine on amphetamine based

reinforcement. Journal of Pharmacy and Pharmacology 25: 174 (1973).

229
DAVIS, W.M. and SMITH, S.G. Blocking of morphine based reinforcement by alphamethyltyrosine. Life Sciences 12: 185-191 (1973)

L-alpha-methyl-p-tyrosine (AMT) was tested for its ability to block the reinforcing action of intravenous doses (32 mu-g/kg) of morphine sulfate in non-dependent,

non-tolerant rats. Three intraperitoneal doses of 75 mg/kg of AMT over 8 hours

preceding an acquisition test blocked the development of self-administration behavior.

The same pretreatment before a session of 100 behaviorally non-contingent pairings

of a buzzer and morphine prevented the establishment of the buzzer as a conditioned

(secondary) reinforcer. Because the latter effect was shown in a test performed

four days after the drug treatment, it is concluded that the results cannot be attributed to non-specific motor inhibitory properties of AMT.

DAVIS, W.M. and SMITH, S.G. Central cholinergic influence on self-administration

of morphine and amphetamine. Life Sciences 16: 237-246 (1974)

Atropine and methylatropine were tested in rats for an ability to alter

the reinforcing action of intravenous morphine sulfate and d-amphetamine

sulfate (60 mu-kg/injection). Atropine blocked the self-administration of

morphine, but methylatropine did not. Similarly, atropine but not methylatropine prevented the establishment of a conditioned reinforcer based on

passive intravenous infusions of morphine. Self-administration of damphetamine was enhanced by atropine but not by methylatropine. The results

indicate that a central cholinergic system exerts an influence on the brain mechanisms which are affected by morphine or d-amphetamine to produce positive reinforcement.

DAVIS, W.M. and SMITH, S.G. Noradrenergic basis for reinforcement associated with

morphine action in nondependent rats. Clinical Toxicology 7: 265 (1974)

DAVIS, W.M. and SMITH, S.G. Noradrenergic basis for reinforcement associated

with morphine action in non-dependent rats. Drug Addiction: Neurobiology

and Influences on Behavior, Vol. 3. Edited by J. M. Singh and H. Lal.

New York: Stratton Intercontinental Medical Book Company, 1974. Pp. 155-168.

DAVIS, W.M. and SMITH, S.G. Positive reinforcing effects of apomorphine, d-amphetamine and morphine: Interaction with haloperidol. The Pharmacologist 16(2): 16

(1974)

Positive reinforcement after small i. v. doses of apomorphine HCl (APO),

d-amphetamine sulfate (AS), or morphine sulfate (MS) was demonstrated both by

self-administration (SA) behavior and by the establishment of a buzzer stimulus

as a conditioned reinforcer through pairings of buzzer and drug infusions (as per

Davis & Smith, Life Sci. 12:185, 1973). Male albino rats were allowed to selfinject (SI) drug solutions during a 6-h session on a continuous reinforcement

schedule. Rats so treated learned to SI APO (60 mu-g/kg) as quickly as others did

to SI AS (15 mu-g/kg)or MS (60 mu-g/kg). Some rats died from overdosing with

APO in the 1st test session (up to 1129 doses were taken). Others overdosed later

after several days of moderate intake. Both fatal and non-fatal levels of APO intake were accompanied by pronounced stereotypic behaviors, but these were not

responsible for SI. Some individuals seemed to learn to regulate their SA so that

toxic properties of APO were largely avoided. The possible dopaminergic basis

of SA for all 3 drugs was tested by means of i. p. haloperidol (HAL) pretreatment.

Drug-associated reinforcement was prevented by HAL in the case of APO and AS,

but not for MS.

230
DAVIS, W.M., SMITH, S. G. and CROWDER, W.F. Morphine based conditioned reinforcement. Fifth International Congress on Pharmacology, July 23-28, 1972.

Until recently only inverse relationships for magnitude of reinforcement

effects have been found for self-administered drugs. With a new conditioned

reinforcement technic we find a direct relationship between morphine dose and

response strength. Rats were given non-contingent pairings of a buzzer (B) with

IV inj. of morphine sulfate (MS) in doses of 0.0032, 0.032 or 0.32 mg/kg. The

next day B and a saline infusion (SI) were presented together contingently on barpressing. Response levels were elevated above respective operant levels and

showed a linear trend. The results show conditioned reinforcement the magnitude

of which increased with dosage of MS. To test the hypothesis that the reinforcement mechanism (RM) involves a stimulatory action, pretreatment with L-alphamethyltyrosine (AMT) or saline was given before pairing of 0.032 mg/kg MS and

B. Antagonism of morphine-induced locomotor excitation by AMT was reported

(Pharmacologist 13, 280, 1971). Rats were trained as above. Nine were given

3 IP injections of 75 mg/kg AMT at 4 hr. intervals, the last at 15 min. prior to

MS-B pairings. Nine were given equal vol. of saline. Results of tests after the

pairings were: mean total responses for AMT group of 23.6, and for the saline

group of 111.1. The AMT response did not differ from operant level. These

findings suggest that function of the RM was blocked by AMT, and that RM may

be catecholamine based.

1974. Pp. 599-611.

DEMENT W.C., ZARCONE, V.P., HODDES, E., SMYTHE, H. and CARSKADON, M.

Sleep laboratory and clinical studies with flurazepam. The Benzodiazepines.

Edited by S. Garattini, E. Mussini and L. 0. Randall. New York: Raven Press,

Laboratory studies were conducted on male insomniacs to evaluate the

effectiveness of flurazepam on sleep induction and maintenance and to investigate

the effects of the drug on sleep stages, particularly rapid eye movement (REM)

and slow wave nonrapid eye movement (NREM). Flurazepam was shown to

effectively induce and maintain sleep without profoundly suppressing REM sleep.

DENEAU, G.A. Use of the monkey colony in studies of tolerance and dependence.

University of Michigan Medical Center Journal 36: 212-215 (1970)

DENEAU, G.A. and WILSON, M. Evaluation of sedative-hypnotic agents for barbituratelike physiological dependence capacity in the dog. Committee on the Problems of

Drug Dependence. Washington, D.C.: National Academy of Sciences, National

Research Council, 1970.

DENEAU, G., YANAGITA, T. and SEEVERS, M.H: Self-administration of psychoactive

substances by the monkey. Psychopharmacologia 16: 30-48 (1969)

231
DEVYNCK, M.A., BOQUET, P.L., FROMAGEOT, P. and SIMON, E.J. On the mode

of action of levallorphan on Escherichia coli: Effects on cellular magnesium.

Molecular Pharmacology 7(6): 605-610 (1971)

Inhibition of the growth of Escherichia coli by levallorphan increased in

effectiveness as the medium concentration of Mg++ was decreased. Two molecules

of levallorphan were shown to compete with 1 atom of Mg++, presumably on the

cell surface. Active transport of Mg+ was altered in the presence of the drug,

and this effect could be prevented by high concentrations of Ca+. Reduction of

cellular Mg++ content in the presence of levallorphan is suggested to be one

possible cause of growth inhibition.

DEWEY, W.L. The pharmacology of pentazocine. Neuroleptanesthesia 11(3): 139 (1973)

Pentazocine is an effective analgesic that is one-third as potent as morphine

by most parenteral routes of administration. The drug appears to have 2 distinct

advantages over morphine and most other narcotic analgesics. First, it is active

when given orally, and second, it has a lower addiction potential than the other

potent analgesics presently available. However, some have abused this drug and it

should be prescribed with caution for the dependency prone person. Pentazocine

appears to have little hematological, hepatic. or renal toxicity but depresses the

respiratory system in a manner comparable to morphine at equianalgesic doses.

Pentazocine has a wide range of application in relieving severe pain. It is used

preoperatively and postoperatively for a number of surgical conditions and in

obstetrics for the relief of pain during labor. In the field of dentistry it is used

frequently in combination with nitrous oxide anesthesia to relieve pain or as a

preoperative agent.

DEWEY, W.L., HARRIS, L.S., HOWES, J.F. and NUITE, J. The effect of various

neurohormonal modulators on the activity of morphine and the narcotic antagonists in the tail-flick and phenyquinone tests. The Journal of Pharmacology

and Experimental Therapeutics 175(2): 435 (1970)

The effect of a number of agents which alter central neurohumeral tone on

the activity of morphine and the narcotic antagonists in the tail-flick and the

phenylquinone tests was studied. In general, an increase in central adrenergic

tone caused an increase in the activity of morphine in the tail-flick test. However,

some exceptions were observed which suggest that mechanism other than changes

in neuromodulator tone might be responsible for the alterations of the potency

of morphine. A number of these have been investigated and were found not to be

contributing factors. Drugs which decrease adrenergic tone decreased the activity of morphine in this procedure. Alterations in adrenergic tone did not affect

the analgesic activity of the antagonists.

Five-hydroxy-tryptophan caused an increase in the potency of morphine in

the tail-flick procedure, thus indicating a possible involvement of central serotonergic mechanisms. A correlation between adrenergic or cholinergic tone and

activity in the P-phenylquinone test was not evident. The significance of these

results and the resultant validity of these procedures as screens for analgesics

are discussed.

232
DEWEY, W.L., JENKINS, J., O’ROURKE, T. and HARRIS, L.S. The effects of chronic

administration of trans-delta-9-tetrahydrocannabinol on behavior and the cardiovascular system of dogs. Archives internationales de Pharmacodynamie et de Therapie

198: 118-131 (1972)

For abstract, see Section II. Drug Chemistry and Metabolism.,

DEWEY, W.L., McMILLAN, D.E., HARRIS, L.S. and TURK, R.F. Distribution of

radioactivity in brain of tolerant and nontolerant pigeons treated with 3H-delta-9-

tetrahydrocannabinol. Biochemical Pharmacology 22: 399-405 (1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

DINGLEDINE, R. and GOLDSTEIN, A. Morphine effect on neurons in the guinea pig

myenteric plexus under conditions of synaptic transmission blockade.

Federation Proceedings (in press)

DINGLEDINE. R., GOLDSTEIN, A. and KENDIG, J. Effects of narcotic opiates and

serotonin on the electrical behavior of neurons in the guinea pig mycnteric plexus.

Life Sciences 14: 2299-2303 (1974)

Action potentials were recorded extracellularly from spontaneously firing

neurons in the myenteric plexus of the guinea pig ileum. Morphine, which inhibits acetylcholine release from the myenteric, plexus, inhibited the spontaneous

electrical activity of about half the cells studied, while serotonin elevated the

firing rate of these cells. Units not stimulated by serotonin were not inhibited

by morphine or levorphanol. Morphine also prevented the increase in firing

rate caused by serotonin. These effects of morphine were stercospecific and

blocked by naloxone, and are therefore considered to he specific opiate effects.

This study demonstrates opposing effects of narcotic opiates and serotonin on

the electrical activity of serotoninoceptive neurons in the myenteric plexus.

DITMAN, K.S., MOSS, T., FORGY, E.W., ZUNIN, L.M., LYNCH, R.D. and

FUNK, W.A. Dimensions of the LSD, methylphenidate and chlordiazepoxide

experiences. Psychopharmacologia 14(1): 1-11 (1969)

Dimensions of the LSD, methylphcnidate and chlordiazepoxide experiences

are studied. Through the retrospective use of the 156 item DWM card sort, the

experiences from a single intravenous dose of 200 mg of LSD, 75 mg of methylphenidate (ritalin) and 75 mg of chlordiazepoxide (librium) were compared in a

population of 99 chronic male alcoholics treated in an “LSD setting” in a doubleblind study. Surprisingly, 96 of the 156 items proved significantly different among

the 3 groups. LSD was unique in producing sensory and perceptual distortions

(including hallucinations or illusions), and mystical, religious or paranormal

sensations. However, contrary to expectation, LSD did not uniquely produce the

traditional “therapeutic” experience, but appeared to be surpassed in that area

by methylphenidate. Both drugs also produced some anxiety, while chlordiazepoxide produced relaxation, and enhanced music appreciation.

2 3 3
DOLBY, T.W. and KLEINSMITH, L.J. Effects of delta-9-tetrahydrocannabinol on the

levels of cyclic adenosine 3', 5'-monophosphate in mouse brain. Biochemical

Pharmacology 23: 1817-1825 (1974)

The effects of intraperitoneal injections of various doses of delta-gtetrahydrocannabinol (delta-9-THC) on brain levels of cyclic adenosine 3', 5'-

monophosphate (cyclic AMP) have been studied in mice. Doses of delta-9-THC

in the range of 0.1 to 1.0 mg/kg cause a 50-160 percent elevation of cyclic AMP

levels compared to controls (P less than 0. 00051, while doses of delta-9-THC in

the range of 2.0 to 10.0 mg/kg cause a 30-60 percent depression of cyclic AMP

levels (P = 0.025 to 0.0005). This pattern was obtained in whole brain, as well

as in dissected samples of cortex, cerebellum and medulla. This over-all

biphasic effect of THC on cyclic AMP levels correlates with known changes in

biogenic amines, temperature regulation, and behavior caused by this drug.

DOLE, W.P. and SIMON. E.J. Effects of levorphanol on phospholipid metabolism in

the giant axon of the squid. Journal of Neurochemistry 22: 183-185 (1974)

We have reported that levorphanol and other morphine type narcotic

analgesics block the evoked action potential in the isolated giant axon of the

squid (Simon & Rosenberg, 1970). This finding has led us to investigate the

effect of levorphanol on another aspect of the membrane physiology of the

squid axon, namely, the metabolism of phospholipids. The results reported

here indicate that incubation of squid giant axons with levorphano! alters

phospholipid metabolism at a concentration which blocks electrical conduction,

DOMINO, E.F., HUDSON, R.D. and ZOGRAFI, G. Drugs Affecting the Central Nervous

System, Vol. 2. Edited by A. Burger. New York: Marcel Dekker, Inc. 1968.

Pp. 327-397.

DOMINO, E. F. and WILSON, A. E. Decreased rat brain acetylcholine utilization following heroin and cross tolerance to l-methadone. Biochemical Pharmacology (in

press)

DORNBUSH, R.L., CLARE, G., ZAKS, A., CROWN, P., VOLAVKA, J. and FINK, M.

21-Day administration of marijuana in male volunteers. Current Research in Marijuana.

Edited by M.L. Lewis. New York: Academic Press. 1972.

DORRANCE, D.L., BEIGHLIE. D.J., YOSHII, V., JANIGER, O., BRODETSKY, A.M.

and TEPLITZ, R.L. Studies on the mechanism of interactions between lysergic

acid and chromoSomes. Journal of Laboratory and Clinical Medicine 84(1): 36-41

(July, 1974)

The present communication presents data on the effects of pure lysergic acid

diethylamide (LSD) at varying concentrations (in vitro) upon chromosome structure

and number. In addition, this study explores the effects of the drug upon the ability

of cells to repair ultraviolet-damaged DNA. The latter test was based on published

data indicating intercalation of LSD into the helix of DNA. Significant changes of

chromosomes occurred only at high doses. Neither LSD nor drugs which bound or

intercalated into DNA affected the DNA repair process.

234
DORRANCE, D., JANIGER. O. and TEPLITZ, R.L. In vivo effects of illicit hallucinogens on human lymphocyte chromosomes. Journal of the American Medical

Association 212(9): 1488 (June, 1970)

Fourteen subjects exposed to illicit lysergic acid diethylamide (LSD) and nine

exposed to marihuana were compared to age-matched controls for effects upon

lymphocyte chromosomes. Eight out of 1,284 in the group given LSD, or 0.76%,

exhibited chromosomal abnormalities; seven out of 816, or 0.86%, in the group

given marihuana; and eight out of 1,018, or 0.79%, in the control group. Cells

were grown in medium unenriched with nucleotide precursors. Thus, our negative

results mitigate against medium deficiency as contributing toward positive effects.

Similarly, our results on individuals whose last dosage was within an hour or so of

specimen procurement indicates that this factor may not explain conflicting results.

DREW, W.G. and MILLER, L.L. Cannabis: Neural mechanisms and behavior--a

theoretical review. Pharmacology 11: 12-32 (1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

DREW, W.G., MILLER, L.L. and BAUGH, E.L. Effects of delta-9-THC, LSD-25 and

scopolamine on continuous, spontaneous alternation in the Y-maze.

Psychopharmacologia 32: 171-182 (1973)

The effects of delta-9-THC, LSD-25 and scopolamine on continuous, spontaneous alternation of the hooded rat in the Y-maze were determined. LSD and

scopolamine decreased the number of arm entries (responsivity) while concomitantly reducing percent alternation. THC however, reduced responsivity and

percent alternation more at the lower dose (1 mg/kg) when compared to control than

at the higher dose (3 mg/kg). Only scopolamine induced a significant increase in

stimulus perserveration. The results are discussed in relation to the advantages

afforded by the continuous spontaneous alternation procedure.

DREW, W.G. and SLAGEL, D.E. Delta-9-THC: Selective impairment of corticosterone

uptake, by limbic structures of the rat. Neuropharmacology 12: 909-914 (1973)

Delta-9-tetrahydrocannabinol (THC) has a marked influence on the selective

uptake of 3H-corticosterone by the hippocampus and septum of the rat. Analysis of

variance on blood/tissue ratios showed that a dose of 9 mg/kg of delta-9-THC Bignificantly (Pless than 0.01) lowered 3H-corticosterone uptake in the hippocampus.

Compared with uptake in frontal and hind cortices, delta-9-THC selectively depressed

3H-corticosterone uptake within the septum and hippocampus. The decrease in uptake

across the 3 and 9 mg/kg doses for the limbic system components compared with the

cortical samples is highly significant (P 1ess than 0.001) and suggests that delta-gTHC exerts differential actions on hormone uptake within the central nervous system.

DUARTE-ESCALANTE, O. and ELLINWOOD, E.H., JR. Central nervous system cytopathological changes in cats with chronic methadrine intoxication. Brain Research

21: 151-155 (1970)

235
DUARTE-ESCALANTE, O. and ELLINWOOD, E., JR. Depletion of biogenic amines

and enhancement of cholinergic activity in the olfactory bulb and central

olfactory connections with chronic methedrine intoxication. Arquivos de NeuroPsiquiatria 28(2): 110-117 (June, 1970)

For abstract, see Section II. Drug Chemistry and Metabolism.

ECHOLS, S.T. and JEWETT, R.E. Effects of morphine on sleep in the cat.

Psychopharmacologia 24:435-448 (1972)

The effects of morphine sulfate, 300 mu-g/kg s.c., on the sleep of

cats was studied by electroencephalographic techniques. In contrast to

placebo experiments the animals were awake for approximately 6 h after

administration of morphine; the return of regular sleep patterns occurred

after about 11 h. A rebound increase in rapid eye movement (REM) sleep time

and percentage was noted during the 11th through the 17th hour of the study.

Sleep following manual sleep deprivation for 10 h showed a rebound increase

in REM and non-rapid eye movement (NREM) sleep time. NREM sleep rebound

after manual sleep deprivation exceeded that occurring after morphine. The

alerting actions of morphine could be blocked by naloxone, 100 mu-g/kg s.c.,

for about 90 min. Naloxone alone increased REM sleep time and percentage.

Single (84 mg/kg) or multiple (51 mg/kg for 4 injections) doses of dl-alphamethyltyrosine i.p. did not block the alerting action or REM sleep rebound

caused by morphine. 5-Hydrotryptophan (30 mg/kg) i.p. did not antagonize

the alerting action of morphine.

EHRENPREISS, S., GREENBERG, J. and COMATY, J. The ileum of chronically morphinized

guinea pig develops tolerance to injected morphine. Federation Proceedings (in press)

Injection of a large dose of morphine into a guinea pig results in a block

of electrically-induced contractions of the ileum in vitro. A similar dose is almost

ineffective in guinea pigs given morphine chronically (Ehrenpreis, et al in “Drug

Addiction: Experimental Pharmacology”, Singh et al, eds., 1972 p. 319). The time

course for development of this tolerance has been determined in guinea pigs injected

twice daily with morphine 100 mg/kg and challenged on various days with 750 mg/kg

of the drug. Animals similarly injected but not challenged served as controls. The

inhibitory effect of the challenging dose on electrical stimulation of longitudinal muscle

decreased with successive days of morphine administration; by the 10th day there was

almost complete tolerance to the challenging dose. Dose-response curves of

acetylcholine, 5HT or histamine of 10 day control (unchallenged) tissue showed

essentially no change compared with uninjected animals. The potency of exogenous

morphine in blocking electrical stimulation was also unchanged and thus tolerance

to injected morphine cannot be explained by reduced sensitivity of the drug for the

opiate receptor. However, tissues of chronically morphinized animals gave a

contraction with naloxone, extent of contraction increasing with time of drug

administration. This naloxone effect has been attributed to displacement of morphine

from an induced new opiate receptor (Ehrenpreis et al, op cit) which may be involved

in tolerance to injected drug.

EIDELBERG, E. and BARSTOW, C.A. Effects of morphine on hypothalamic electrical

activity in monkeys. Committee on the Problems of Drug Dependence. Washington, D.C.:

National Academy of Sciences, National Research Council, 1971.

Morphine administration in monkeys produced paroxysmal “epileptic” or

“epileptord” discharges at the time in which the animals appeared to be sedated by the

narcotic. This phenomenon was temporarily blocked by concurrent administration

of an opioid antagonist. Both tolerance and disappearance of tolerance after

withdrawal were also observed. No discharges of this type were observed during

precipitated abstinence.

236
EIDELBERG, E. and BARSTOW, C.A. Morphine tolerance and dependence induced

by intraventricular injection. Science 174: 74-76 (1971)

Injection of small quantities of morphine into the cerebral ventricular

system of awake, relatively unrestrained, monkeys depressed or abolished

operant food-reinforced lever pressing. After repreated Injections progressively

higher doses of morphine were needed to depress responding. Also, dependence

could be demonstrated in these animals by precipitating specific abstinence signs

with an antagonist.

EIDELBERG, E. and BOND, M.L. Effects of morphine and antagonists on hypothalamic

cell activity. Archives internationales de Pharmacodynamie et de Therapie

196: 16-24 (1972)

These experiments were carried out on urethane-anesthetized rats. The

activity of single cells in the anterior hypothalamic region was recorded extracellularly,

and the effects of low doses of morphine, given intravenously, were assessed on the firin

frequency and pattern of these units. Both “naive” and morphine-dependent rats were

used. In addition, precipitated abstinence was induced in dependent rats by an antagonist

(Naloxone). Both morphinization and precipitated abstinence resulted in marked changes

the frequency and pattern of discharge of the great majority of cells studied. In the

naive animals morphine depressed firing and naloxone did not modify it substantially.

In dependent rats low doses of morphine produced marked acceleration of cell firing,

and so did naloxone. However, morphine caused a bursting type of discharge while

naloxone did not. We conclude that the hypothalamus is an important locus of action of

opioid narcotics, and that it may become possible to interpret their cellular mechanisms

of action in terms of present knowledge of synaptic transmitter action.

EIDELBERG, E. and ERSPAMER, R. Dopaminergic mechanisms of opiate actions in

brain. The Journal of Pharmacology and Experimental Therapeutics (in press)

EIDELBERG, E. and ERSPAMER, R. Failure of naloxone to prevent acute morphine

tolerance and dependence.

211(1): 58-63 (1974)

Archives internationales de Pharmacodynamie et de Therapie

Concurrent administration of an opioid antagonist with morphine antagonized

analgesia, but not acute tolerance and dependence in mice.

EIDELBERG, E., ERSPAMER, E., KREINICK, C. and HANIS, J. Genetically

determined differences in the effects of morphine on mice. European Journal of

Pharmacology (in press)

EIDELBERG, E. and LOSHIAVO, C.M. Effects of morphine and opioid antagonists

on the central nervous system. Committee on the Problems of Drug Dependence.

Washington, D.C.: National Academy of Sciences, National Research Council, 1969.

EIDELBERG, E. and SCHWARTZ, A.S. Possible mechanisms of action of morphine

on brain. Nature 225(5238): 1152-1153 (March, 1970)

ELLINWOOD, E.H., JR. Chronic amphetamine intoxication in several experimental

animals. Psychopharmakologie 4:351 (1971)

237
ELLINWOOD, E.H. JR,, SUDILVOSKY, A. and GRABOWY, R. Olfactory forebrain

seizures induced by methamphetamine and disulfiram. Biological Psychiatry

7(2): 89-99 (1973)

A combination of disulfiram and methamphetamine was administered to cats

over a period of days in doses sufficient to induce generalized seizures. The original

anatomical focus of discharge and process of seizure development were studied. Highvoltage olfactory bulb spindle activity appeared to induce epileptic discharges which

emanated from the anterior olfactory system (olfactory bulb and tubercle, accumbens,

and amygdala). Computer analysis showed that the spindle activity which preceded

the discharges formed a recognizable pattern with the discharges. The substantia

nigra and interpeduncular nucleus were involved in the spread of seizure discharges

leading to generalized seizures. Norepinephrine was implicated as an inhibitor of

seizure activity; dopamine may potentiate seizure activity. The importance of electrographic events in relation to the mechanisms underlying psychomotor epilepsy and

amphetamine psychosis is stressed.

ELLIOTT, H.W. and CUMMINS, J.T. Effect of morphine on the K + induced increase

in the level of NAD (P)H in brain slices. Federation Proceedings (in press)

The level of NAD(P)H in brain cortex slices from control and morphinetolerant (implanted pellet) rats was measured by dual wavelength spectrophotometry.

The steady state level of NAD(P)H in slices from both groups of rats was increased

by the addition of 30 mM K+ to low Ca++ (0.19 mM) and to normal Ca++ (0.75 mM)

containing media. The K+ induced response in slices respiring in low Ca++ but not

in normal Ca++ containing media and obtained from control but not from morphinetolerant rats was inhibited by 2 x 10-3 M morphine. Cortex slices made from

morphine-tolerant rats given 10 mg/kg naloxone i.p. one hour earlier gave the same

response to K+ as slices from control or morphine-tolerant rats and the same

response to morphine as slices from control rats. Similar results were obtained

with slices from the caudate nucleus. The results indicate that the effects of morphine

on brain slice metabolism involve Ca++ and that the site (or receptor) at which

morphine acts is modified in the tolerant rats in some manner that involves Ca++.

FAITH, M.E., YOUNG, L.D., GRABARITS, F. and HARVEY, J.A. Differences

in the duration of reserpine action in the rat depending on the measure employed.

International Journal of Neuropharmacology 7:575-585 (1968)

The effects of reserpine were determined on eleven measures of drug action at

2, 26, and 50 hr following an acute injection. All measures were almost equally affected

at 2 hr after injection and estimates of ED-50 from the log dose-effect curves ranged from

1.20 to 2.12 mg/kg. There were large differences, however, between the various indices

in the time required for recovery from reserpine action. Five separate patterns of recovery

could be distinguished. (1) Complete recovery within 26 hr; tremor and conditioned escape.

(2) Partial recovery at 26 hr and complete recovery by 50 hr; muscle tone and hunched

posture. (3) Little or no recovery at 26 hr but complete recovery by 50 hr; ptosis, exploratory

behavior and lever pressing on variable interval schedules. (4) No recovery at 26 hr and

only partial recovery by 50 hr; spontaneous locomotor activity and lever pressing on a

continuous reinforcement schedule. (5) No recovery at 26 or 50 hr; the conditioned

avoidance response. These differences in the duration of reserpine action are discussed

with respect to differences in duration of neurochsmical effects of the drug on monoamine

in the brain.

238
FANN, W.E., DAVIS, J.M., JANOWSKY, D.S. and OATES, J.A. Amine uptake in

the pharmacology of affective disorders. Biogenic Amines in Psychiatry.

Edited by S. Gershon and W. Bunney. New York: Plenum Publlshing

Company, 1973.

FANN, W.E., DAVIS, J.M., JANOWSKY, D.S., KAUFMANN, J.S., GRIFFITH, J.D.

and OATES, J. A. Effect of iprindole on amine uptake in man. Archives of

General Psychiatry 26(2): 158-162 (February, 1972)

Iprindole is a clinically effective antidepressant similar to other

tricyclic drugs in structure. In animal studies it does not appera to inhibit the

levarterenol membrane pump. Investigation was made of iprindole’s

effect on the peripheral adrenergic levarterenol pump in man utilizing blood

pressure response to tyramine and Levarterenol. Other clinically effective

tricyclic drugs exert, by blocking its uptake, a potent blocking effect on the

blood pressure response to tyramine and, in a similar manner, augment

the pressure response to infused levarterenol. In contrast, iprindole showed

no significant effect on tyramine and levarterenol blood pressure response.

Other tricyclics also reduce-platelet serotonin content, probably by

inhibiting membrane uptake of this amine. Iprindole failed to alter platelet

serotonin content. These findings call into quedtion that aspect of the

biogenic amine theory of depression which states that the tricyclic drugs

exert their antidepressant action by inhibiting the membrane pump. The

clinical implications for cardiovascular toxicity is discussed.

FEINBERG, I. Absence of REM rebound after barbiturate withdrawal. Science

185: 534-535 (August, 1974)

Administration of three different barbiturates reduced rapid eye movement

(REM) sleep. Drug withdrawal led to a return to baseline REM values without

significant overshoot. Similar results are observed with administration of benzodiazepin:

in pharmacologically equivalent dosages; therefore, a distinction between these two

drug classes on the basis of withdrawal effects on the sleep electroencephalogram

appears unwarranted. Further investigation is required to determine why high

REM levels are sometimes associated with the withdrawal of sedative-hypnotic

agents.

FEINBERG, I., HIBI, S., BRAUN, M., CAVNESS, C., WESTERMAN, G. and SMALL, A.

Sleep amphetamine effects in MBDS and normal subjects. Archives of General

Psychiatry 31: 723-731 (November, 1974)

Electroencephalographic sleep patterns in children with minimal brain

dysfunction syndrome (MBDS or hyperkinesis) before and during stimulant

treatment differed little from those of age-matched controls. It is unlikely

that the therapeutic mechanisms of amphetamines in MBDS are exerted

on or reflected in physiological sleep patterns.

Neither MBDS children nor normal young adults showed withdrawal elevations

of rapid eye movement (REM) sleep after administration of amphetamines in

constant dosage. Young adults showed REM rebounds only when the dosage was

increased prior to withdrawal.

In contrast to sedative-hypnotics, stimulant drugs do not reduce eye

movement activity during REM sleep. This difference is emphasized for the

specificity hypothesis--that different classes of psychoactive drugs differentially

alter physiological sleep patterns--would be untenable if sedatives and stimulants

produced the same effects on sleep.

239
FEINBERG, M.P. and COCHIN, J. Effect of weekly doses of cyclohexamide on tolerance

to morphine in the rat. The Pharmacologist 11: 256 (1969)

In continuing previously reported work (Feinberg and Cochin, The

Pharmacologist: 10: 188, 1968) we decided to test the effect of cycloheximide

(CX) on the development of tolerance to morphine sulfate (MS) in the rat.

Although Way, et. al. have shown that chronic CX inhibits the development

of tolerance and physical dependence in the mouse (Science, 162: 1290, 1968), we chose

CX because it inhibits protein synthesis appreciably when given acutely, while

cyclophosphamide does so only on chronic administration. Male rats were

divided randomly by weight into two groups: A (CX + MS) and B (MS). All rats

received MS (10 mg/kg. s.c.) weekly, and were tested every other week for analgesic

response by the hot-plate method of Eddy and Leimbach. Rats in Group A received

CX (1 mg/kg, s.c.) one hour before each weekly injection of MS. On test days,

CX was given immediately after the baseline readings were obtained.

FEINBERG, M.P. and COCHIN, J. Effects of cyclophosphamide (cytoxen) on tolerance

to morphine. The Pharmacologist 10: 188 (1968)

Cochin and Kornetsky (J. Pharmacol 145: 1, 1964) have hypothesized

that tolerance to narcotic analgesics may be an immune phenomenon. We wished

therefore, to test the effect on tolerance of a drug which inhibits protein synthesis

and affects the immune response. Male rats (Goffmoor Farms) were randomized by weight

into two groups: A (treated) and B (control). Group A received 10 doses of

cyclophosphamide (CP), each 15 mg/kg, spread evenly over 3 weeks. On the day

of the 10th injection (day 22) all rats received 10 mg/kg of morphine sulfate (MS).

Analgesic response was tested by the hot-plate method of Eddy and Leimbach

(J. Pharmacol. 107: 385, 1953) All rats again received MS on days 29 and 36, and were

tested for analgesia as above. Rats in group A received CP, 15 mg/kg, on days 28

and 35. Rats in group B never received CP. Rats in group A showed significantly

less tolerance to MS than did rats in group B. Data were analyzed by analysis of covariance

performed on an IBM 360 computer. .

FINK, M. Brain, behavior and anticholinergic drugs. Anticholinergic Drugs and Brain

Functions in Animals and Man. Edited by P. Bradley and M. Fink. Amsterdam,

the Netherlands: Elsevier, 1967. Pp. xii-xvi.

FINK, M. Drugs, EEG, and behaviour: EEG profiles and bioavailability measures for

clinical psychopharmacology. Electroencephalography and Clinical Neurophysiology

34: 754 (1973).

240
FINK, M. EEG classification of psychoactive compounds in man: Review and theorv of

behavioral associations. Psychopharmacology: A Review of Progress, 1957-1967.

Edited by D. Efron, J. Cole, J. Levine and J.R. Wittenborn. Washington, D.C.:

U.S. Government Printing Office, 1968. Pp. 497-507.

FINK, M. EEG effects of drug dependence. Clinical and Biological Aspects of Drug

Dependence. Edited by S.J. Mule and H. Brill. Cleveland, Ohio: Chemical

Rubber Company Press, 1972.

FINK, M. Effects of cannabis on human EEG and heart rate--evidence of tolerance development

on chronic use. Psychopharmacology, Sexual Disorders and Drug Abuse. Edited by

T.A. Ban, J.R. Boissier, G.J. Gessa, H. Heimann, L. Hollister, H.E. Lehmann,

FINK, M. EEG and human psychopharmacology. Annual Review of Pharmacology 9: 241-258

(1969)

FINK, M. Levomethadyl (LAAM): A long-acting substitute for methadone in

maintenance therapy of opiate dependence. Current Psychiatric Therapies.

Edited by J.H. Masserman. New York: Grune and Stratton, 1973.

FINK, M. Marihuana, EEG and behavior. Annals of the New York Academy of Science

191: 206-215 (1971)

For abstract, see Section I. Methodology of Drug Research.

I Munkvad, H. Steinberg, F. Sulser, A. Sundwall and O. Vinar, Amsterdam, the

Netherlands: North-Holland Publishing Company, 1973.

Psychoactive drugs affect behavior through biochemical alterations of

the central nervous system. The methods of measuring changes in CNS activity

in man are limited to measures applicable to the intact organism so that most

studies have been focused on the scalp-recorded EEG.

Problems of dosage, route and duration of drug administration, location

of electrodes and qualities of amplifiers, state of vigilance of the subject,

‘and the methods of neurophysiological analysis provide great variations in

the data. Changes in frequency, power, and amplitude of the waking and

the sleep EEG are the principal parameters studied. The averaged evoked

response to sensory stimulation is also frequently studied.

Despite variations in methods and populations, psychoactive drugs induce

characteristic changes in the human scalp EEG which bear direct relations

to the associated behavioral changes. Reports of “dissociation” of EEG

‘and behavior with anticholinergic drugs are special instances ‘of insufficient

definitions of behavior and EEG in animals, and when these drugs are studied

in man with better definitions of the relevant variables, dissociation is ‘not

evident.

The EEG-psychoactive literature is consistent with a theory of association

of EEG and behavior. Applications are described in the classification of

psychoactive drugs by EEG criteria, in the identification of compounds for

clinical trial, in providing biological models of classifications of mentally

ill populations, and in studies of the pathophysiology of disordered mental states.

241
FINK, M. Neurophysiology of the phantastica: EEG and behavioral relations in man.

Psychopharmacology: A Review of Progress, 1957-1967. Edited by D. Efron,

J. Cole, J. Levine and J.R. Wittenborn. Washington, D.C.: U.S. Government

Printing Office, 1968.

FINK, M. Psychoactive drugs, brain function and human behavior. Proceedings of the

World Congress on Psychiatry. Amsterdam, the Netherlands: Excerpta Medica

Foundation, 1974.

FINK, M. Questions in cyclazocine therapy of opiate dependence. Opiate Addiction:

Origins and Treatment. Edited by S. Fisher and A. Freedman. Washington,

D.C.: V.H. Winston and Sons, Inc., 1974.

FINK, M. A rational therapy of opiate dependence: Narcotic antagonists. Drug Abuse:

Proceedings of the International Conference. Edited by C. J. D. Zarafonetis.

Philadelphia, Pennsylvania: Lea and Febiger. 1971.

FINK, M. Treatment and prevention of opiate dependence. Contemporary Drug Problems

Washington, D.C.: Federal Legal Publications, 1972.

FINK, M. and BRADLEY, P. Anticholinergic drugs and brain function in animals and

man. Neuropsychopharmacolopy. Edited by H. Brill. Amsterdam, the

Netherlands: Excerpta Medica Foundation, 1967.

FINK, M. and ITIL, T. Anticholinergic hallucinogens and their interactions with

centrally active drugs. Neuropsychopharmacology. Edited by H. Brill.

Amsterdam, the Netherlands: Excerpta Medica Foundation, 1967.

A review of the changes in the spontaneous EEG of alert man in response

to a wide variety of hallucinogens indicates that characteristic associations of

EEG and behavior occur.

Decreased EEG alpha abundance and increased fast frequencies are

characteristic of active hallucinogens. The altered consciousness associated with

some hallucinogens (deliriants, thymoleptic drugs) is accompanied, in addition,

by an increase in the abundance of EEG slow wave activity.

These patterns are part of a theory of the association of changes in the

alert EEG and human interactive behavior in response to psychoactive drugs.

The symposium reviewed recent studies of the neurophysiological and

behavioral effects of anticholinergic agents in animals and man focusing on the

role of cholinergic mechanisms in behavior, the question of dissociation of

EEG and behavior, and new techniques for evaluation of cholinergic mechanisms.

In a study of the effects of Ditran and of atropine, three patterns of

behavioral and EEG effects were described, and related to differences in

dosage.

242
FINK, M. and ITIL, T. EEG and behavioral aspects of the interaction of anticholinergic

hallucinogens with centrally active compounds. Anticholinergic Drugs and Brain

Functions in Animals and Man. Edited by P. Bradley and M. Fink. Amsterdam,

the Netherlands: Elsevier, 1967. Pp. 149-166.

FINK, M. and ITIL, T.M. EEG and human psychopharmacology. IV: Clinical

antidepressants. Psychopharmacology: A Review of Progress, 1957-1967.

Edited by D. Efron, J. Cole, J. Levine and J.R. Wittenborn. Washington,

D.C.: U.S. Government Printing Office, 1968. Pp. 671-682.

For abstract, see Section I. Methodology of Drug Research.

FINK, M., ITIL, T.. ZAKS, A. and FREEDMAN, A. EEG patterns of cyclazocine.

a narcotic antagonist. Neurophysiological and Behavioral Aspects of Psychotropic

Drugs. Edited by A. Kareczman and W.P. Koella. Philadelphia, Pensylvania:

C.C. Thomas, 1971.

FINK, M. and SHAPIRO, D. M. EEG indices of CNS bioavailability of psychoactive

drugs. Electroencephalography and Clinical Neurophyeiology 33: 246-247 (1972)

For abstract, see Section I. Methodology of Drug Research.

FINK, M. and SHAPIRO, D.M. EEG patterns as an index of clinical activity of

FINK, M., SHAPIRO, D.M. and ITIL, T.M. EEG profiles of fenfluramine, amobarbital

psychoactive drugs.

27: 710 (1969)

Electroencephalography and Clinical Neurophyeiology

For abstract, see Section I. Methodology of Drug Research.

and dextroamphetamine in normal volunteers. Psychopharmacologia 22: 369-383

(1971)

As part of a clinical evaluation of cyclazbcine, EEG studies were

undertaken to determine the relation, if any, between the induced EEG patterns,

the clinical efficacy and the psychoactive classification of cyclazocine. The

studies also served as a measure of the degree of antagonism between cyclazocine

and the acute administration of opiates.

A quantitative EEG study in volunteer adults was undertaken to distinguish

single oral administrations of 50 and 100 mg amobarbital, 10 mg dextroamphetamine, 40 mg fenfluramine and placebo. Four hour EEG recordings were

monitored by frequent auditory reaction time tasks. The EEG changes were measured

by digital computer period analysis.

In the analysis, each drug was distinguished from placebo, and from each

other, with the best discriminations for 50 mg amobarbital and dextroamphetamine,

and the poorest discrimination of fenfluramine from 50 mg amobartbital.

These observations are consistent with the clinical pharmacology of the

compounds and suggest further applications of quantitative EEG for the classification

of psychoactive drugs.

243
FINK, M., SIMEON, J., ITIL, T. and FREEDMAN, A. Clinical antidepressant activity

of cyclazocine - a narcotic antagonist. Clinical Pharmacology and Therapeutics

11(1): 41-48 (1970)

Cyclazocine is a benzomorphan derivative with analgesic and antinarcotic

activity. During a clinical evaluation in the treatment of opiate dependence,

elation, insomnia and increased libido with administration and a “grippe-like”

syndrome on acute withdrawal were recorded as secondary effects. In the scalprecorded electroencephalogram (EEG), desynchronization, decreased alpha

abundance, and increased fast and theta activities were recorded concurrently.

Because the clinical and EEG patterns were most similar to those with the

tricyclic antidepressants, a clinical trial in depressive disorders was undertaken.

In an open clinical trial in severely depressed chronic mentally ill patients,

improvement in depressive symptoms and in clinical evaluations occurred

within 4 weeks in 8 of 10 subjects, receiving 1.0 to 3.0 mg of cyclazocine daily.

In a clinical trial in imipramine treatment failures in an outpatient mental health

clinic, 10 of 19 patients improved in depressive symptoms within 8 weeks as dosages

of 1.0 to 3.0 mg. daily. In both studies, secondary effects were common, suggesting

a narrow therapeutic range. Cyclazocine is an active antidepressant as well as

an active antinarcotic agent. The antidepressant activity is correlated with the

EEG patterns and is consistent with recent EEG classifications of psychoactive

drugs. The antidepressant activity does not seem to be related to the antinarcotic

activity. In the treatment of opiate dependence, the efficacy of cyclazocine may

be related in part to its antidepressant activity.

FINK, M., VOLAVKA, J., DORNBUSH, R. and CROWN, P. Effects of THC-delta-9,

marijuana and hashish on EEG, mood and heart rate in volunteers. Psychopharmacologia

26: 126 (1972)

Male volunteers received varying doses of cannabis by smoking marijuana,

hashish, THC-delta-9 impregnated oregano, and, as placebo, either oregano

or THC-free marijuana in consecutive studies. Dosages equivalent to 8 to 25

mg THC-delta-9 were smoked in 4-8 minutes.

EEG changes were of rapid onset (within the smoking period) and included

increased alpha abundance, decreased beta and theta activities. EEG changes

were accompanied by subjective feelings of euphoria and by tachycardia.

These effects were dose-related.

In chronic administration of 14 mg THC-delta-9 daily for 21 days, volunteers

exhibited similar effects on EEG, heart rate, and behavior. The changes

decreased on successive exposures, suggestive of “tolerance”. No adverse

effects were observed.

FINK, M., ZAKS, A., RESNICK, R.B. and FREEDMAN, A. M. Narcotic antagonists

in the treatment of opiate dependence. International Journal of Clinical

Pharmacology, Therapy and Toxicology 4: 455-458 (1971)

In our trials with a pharmacologic-rehabilitation approach to the treatment

of opiate dependence, my associates and I confirmed the reports of the therapeutic

efficacy of methadone; we are concerned with the too rapid acceptance of

this model for political expedience; we are satisfied with the initial clinical efficacy

of antagonists, particularly cyclazocine; and we are hopeful that the development

of a long-acting naloxone will provide a specially useful therapy of opiate

dependence.

244
FINK, M., ZAKS, A., RESNICK, R. and FREEDMAN, A.M. Opiate antagonists in the

treatment of heroin dependence in man. Narcotic Drugs: Biochemical Pharmacology.

Edited by D. Clouet. New York: Plenum Press, 1971.

FINK, M., ZAKS, A., VOLAVKA, J. and ROUBICEK, J. Electrophysiological

studies of opiates and antagonists in man. Narcotic Drugs: Biochemical

Pharmacology. Edited by D. Clouet. New York: Plenum Press, 1971.

This report describes our clinical trials with cyclazocine and naloxone

in an effort to provide “engagement” to the rehabilitation program and to test

the conditioning theory or opiate dependence.

In these studies of antagonists, randomly assigned subjects have also

received other agents, such as methadone (Freedman at. al., 1967; Resnick

et. al., in press: Zaks et. al., 1969: Roubicek et. al., in preparation) and

tybamate (Veress et. al., 1969). The subjects of these studies are male

opiate addicts who volunteered for admission to an in-patient treatment

center in a municipal hospital in the East Harlem section of New York City.

The population of this community is very low income, predominantly Negro and

‘Puerto Rican, with low educational levels and large numbers receiving

extensive welfare assistance. The ages for those reported here ranged from

17 to 54 with a mean of 26 years, and the duration of addiction was 2 to 30 years.

All patients applying for treatment were accepted for cyclazocinc induction

except those who were actively psychotic, dependent on non-narcotic drugs

or physically ill.

Male patients applying for treatment are asked to sign a permit for an

“‘experimental” treatment of their addiction. Some volunteered and were

placed on a waiting list but never appeared for admission. Others left during the

detoxification period or immediately thereafter.

On admission to the study ward, the narcotic usage of each patient is

estimated by inquiry. Methadone is given in reducing amounts for detoxification,

usually within four to seven days, and a drug-free period of observation allows

medical and laboratory examinations before induction with an antagonist.

FISHMAN, J., NORTON, B. and HAHN, E. Differential distribution of opiate agonists

and antagonists in the rat brain as determined by double isotope techniques.

Presented at Meeting of the American Society of Biological Chemists, 1974.

For abstract, see Section I. Methodology of Drug Research.

FITZWATER, J.E., WHITE, R.P. and NASH, C.R. Selective blockade by

mephentermine of reserpine -induced scrotonin depletion. Experientia

24: 698 (1968)

FOG, R. On stereotypy and catalepsy: Studies on the effect of amphetamines and

neuroleptics in rats. Acta Neurologica Scandinavia 48(Supplement 501 (1972)

FOG, R. and PAKKENBERG, H. Loss of brain cells in rats after long-term neuroleptic

treatment. Presented at the First World Congress of Biological Psychiatry,

Buenos Aires, Argentina, September, 1974.

FOG, R.L., Role of the corpus striatum in typical behavioral effects in rats produced

by both amphetamine and neuroleptic drugs. Acta Pharmacologia et Toxicologia

24(Supplement 4): 59 (1967)

245
FOG, R.L. and PAKKENBERG, H. Behavioral effects of dopamine and p-hydroxyamphetamine injected into corpus stilatum of rats. Experimental Neurology

31: 75-85 (1971)

Bilateral intrastriatal 5-mu-1 microinjections of p-hydroxyamphetamine

(100 mu-g/side) and of dopamine (200 mu-g/side) were made in awake rats.

Neither drug passes the blood-brain barrier well. The injections gave rise

to a stereotyped hyperactive behavior similar to that seen after subcutaneous

injection of amphetamine. Control injections in the thalamus and hippocampus

were without effect, neither were injections of noradrenaline (100-200 mu-g

side) in the corpus striatum. Spreading of tritiated dopamine intracerebrally

was controlled by using autoradiography and scintillation counting. These

experiments, along with earlier ones, strongly indicate that the amphetaminetype of stereotyped behavior is mediated through dopaminergic mechanisms in

the corpus striatum.

FOG, R.L. and PAKKENBERG, H. Intracerebral lesions causing stereotyped

behaviour in rats. Acta Neurologica Scandinavia 47: 475-484 (1971)

Bilateral lesions performed with a microcannula in corpus striatum,

hippocampus or thalamus induce in reserpinized rats a stereotyped

hyperactive behaviour for 6-8 min consisting of continuous biting without

normal activities and resembling the amphetamine induced stereotypy.

Bilateral cannula lesions of the dorsal cortex give a shorter response.

The behavioural response is not influenced by inhibition of dopaminergic

mechanisms in the brain and is prolonged by pretreatment with an anticholinergic drug. This lesion stereotypy is thus of neither dopaminergic

nor cholinergic origin and, therefore, differs from the amphetamine stereotypy (dopaminergic) as well as the paradoxical reserpine stereotypy

(cholinergic). Pretreatment with DOPA or a small dose of amphetamine as

well as intracerebral injection of 25% KCl or saline does not change the

stereotypy.

FOG, R.L., RANDRUP, A. and PAKKENBERG, H. Chlorpromazine and related

neuroleptic drugs in relation to the corpus striatum in rats. The Present Status

of Psychotropic Drugs. Edited by A. Cerletti and F. Bove. Amsterdam, the

Netherlands: Excerpta Medica Foundation, 1969. Pp. 278-279.

FOG, R.L., RANDRUP, A. and PAKKENBERG. H. lntrastriatal injection of quaternary

butyrophenones and oxypertine: Neuroleptic effects in rats. Psychopharmacologia

19: 224-230 (1971)

Bilateral intrastriatal microinjections in rat brains of quaternary neuroleptic drugs of the butyrophenone type (haloperidol, benperidol, floropipamide)

and the indole type (oxypertine) antagonize amphetamine-induced stereotyped

behaviour, with the development of catalepsy. These two behavioural effects are

also typical for neuroleptics given subcutaneously. No effect was observed when

placebo was injected intrastriatally or when quaternary haloperidol was injected

into the thalamus or hippocampus. The neuroleptic effect may be exerted through

dopaminergic mechanisms in the corpus striatum.

246
FOG, R.L., RANDRUP. A. and PAKKENBERG, H. Lesions in corpus striatum and cortex

of rat brains and the effects of pharmacologically induced stereotyped, aggressive

and cataleptic behaviour. Psychopharmacologia 18: 346-356 (1970)

Large bilateral lesions affecting 30-90% of the corpus striatum inhibit

stereotyped behaviour in rats injected subcutaneously with amphetamine, but do

not prevent rage reactions induced by injection of a monoamine oxidase inhibitor

followed by injection of 1-dopa. The stereotyped phase normally following this

rage reaction is, however, absent in the operated rats. Small bilateral lesions

in the corpus striatum (5-20%) cause a modified amphetamine stereotypy and

prevent the usual cataleptic behaviour produced by subcutaneous injection of a

neuroleptic drug (perphenazine). Additional ablation of. the overlying dorsal

cortex enhances these behavioural effects without qualitative changes. Both

amphetamine and neuroleptics seem thus to mediate their behavioural effects

through dopaminergic mechanisms in the corpus striatum.

FOG, R.L., RANDRUP, A. and PAKKENBERG, H. Neuroleptic action of quaternary

chlorpromazine and related drugs injected into various brain areas in rats.

Psychopharmacologia 12: 428-432 (1968)

In rats micro-injections in corpus striatum of quaternary chlorpromazine and related drugs give rise to highly characteristic neuroleptic effects;

antagonism of amphetamine-induced stereotyped behaviour and development of

catalepsy. There is no effect of injections in hippocampus or septum.

Dopaminergic mechanisms in corpus striatum seem to play a central role in

neuroleptic action.

FOOTE, W.E., SHEARD, M.H. and AGHALANIAN, G.K. Comparison of effects of LSD

and amphetamine on midbrain raphe units. Nature 222(5193): 567-569 (1969)

To determine whether the inhibition of raphe neurons is specific

for LSD and related psychotogenic compounds or whether this effect would

generally follow from any sort of stimulant, an investigation has been

made comparing the effects of LSD and amphetamine. The study showed

that amphetamine failed to inhibit raphe units and hence the inhibitory

effect of LSD on these units cannot be explained in terms of some nonspecific stimulant action.

FORBES, J.E., DEWEY, W.L. and HARRIS, L.S. The effect of narcotics and narcotic

antagonists on ganglionic transmission in rat. Federation Proceedings (in

press)

For abstract, see Section II. Drug Chemistry and Metabolism.

FORD, D.H., RHINES, R.K. and VOELLER, K. Morphine effects on neurons of the

median eminence and on other neurons. Narcotics and the Hypothalamus.

Edited by E. Zimmermannand R. George. New York: Raven Press, 1974.

247
FORD, D.H., VOELLER, K., CALLEGARI, B. and GRESIK, E. Changes in neurons

of the median eminence-arcuate region of rats induced by morphine

treatment: A electronmicroscopic study. Neurobiology 4: 1-11 (1974)

Electronmicroscopic examination of male rats killed 2 or 24 hours after a

single intraperitoneal injection of morphine sulfate (60 mg/kg) or after a 5-day

series of increasing dosages given every 8 hours (starting at 30 mg/kg) demonstrated

changes in the median eminence-arcuate region. This consisted of the formation of

whorl bodies which appear to have been derived from the endoplasmic reticulum

and which were located in the soma and dendrites of neurons. Sections from the

cerebral cortex, hippocampus and the nucleus gigantocellularis showed no such

change, while in one of the 5-day morphine treated animals there was a whorl

body in the preoptic area. Of 5 controls, only one showed development of whorls,

which were very scarce.

Synaptic vesicle changes were noted in the medianeminence-arcuate

region of the morphine treated rats which represent an exaggeration and alteration

in frequency of structural characteristics observed in control animals. Thus,

there was an increased frequency of pleomorphism, increased packing density

and increased number of synapses in which the vesicles were arranged in a

crystalline-like array.

FORD, D.H., WEISFUS. D., LEVI, N. and RHINES, R.K. Accumulation of 3H-1-lysine

by brain and plasma in male and female rats treated acutely with morphine

sulfate. Acta Neurologica 50: 53-75 (1974)

Adult male and female Wistar rats were injected with a single dose of

40 mg/kg of morphine sulfate via indwelling intrajugular cannulas and killed

two hours later. 3H-l-lysine was injected at various time intervals before the

death of the animals. The distribution of the labelled amino acid was then

determined in the free amino acid and lipid-nucleoprotein-extracted protein

fractions of plasma and cerebral grey matter. The accumulation of 3H-activity

‘was also determined in various areas of the brain, dorsal root ganglia

muscle and liver. Morphine-treatment produced an elevation of free 3

pectoral

H-activity

lysine levels in plasma and cerebral grey matter and a decrease in incorporation into protein. A si nificant sex difference was noted, such that in control

males the plasma free 3H-lysine and protein fractions were higher than in

females. In the morphine-treated group the values obtained from males were

lower than for females. In cerebral grey matter, the free 3H-lysine was

significantly lower in control and morphine-treated males than in females. In

the protein fraction, such sex differences varied with the time elapsed after

injection of amino acid and did not clearly favor either sex, The accumulation

of 3H-activity in tissue blocks taken from various regions of CNS was unaffected

by morphine-treatment in subcortical components. The values were generally

higher in females. 3H-accumulation was significantly altered in cortical

components in the male group. In cerebral white matter, the morphine-treated

males showed significant elevations of accumulation. Females showed an

elevation of 3H-accumulation in the morphine-treated group only when the data

was subjected to a group comparison. In the peripheral nervous system, 3Haccumulation was significantly depressed by morphine-treatment only in males.

The female values were again significantly higher than those from the males.

The male liver demonstrated a significant depression in accumulation of 3Hactivity in the morphine-treated group. Liver tissue from females was less

responsive and had higher uptakes than in males. Skeletal muscle showed no

alteration in 3H-accumulation after morphine treatment in either sex.

248
FORREST, F.M., FORREST, I.S. and SERRA, M.T. Modification of chlorpromazine

metabolism by some other drugs frequently administered to psychiatric

patients. Biological Psychiatry 2:53-58 (1970)

For abstract, see Section II. Drug Chemistry and Metabolism.

FORREST, I.S. The nature of the interaction between melanin and drugs.

Psychopharmacology Bulletin 10(4): 38-40 (1974)

FORREST, I.S., FORREST, F.M. and SERRA, M.T. Chlorpromazine retention.

American Journal of Psychiatry 126: 271-272 (August, 1969)

FREEMAN. J.J. and SULSER, F. Iprindole-amphetamine interactions: The role of

aromatic hydroxylation of amphetamine in its mode of action. The Journal

of Pharmacology and Experimental Therapeutics 183:307-315 (1972)

The present investigations were undertaken to study the mechanism

by which iprindole enhances the psychomotor stimulation (locomotor and

stereotyped activity) of amphetamine and to elucidate the role of the

hydroxylated metabolites of amphetamine in its mode of action. The enhanced

psychomotor stimulation and the increased levels of amphetamine in tissue

after iprindole pretreatment resulted from an inhibition of the

p-hyroxylation of amphetamine. Iprindole markedly reduced the accumulation

of p-hydroxyamphetamine in urine and p-hydroxymorephedrine in tissue after the

administration of amphetamine. Since pretreatment with iprindole enhanced’ the

central action of amphetamine and did not prevent the initial depletion of

norepinephrine in brain or heart, the formation of the hydroxylated metabolites

of amphetamine does not seem to be required for these pharmacological or

biochemical effects. The maintenance of depletion of norepinephrine caused by

amphetamine, however, was associated with the accumulation of

p-hydroxynorephedrine in tissue. Unlike desipramine, iprindole altered

neither the initial accumulation nor the metabolism of tritiated norepinephrine

in brain or heart. The results show that iprindole is a “cleaner” tool to study

the mechanism of action of amphetamine and suggest that a blockade of the

neuronal membrane pump is not a requirement for the therapeutic efficacy of

tricyclic antidepressants.

FREEMAN, J.J. and SULSER, F. On the peripheral mode of action of amphetamine and

desipramine. Presented at the Fifth International Congress on Pharmacology,

San Francisco, California, 1972.

249
FREY, L.G. and WINTER, J.C. Effects of p-acetyldeoxyephedrine on punished behavior

in the rat. Archives internationales de Pharmacodynamie et de Therapie 201(1):

125-127 (1973)

Rats were trained to press a bar for food on a multiple schedule in

which one component was VI 30 (food) and the other was FR 10 (concurrent food

and, electric shock). The effects of p-acetyldeoxyephedrine (p-ADE), a drug

which produces a transient decrease in tissue levels of 5-hydroxytryptamine

(5-HT), were then examined. It was found that the doses of p-ADE which are

required to deplete 5-HT produce nonspecific suppression of operant behavior.

These observations suggest that p-ADE is not suitable for the study of the

effects of 5-HT depletion on operant behavior in the rat.

FRIEDEL, R.O., BERRY, D.E. and SCHANBERG. S.M. Effects of dopamine and

norepinephrine on phospholipid metabolism of rat brain in vivo: Regional

differences. Journal of Neurochemistry 22: 873 (1974)

FRIEDEL. R.O., JOHNSON, J.R. and SCHANBERG, S.M. Effects of sympathomimetic

drugs on incorporation in vivo of intracisternally injected 33Pi into

phospholipids of rat brain. The Journal of Pharmacology and Experimental

Therapeutics 184(3): 583 (1973)

The effects of norepinephrine, phenylephrine, isoproterenol,

henoxybenzamine and carbamylcholine on the incorporation in vivo of

Pi into phospholipids of rat brain were studied at 5 and 30 minutes

after intracisternal injection of the radionuclide. Norepinephrine, an alpha

and beta adrenergic stimulator, and phenylephrine, an alpha adrenergic

stimulator, enhanced the labeling of phosphatidic acid and phosphatidyl

inositol at both times, whereas isoproterenol, a beta adrenergic stimulator,

had no effect. Phenoxybenzamine, an alpha adrenergic blocking agent,

blocked the stimulatory effect of norepinephrine and phenylephrine. The

pattern of stimulation of individual phospholipids by norepinephrine was

different from that of carbamylcholine, a cholinomimetic agent, in that

norepinephrine had a significantly greater effect on the labeling of

phosphatidic acid and had no effect on the labeling of phosphatidyl choline,

a phospholipid markedly stimulated by carbamylcholine. These studies

suggest that the metabolism of phosphatidic acid and phosphatidyl inositol

in rat brain is associated with rapid membrane process controlled in part

by alpha adrenergic mechanisms and differ from the effects on phospholipid

metabolism which are produced by cholinergic mechanisms. The data also

indicate that the metabolism of phosphatidyl choline may be related to

slower membrane processes controlled by cholinergic mechanisms.

GAONI, Y. and MECHOULAM, R. Hashish XIV. The iso-tetrahydrocannabinols.

Israeli Journal of Chemistry 6:679 (1968)

For abstract, see Section II. Drug Chemistry and Metabolism.

GARRETT, E.R., BRES, J., SCHNELLE, K. and ROLF, L.L., Jr. Pharmacokinetics

of saturably metabolized amobarbital. Journal of Pharmacokinetics and

Biopharmaceutics 2(1): 43-103 (1974)

For abstract, see Section I. Methodology of Drug Research,

250
brain levels and consequently the experimental animal is no longer

physiologically “normal” at the initiation of the study. Mice of CF1

and CFW strain obviate pre-experimental manipulation of brain monoamine levels since the brain 5-HT level as well as the 5-HT turnover

rate is genetically lower in CF1 than CFW strain, whereas brain

norepinephrine and dopamine levels do not differ between them

(Valzelli and Garattini, 19). Using a quantitative bioassay procedure

as well as quanta1 probit analysis of data obtained while determining

equianalgesic morphine doses in CFW and CF1 mice, morphine was

found to be 1.6 times more efficacious in CF1 strain. These results

GEBHART, G.F. and MITCHELL, C.L. Strain differences in the response to morphine

as measured on the hot plate. Archives internationales de

Pharmacodynamie et de Therapie 201: 128-140 (1973)

The relationship of brain monoamines, especially 5-hydroxytryptamine (5-HT), to the analgesic effect of morphine has been widely

investigated. However, studies examining this relationship all suffer

from the fact that monoamine synthesis-blockage or depletion of monoamines either by drug, pretreatment or lesioning is necessary to alter

are contrary to the currently popular hypothesis that decreased 5-HT

brain levels and a decreased analgesic response to morphine is

related. These results notwithstanding, there was no difference

between these two strains of mice in their sensitivity to a presumably

painful stimulus (i.e., heat) since their pre-drug reaction times on

the heated plate did not differ. Finally, there was no apparent

difference in the rates of tolerance development to the analgesic effect

of morphine between the two strains of mice at either of two morphine

dose levels.

GELLER, I. and BLUM, K. The effects of 5-HTP on para-chlorophenylalanine

(p-CPA) attenuation of “conflict” behavior. European Journal of

Pharmacology 9: 319-324 (1970)

“Conflict” was induced in hungry rats by simultaneously rewarding

with food and punishing with shock. lever responses made in the presence of

a tone stimulus. This procedure resulted in a suppression of responses

during tone stimuli. Administration of para-chlorophenylalanine (p-CPA)

attenuated the conflict and reinstated the suppressed responding, an

effect which persisted as long as two weeks. A 15 mg/kg dose of

5-hydroxytryptophan (5-HTP) reversed the p-CPA effects for more than 24

hr. The same dose of 5-HTP was without effect when administered to rats

in which’suppressed responding had been reinstated by lowering shock

levels rather than administering p-CPA. The 5-HTP reversal of p-CPA

effects on “conflict” suggests, the possible interpretation that p-CPA effects

are due to serotonim (5-HT) depletion.

251
GELLER, I., HARTMANN, R.J., CROY, D.J. and HABER, B. Attenuation of conflict

behavior with cinanserin, a serotonin antagonist: Reversal of the effect with

5-hydroxytryptophan and alpha-methyltryptamine. Research Communications

in Chemical Pathology and Pharmacology 7(1): 165 (January, 1974)

Cinanserin, a reported antagonist of brain serotonin, attenuated conflict behavior in rats, an action characteristic of clinically active “anti-anxiety”

agents. eThe effect was counteracted by administering in conjunction with

cinanserin, 5-hydroxytryptophan. the serotonin precursor known to replete brain

serotonin or alpha-methyltryptamine, the long acting serotonin agonist. These

findings provide additional support to the speculation that anxiolytics may

derive their therapeutic efficacy through alterations in the brain serotonergic

system.

GERLACH, J., NIELSEN, M. and RANDRUP, A. Effect of desipramine on rat cortex

slices incubated with 3H-dopamine. Psychopharmacologia 37: 341-349 (1974)

Rat cortex slices were incubated with 3H-dopamine (

3H-DA), and the

effect of desipramine (DMI) was studied on the accumulation of 3H-DA and 3Hnoradrenaline (

3H-NA) in the tissue and the concentrations of 3H-DA and

3H-NA in the incubation medium. This effect was compared with the effect of

cocaine, reserpine and FLA 63 studied by the same technique, in order to

elucidate the mechanisms of action of DMI.

All the drugs induced a significant decrease of 3H-NA accumulation

in the cortical tissue. The 3H-DA retention varied: cocaine and reserpine

caused a significant decrease, FLA 63 a marked, significant increase, and

DMI a slight, but significant increase. In the incubation medium, 3H-DA

significantly increased after DMI, cocaine and reserpine, and remained

unchanged after FLA 63. In all experiments 3H-NA in the medium was very

low.

It is suggested that DMI in cortex slices may exert a double

mechanism of action on the final step in the noradrenaline biosynthesis:

1. an inhibition of the 3H-DA uptake at the level of the noradrener ic cell

membrane, and 2. an inhibition of the intraneouronal transport of 3H-DA

to sites where it is converted to 3H-NA, concomitant with an increased

intraneuronal 3H-DA accumulation. Other possibilities are discussed.

GERLACH. J., REISBY, N. and RANDRUP, A. Dopaminergic hypersensitivity and

cholinergic hypofunction in the pathophysiology of tardive dyskinesia.

Psychopharmacologia 34: 21-35 (1974)

The so-called counterbalancing dopaminergic-cholinergic system

has been studied in a clinical pharmacological investigation of

neuroleptic-induced tardive dyskinesia. Eight hospitalized patients between

the ages of 20 and 69 years were treated with alpha-methyl-para-tyrosine

(AMPT), L-Dopa, physostigimine. scopolamine and biperiden. The results

were evaluated blind with the help of video-technique. AMPT (3 g daily for

3 days) significantly reduced, while L-Dopa (1200 mg daily together with a

peripheral decarboxylase inhibitor for 14 days) and biperiden (18 mg daily

for 14 days) significantly precipitated/aggravated the dyskinesia. The

effects of physostigmine and scopolamine have varied, which is discussed

in relation to the existence of both hypo- and hypercholinergic stereotype.

It is concluded that dopaminergic hypersensitivity, cholinergic

hypofunction and a reduced biological buffer capacity comprise important

elements in the pathophysiology of tardive dyskinesia. Simple prophylactic

and therapeutic directions are given based upon this conclusion.

GESSNER, P.K. Body temperature correlates of the interaction between monoamine

oxidase inhibitors and meperidine. The Pharmacology of Thermoregulation.

Edited by E. Schonbaum and P. Lomax. New York: S. Karger, 1973. Pp. 473-481.

252
GESSNER, P.K. Induction of a diethyl ether withdrawal syndrome in mice by

exposure to ether vapor. The Pharmacologist 16: 304 (1974)

The ability of alcohol and sedative-hypnotic agents to induce a

characteristic withdrawal syndrome in humans and other species is well

known. To determine whether this property was also common to some

gaseous anesthetic agents, mice were exposed to ether vapor (25 mg/l

air) for a period of 3 days. At the end of this period the 22 experimental

and the 10 control (i.e. not exposed to ether) mice were individually

isolated using a double blind procedure and withdrawal signs were scored

at predetermined intervals using a scale developed by Goldstein (J.

Pharmacol. 180, 203, 1972) for alcohol withdrawal. No withdrawal

signs were observed in the control mice. Withdrawal seizures were

observed in 13 of the 22 ether exposed mice. Seizure scores reached

near maximum values within 30 min of withdrawal, plateaued at this

level for the next 4 hrs and then decreased gradually over the next 20 hrs.

in follow up experiments it was found that ether withdrawal seizures were

surpressed by administration of either ethanol or phenobarbital to the

withdrawn animals. These latter results raise the possibility of the

existance of cross-physical dependence between ether and agents such as

ethanol and phenobarbital.

GESSNER, P.K. and CLARKE, C.C. The effects of meperidine and dextromethorphan

on thermoregulation in mice. Temperature Regulation and Drug Action.

Edited by E. Schonbaum and J. Jacob. New York: S. Karger, 19’75.

GESSNER, P.K., CLARKE, C.C. and ADLER, M. The effect of low environmental

temperature on the tranylcypromine-meperidine interaction in mice. The

Journal of Pharmacology and Experimental Therapeutics 189(1): 90-96 (1974)

The effect of a low environmental temperature on the mortality resultant

from the administration of tranylcypromine and meperidine 4 hours apart was

investigated in mice. It was found that exposure to an environmental temperature

of 2°C for 1 hour prior to meperidine administration markedly reduced mortality

among animals removed from the low temperature environment after the

meperidine administration and markedly increased mortality among animals

continued at the low temperature, after meperidine administration. Because

the tranylcypromine-meperidine interaction is normally associated with a

marked hyperthermia, the body temperature correlates of the interaction

were investigated in mice exposed to a low environmental temperature. Under

the conditions of cold exposure, mice administered tranylcypromine and meperidine

did not show a hyperthermic response but rather a hypothermic one. Further

investigation showed this response to be mediated exclusively by meperidine.

In related experiments intertreatment with prednisolone was found to be without

effect on the mortality resultant from the tranylcypromine-meperidine interaction. .

GESSNER, P.K. and GESSNER, T. The interaction of barbital and testosterone

relative to their hypnotic effects. Archives internationales de Pharmacodynamie

et de Therapie 201: 52-58 (1973)

Testosterone administered i.p. in corn oil to mice causes righting

reflex loss the ED 50 for which is 289.6 mg/kg. Under similar conditions

barbital has an ED 50 of 142.1 mg/kg. Coadministered with barbital,

testosterone can act synergistically in producing righting reflex loss. At

high testosterone and low barbital doses the testosterone content of ED 50

mixtures is however not significantly different from the ED 50 for testosterone.

In particular the ED 50 for a 2.8:1 molar testosterone-barbital mixture is

significantly greater than would be expected on the basis of simple dose

additivity. This phenomenon is seen to be associated with the much shorter

onset of action (29 min with an ED 50 dose) of testosterone relative to the

onset of action of barbital (52 min with an ED 50 dose), whereby upon

administration of a testosterone rich mixture the effects observed are almost

exclusively attributable to testosterone.

253
GESSNER, P.K., LAROSA, R.T. and BERGSON, A. Investigation of the mechanism

mediating the tremorgenic effect of LSD in mice. Federation Proceedings

28: 793 (1969)

In common with a number of other hallucinogens, LSD produces

a tremor in mice which even at doses of 1 mu-mole/kg increases significantly

(P less than 0.05) the muscular activity of restrained mice. To elucidate

the mechanism mediating the tremorgenic effect of LSD in mice the effect

of various pretreatments on the tremorgenic effect of LSD was determined.

It was found that the tremorgenic effect of a 3.3 mu-mole/kg dose of LSD was

enhanced by p-chlorophenylalanine (3x100mg/kg, 72, 48 and 24 hrs. prior

respectively, P=0.05) and cocaine (10mg/kg, 30 min prior, P less than

0.05) and decreased by amphetamine (10mg/kg, 1 hr prior, P greater

than 0.05), BOL (30 mu-moles/kg, 10 min prior, P less than 0.05), disulfiram

(400 mg/kg, 12 hrs prior, P greater than 0.05), metrazole (50 mg/kg, 30

min prior, P less than 0.05) and morphine (0,5mg/kg, 20 min prior, P

less than 0.05). The effect of both a 3.3 and a 10 mu-mole/kg dose of LSD

was significantly (P less than 0.05) decreased by 5HTP (100mg/kg. 1 hr

prior), DOPA (600 mg/kg, 15 min prior), reserpine (2 mg/kg, 4 hrs

prior), and chlorpromazine (10 mg/kg, 1 hr prior). These results closely

parallel those obtained when using 5-methoxy-N, N-dimethyltryptamine

instead of LSD. It is tentatively concluded that the action of both these

agents are mediated by their effects on brain monoamine function.

GESSNER; P.K. and SOBLE, A.G. A study of the tranylcypromine-meperdine

interaction: Effects of p-chlorophenylalanine and 5-hydroxtryptophan.

The Journal of Pharmacology and Experimental Therapeutics 186: 276-

287 (1973)

Tranylcypromine and meperidine administered four hours apart to

mice in a ratio of 3:10 by weight exhibited marked superadditivity of their

toxic actions, the LD 50 of the combination being only 0.54 of that which

would be expected on the basis of their individual toxicities. Pretreatment

with p-chlorophenylalanine (100 mg/kg) at 72, 48 and 24 hours before the

experiment markedly lowered the mortality of mice receiving tranylcypromine and meperidine in a 3:10 ratio four hours apart but not those

receiving either tranylcypromine or meperidine alone. Intertreatment

with doses of 5-hydroxytryptophan as low as 5 mg/kg one hour before

meperidine administration markedly increased mortality of mice receiving

the tranylcypromine-meperidine combination. Thus the toxic response of

mice to the tranylcypromine-meperidine combination may be mediated by

5-hydroxytryptamine. Meperidine administration four hours after

tranylcypromine resulted in a marked hyperthermic response. This

response was significantly augmented if 5-hydroxytryptophan was coadministered with the meperidine. Pretreatment with p-chlorophenylalanine

did not prevent the development of a hyperthermic response to meperidine

in mice administered tranylcypromine four hours earlier; however, the pchlorophenylalanine-pretreated mice had generally lower body temperatures

than control mice.

254
GEYER, M.A. and SEGAL, D.S. Differential effects of reserpine and alpha-methylp-tyrosine on norepinephrine and dopamine induced behavioral activity.

Psychopharmacologia 29: 131-140 (1973)

GEYER, M.A. and SEGAL, D.S. Shock-induced aggression: Opposite effects of

intraventricularly infused dopamine and norepinephrine. Behavioral

Biology 10: 99-104 (1974)

The locomotor activity of rats was monitored during the intraventricular infusion of either dopamine or norepinephrine after intrapertioneal

pretreatment with saline, reserpine (5.0 mg/kg), or acute and chronic alpha-methylp-tyrosine (125 mg/kg - 1 or 8 days). While the hyperactivity produced by

norepinephrine was potentiated 24 h after reserpine, the response to

dopamine was reduced by reserpine. Chronic, but not acute, alpha-methylp-tyrosine enhanced the effect of norepinephrine without altering the

dopamine-induced activity. These results indicate: 1. dopamineinduced hyperactivity is due to its conversion to norepinephrine, and 2.

prolonged depletion of central catecholamines may result in postsynaptic

receptor supersensitivity.

Saline, dopamine, or norepinephrine was infused into the lateral

ventricles of unrestrained rats via chronically implanted cannulae. Immediately after infusion, the amount of shock-induced fighting between pairs of

rats was determined. Low doses of dopamine increased the number of

attacks while norepinephrine infusions markedly reduced fighting. Two weeks

after intraventricular injection of 6-hydrosydopamine, when shock-induced

fighting is increased, the infusion of norepinephrine, but not dopamine.

reduced the amount of attack behavior. The possibility is discussed that this

type of aggressive behavior is modulated in part by a balance between

dopaminergic and noradrenergic systems.

GIANUTSOS, G., HYNES, M.D., PURI, S.K., DRAWBAUGH, R.B. and LAL, H.

Effect of apomorphine and nigrostriatal lesions on aggression and

striatal dopamine turnover during morphine withdrawal: Evidence for

dopaminergic supersensitivity in protracted abstinence. Psychopharmacologia

34: 37-44 (1974)

Reliable aggression was seen in rats which were grouped 30 days after

undergoing continuous withdrawal from morphine. This withdrawal aggression,

associated with long-lasting effects of morphine dependence, was blocked by

morphine or lesions of the nigrostriatal bundle, but not by lesions of the median

forebrain bundle. When the nigrostriatal lesioned rats were treated with a

small dose of aponorphine, the aggression was reinstated. Apomorphine reduced

the turnover of dopamine in the 30-day withdrawn rats at doses which were

ineffective in similarly housed non-dependent rats. These results suggest that

animals undergoing protracted morphine abstinence show aggression due to a

latent dopsminergic supersensitivity, similar to that previously reported during

acute narcotic withdrawal.

255
GINTZLER. A.R. and MUSACCHIO, J.M. Interaction between serotonin and

morphine in the guinea pig ileum. The Journal of Pharmacology and

Experimental Therapeutics 189: 484-492 (1974)

Inhibition of the electrically induced contractions of the guinea-pig

ileum has been shown to be a reliable index of the relative potency of various

narcotic analgesics. This property suggests that this preparation might be

useful in attempts to elucidate the mechanism by which morphine induces

analgesia in the central nervous system. In light of the inhibitory effects of

5-hydroxytryptamine (5-HT) on the ileum and its interactions with morphine

in other tissues, the effect of 5-HT on the inhibitory response of the ileum to

mor hine was studied. Concentrations of 5-HT ranging from 2 X 10-8 to 2 X

10-7 M can potentiate the inhibitory effects of morphine, and vice versa; small

concentrations of morphine (10-8M) can potentiate the inhibitory response to

5-HT. Both of these effects can be abolished by washing. This potentiation

is also observed with both nalorphine and methadone and seems to be due to

a’specific interaction between 5-HT and narcotic analgesics; Similar

concentrations of 5-HT have no effect on the inhibition produced by

norepinephrine, and norepinephrine itself has no effect on the inhibition produced by morphine. Lysergic acid diethylamide (0.1 mu-g/ml) can antagonize

the inhibitory effects of 5-HT but can also produce a marked potentiation of

the response to morphine. The above suggests that 5-HT may play an essential

role in the mechanism by which morphine induces analgesia in the central

nervous system.

GOLDBERG, S.R. Nalorphine: Conditioning of drug effects on operant performance.

Stimulus Functions of Drugs. Edited by G. Heistad, T. Thompson and R.

Pickens. New York: Appleton-Century-Crofts, 1970.

GOLDSTEIN, A. Biochemistry and pharmacology of the addictive process. Abstracts

of the 119th Annual Meeting of the American Pharmaceutical Association, Vol. 2.

Washington, D. C.: The American Pharmaceutical Association, 1972. P. 31.

GOLDSTEIN, A. Molecular aspects of narcotic addiction. Annals of Internal Medicine

78: 813 (1973)

To understand fully the way any drug produces its pharmacologic

effects, we have to learn not only where it acts (what organs, tissues, and

cells are primarily affected) but also exactly what it does at the site(s) of

action. Considerable progress is being made in identifying and isolating,

drug receptors--the macromolecules with which drugs interact to initiate

the sequence of biochemical changes that ultimately produce the characteristic

drug effect in the whole organism.

The opioid narcotics are of particular interest for their ability to

produce tolerance and physical dependence, which play a role in the

addiction process. In this lecture I shall review recent investigations that

have led to some plausible hypotheses about the sites and molecular

mechanisms of narcotic action and about the molecular basis of tolerance

and physical dependence.

GOLDSTEIN, A. Opiate receptor mechanism. NRP Bulletin (1974)

GOLDSTEIN, A. Opiate receptors. Life Sciences 14: 615 (1974)

256
GOLDSTEIN, A. Recent studies on the binding of opiate narcotics to possible receptor

sites. New Concepts in Neurotransmitter Regulation. Edited by A. J.

Mandell. New York: Plenum Press, 1973.

GOLDSTEIN, A. and JUDSON, B.A. Alcohol dependence and opiate dependence: Lack

of relationship in mice, Science 172: 290-292 (April 16, 1971)

For abstract, see Section II. Drug Chemistry and Metabolism.

GOLDSTEIN, A., JUDSON, B.A. and SHEEHAN, P. Cellular and metabolic

tolerance to an opioid narcotic in mouse brain. British Journal of

Pharmacology 47(1): 138 (1973)

Running activity and brain levorphanol concentration were measured

in nontolerant and tolerant mice given various doses of 3H-levorphanol.

The principal factor responsible for tolerance in the mouse is a loss

of sensitivity to the narcotic drug at the cellular level in brain; despite

adequate brain concentrations, the pharmacological effects are dimished or

absent.

There is also metabolic tolerance; a given dose establishes a lower

brain concentration in tolerant than in non-tolerant animals.

The two kinds of tolerance are distinguished here and the contribution

of each is assessed.

GOLDSTEIN, A., LOWERY, P.J. and LOWNEY, L.I. Increased binding of an opiate

narcotic to a receptor proteolipid in the presence of naloxone. Federation

Proceedings 33(3): 474 (March, 1974)

We have reported elsewhere (Science, Life Sci., in press) the partial

purification of a proteolipid from mouse brain with opiate receptor (R) binding

properties. Fractionation was on Sephadex LH-20 columns with increasing

methanol (M) in chloroform (C); ligand-free R elutes in a 50% M fraction.

After preincubation of R with the opiate agonist levorphanol (190 nM), the

levorphanol-R complex elutes much earlier, in pure C. When the antagonist

naloxone (100 nM) is also present in the preincubation, an additional peak of

complexed levorphanol appears , and the total complexed levorphanol is

increased 2- to 3-fold. At higher naloxone concentration (10-100 mu-M),

Ievorphanol binding is prevented, as already reported.

It is evident from these results that naloxone and levorphanol can

combine simultaneously with R. Our findings suggest the possibility that R

may be an allosteric oligomer. It is not yet clear, however, in what way the

phenomena observed here may relate to the phenomenon of narcotic

antagonism in vivo. One interpretation is consistent with an idea advanced

by one of us (A. Goldstein, First Int. Conf. on Narcotic Antagonists, in

press) that agonists cause a conformation change in R, and that antagonists

prevent such conformation change.

257
GOLDSTEIN, A., LOWNEY, L.I. and PAL, B.K. Stereospecific and nonspecific

interactions of the morphine congener levorphanol in subcellular

fractions of mouse brain. Proceedings of the National Academy of

Sciences. 68(8): 1742-1747 (August, 1971)

For abstract, see Section I. Methodology of Drug Research.

GOLDSTEIN, A. and SHEEHAN, P. Tolerance to opioid narcotics. I. Tolerance

to the “running fit” caused by levorphanol in the mouse. The Journal of

Pharmacology and Experimental Therapeutics 169(2): 175-184 (1969)

The running fit induced by opioid narcotics in mice serves as a

convenient graded measure of the effect of these drugs. It is at least as

sensitive a measure as analgesia. By using D(—)-levorphanol and its L(+)-

isomer, a high degree of stereospeificity has been demonstrated. A number

of criteria have been applied to show that the running fit is a typical

pharmacologic effect of this family of drugs. The development of tolerance

has been studied with repeated injections of levorphanol, and the loss of

tolerance has been studied upon discontinuance of the drug. The rate of

onset of tolerance and the degree of tolerance eventually attained are

determined by the frequency of administration of a constant drug dose or by

the size of the dose at a fixed interval. The duration of drug administration

is irrelevant. Tolerance is revisible at a rate roughly the same as the rate

of onset, and recovery of sensitivity to levorphanol is complete. Subsequent

cycles of onset and offset of tolerance are indistinguishable from the first.

GOLDSTEIN, A., SHEEHAN, P. and GOLDSTEIN, J. Unsuccessful attempts to transfer

morphine tolerance and passive avoidance by brain extracts. Nature

233 (531.5): 126-129 (September, 1971)

GONZALEZ, L.P., ALTSHTHULER, H.L. and BURCH, N.R. Period analytic descriptors

of the effects of psychotropic drugs in the subhuman primate. Proceedings

of the Society for Neurosciences 3(6): 226 (1973)

Period analysis of the electroencephalogram (EEG) has been used to

evaluate the human EEG, but only to a limited degree in animal experiments.

These studies were designed to establish its efficacy as a means to evaluate

the effects of centrally active drugs on the electrical activity of the brain

and behavior. Three rhesus monkeys were used in this study. They were

restrained in monkey chairs and placed in a quiet, shielded room for the

experiments. Intravenous saline injections were used for control studies.

Intravenous doses of pentobarbitol (2.0-20.0 mg/kg), morphine sulfate

(0.5-5.0 mg/kg) or chlorpromazine (1.0-10.0 mg/kg) were administered to

each animal according to a modified Latin Square design. The EEG was

continuously recorded for two hours after each dose and the analogue data

base reduced by computer-based period analysis. Major emphasis was

placed on the changes observed in the minor period. All three compounds

decreased the major and intermediate period counts below saline controls

in a dose-related fashion. All three drugs induced substantial and

distinctive changes in the second derivative function, the minor period,

Minor period counts were generally reduced for the higher doses of each

drug, and lower doses occasionally increased minor period counts at upper

frequency bands. The data demonstrate the efficacy of the period analysis

technique in distinguishing between different psychoactive drugs and serve

to provide data base for studies of the EEG correlates of the behavioral

changes induced by these and similar compounds.

258
GREEN, J.P., DRESSLER, K.P. and KHAZAN, N. Mescaline-like activity of

2-amino-7-hydroxytetralin. Life Sciences 12 (part I) 475-479 (1973)

2-Amino-7-hydroxytetralin has sleep effects in rats like mescaline

and D-LSD, and it showed cross-tolerance with mescaline, as did D-LSD.

These properties had been predicted by total valence electron calculations.

GREEN, T.K. and HARVEY, J.A. Enhancement of amphetamine action after

interruption of ascending serotonergic pathways. The Journal of

Pharmacology and Experimental Therapeutics 190: 109-117 (1974)

Large lesions, producing 60 to 90% destruction of the medial

forebrain bundle (MFB) and a 60 to 84% decrease in telencephalic

content of scrotonin, also preduced a 3-fold enhancement of amphetamine

action as measured by increased rates of responding on a variableinterval 60-second schedule of reinforcement. These lesions had no effect

on the action of chlorpromazine. Smaller lesions, producing 10 to 50%

destruction of the MFB and a 1 to 59% decrease in serotonin, had no effect

on amphetamine action. The correlation between the decrease in

serotonin and the enhanced action of 1 mg/kg of amphetamine sulfate

was 0.81 for 16 rats with MFB lesions. Lesions in the septal area, central

gray, dorsomedial tegmentum or ventrolateral tegmentum produced only

small (12-19%) decreases in serotonin and had no effect on amphetamine

action. The enhanced action of amphetamine after MFB lesions could not

be attributed to base-line rates of lever pressing, water consumption,

body weight or changes in catechoamines. It was concluded that the

serotonergic system plays an important role in determining the magnitude of amphetamine effects on behavior.

GROVER, T., PIETLE, L.H. and MANIAN, A. Hydroxylation of 7-hydroxychlorpromazine by mushroom tyrosinase. Proceedings of the Third

International Conference on Phenothiazines. New York: Raven Press,

1973.

GROVES, P.M. and REBEC, G.V. The action of d-amphetamine on spontaneous

activity in the caudate nucleus and reticular formation of the rat.

Journal of Behavioral Biology 11(1): 33-47 (1974)

Dextro-amphetamine sulfate injected intraperitoneally in paralyzed,

locally anesthetized rats, resulted in a biphasic alteration in spontaneous

activity in the caudate nucleus. An initial dose-dependent potentiation of

activity occurs 5-10 min after injection followed by a prolonged dosedependent depression of activity which may last as long as several hours.

Similar injections result in a different time-course of alterations in the

mesencephalic reticular formation consisting of a prolonged increase

followed by a depression of spontaneous activity. Spontaneous activity in

the caudate nucleus was relatively unaffected by mephentermine sulfate,

a peripheral sympathominletic. The depression of activity produced by

amphetamine could be reversed by haloperidol, a dopaminergic blocking

agent. Haloperidol injected alone produced a transient potentiation of

activity followed by a return to control firing rate. These results provide

electrophysiological support for the inhibitory synaptic function of

dopamine in the caudate-putamen and for the alleged action of amphetamine

and haloperidol at these sites. Both the differential biochemical and

neurophysiological effects of amphetamine on the caudate nucleus and

reticular formation may have functionally significant behavioral consequences.

259
GROVES, P.M., REBEC, G.V. and HARVEY, J.A. Alteration of the effects of

d-amphetamine on neuronal activity in the caudate nucleus following lesions

of the nigrostriatal bundle. Neuropharmacology (in press)

GRUBB, M.N. and BURKS, T.F. Modification of intestinal stimulatory effects of

5-hydrorytryptamine by adrenergic amines, prostaglandin E1 and

theophylline. The Journal of Pharmacology and Experimental

Therapeutics 189(2): 476 (1974)

A study was designed to examine the intestinal stimulatory effects

of 5-hydroxytryptamine (5-HT) in the presence of three types of drugs which

are known to decrease intestinal motility. Dog isolated intestinal segments

were perfused via thevasculature with Krebs-bicarbonate solution with or

without drugs which depress motility: adrenergic amines, prostaglandin

El and theophylline. The excitatory agonists tested were 5-HT, bethanechol

and dimethylphenylpiperazinium (DMPP), Isoproterenol (1 and 5 mu-g/ml)

shifted the 5-HT dose-response curve to the right but did not affect

intestinal contractions produced by the cholinergic agonists, bethanechol

and DMPP. Prostaglandin El (1 mu-g/ml) did not alter responses to

bethanechol, but caused a slight decrease in responses to DMPP. The

prostaglandin shifted the 5-HT dose-response curve to the right.

Theophylline (180 mu-g/ml) had no effect on responses to bethanechol or

DMPP but produced a shift to the right in the dose-response curve for

5-HT. Norepinephrine (0.1 and 0.2 mu-g/ml) had no effect on responses

to bethanechol, but produced shifts to the right in dose-response curves

for DMPP and 5-HT. Methoxamine (10 and 50 mu-g/ml) caused effects

similar to those produced by norepinephrine. These data indicate that beta

adrenergic agonists, prostaglandin El and theophylline, which have in

common the ability to increase intestinal cyclic adenosine monophosphate

(cyclic AMP), antagonize motility responses to 5-HT but have little or no

effect on motility responses to cholinergic agonists. The effect of

norepinephrine on DMPP can be explained in terms of alpha adrenergic

receptor actions since methoxamine had similar effects on DMPP responses.

It is hypothesized that 5-HT produces contractions of intestinal smooth muscle

by somehow lowering intracellular levels of cyclic AMP or by blocking cyclic

AMP inhibitory effects.

HAAVIK, C.O. and HARDMAN, H.F. The effect of tetrahydrocannabinols on body

temperature. Proceedings of the Fifth International Congress on Pharmacology.

Satellite Sympozium on the Pharmacology of Thermoregulation, San Francisco,

1972.

HAHN, D.L. and GOLDSTEIN, A. Amounts and turnover rates of brain proteins in

morphine-tolerant mice. Journal of Neurochemistry 18: 1887-1893 (1971)

For abstract, see Section II. Drug Chemistry and Metabolism.

260
HAIGLER, H.J. and AGHAJANIAN, G.K. Lysergic acid diethylamide and serotonin:

A comparison of effects on serotonergic neurons and neurons receiving a

serotonergic input. The Journal of Pharmacology and Experimental

Therapeutics 188(3): 688-699 (1974)

Lysergic acid diethylamide (LSD) administered systemically to

rats has been shown to reversibly inhibit serotonin (5-HT) containing

neurons of the raphe nuclei (serotonergic neurons). This inhibition could

be due to either a direct effect or an indirect action via a postsynaptic

neuronal feedback loop. To compare the responsivity of serotonergic

neurons and postsynaptic neurons to LSD, raphe neurons and neurons

in 4 areas (ventral lateral geniculate, amygdala, optic tectum and

subiculum) with an identified 5-HT input from the midbrain raphe nuclei

were tested for their response to microiontophoretically ejected and

systemically administered LSD. Compared to the raphe, cells in these

postsynaptic areas were relatively insensitive to microiontophoretic LSD

Raphe cells could be totally inhibited by LSD at ejection currents too low

to have any effect on the postsynaptic neurons. In contrast, 5-HT was

very nearly equipotent in depressing the firing of the presynaptic (raphe)

cells and the postsynaptic cells. To determine if LSD has any indirect

inhibitory effect upon raphe neurons via a neuronal feedback, LSD was

administered to animals with a mesencaphalic-diencephalic

transection. In these animals LSD still produced inhibition of raphe

cells at doses comparable to those in control animals. It is concluded:

1) Raphe neurons are more sensitive to inhibitory effects of LSD than

are postsynaptic neurons (i.e., neurons receiving an identified 5-HT

input); and 2) the inhibitory effect of low doses of LSD on the presynaptic

(raphe) cells is caused by a direct inhibitory action rather than an

indirect action via a neuronal feedback.

HARRIS, L.S., DEWEY, W.L., SPAULDING, T.C., LEVY, J.A. and PLAINTIDOSI,

S. Recent studies on the development of tolerance and physical

dependence in rodents. Presented at the American Chemical Society

Meeting, Rochester, New York, October 15, 1973.

HARRIS, L.S., MUNSON, A.F., FRIEDMAN, M.A. and DEWEY, W.L. Retardation

of tumor growth by delta-9-tetrahydrocanabinol. The Pharmacologist 390

(1974)

Oral administration of delta-9-THC (25-100 mg/kg) bound to bovine

serum albumin was investigated for potential antitumor action on Lewis

lung carcinoma. BDG1

 male mice were inoculated with 106 tumor cells

into right hind leg and treated daily for 10 days beginning 24 hrs. after tumor

implantation. On day 12 of this experiment , delta-9-THC retarded primary

tumor growth 48%, 72% and 75% at 25, 50 and 100 mg/kg, respectively. Mice

receiving 100 mg/kg survived 36% longer than control as compared to 45% for

the cyclophosphamide positive control. Mice treated for 20 days showed

slightly less inhibition of primary tumor growth with no increase in lifespan.

In this study, cannabinol, at the same doses at delta-9-THC. administered

for 20 days showed slightly less activity on tumor growth and did not prolong

survival time. In preliminary mechanismistic studies, delta-9-THC

administered acutely, inhibited 3H thymidine uptake into tumor DNA but not

in brain, testes, spleen or bone marrow. Twenty-four hours after a single

oral gavage of 400 mg/kg delta-9-THC, DNA synthesis was reduced 75%. DNA

synthesis was not significantly altered in primary tumor or tissues of mice

similarly treated for 20 days.

261
HARVEY, J.A., editor. Behavioral Analysis of Drug Action. Glenview, Illinois:

Scott, Foresman and Company, 1971.

HARVEY, J.A. and LINTS, C.E. Lesions in the medial forebrain bundle: Relationship

between pain sensitivity and telencephalic content of serotonin. Journal of

Comparative and Physiological Psychology 74:28-36 (1971)

Lesions in the medial forebrain bundle (MFB) or injection of p-chlorophenylalanine decreased brain content of serotonin and decreased jump

thresholds in rats. The effects of lesion and drug were not additive indicating that a common system was being affected by both procedures. Injection

of 75 mg/kg DL-5-hydroxytryptophan into rats with lesions returned both the

jump threshold and serotonin content to normal values. The correlation

between jump threshold and telencephalic serotonin was +.80. Brainstem

serotonin was not related to jump threshold. Decreases in jump threshold

were interpreted as indicating an increased pain sensitivity. It was concluded

that this behavioral effect of the MFB lesion is secondary to the effects of the

lesion on serotonin content of the telencephalon.

HARVEY, J.A., SCHLOSBERG. A.J. and YUNGER, L.M. Behavioral correlates of

serotonin depletion. Federation Proceedings (in press)

HARVEY, J.A., SCHLOSBERG, A.J. and YUNGER, L.M. Effect of p-cpand brain

lesions on pain sensitivity and morphine analgesia in the rat. Advances

in Biochemical Psychopharmacology, Vol. 10. Edited by E. Costa, G. L.

Gessa and M. Sandler. New York: Raven Press, 1974.

HASSELAGER, E., ROLINSKI, Z. and RANDRUP, A. Specific antagonism by dopamine

inhibitors of items of amphetamine induced aggressive behaviour.

Psychopharmacologia 24: 485-495 (1972)

d-Amphetamine in a dose of 15 mg/kg elicits both aggressive activities

and stereotyped sniffing, licking and biting of the cage in mice. A selective

inhibition of the aggressive activities (without general sedation of the mice)

was obtained by small doses of the neuroleptics spiramide and trifluperazine,

indicating that this behaviour was mediated by increased activity of dopmaine

in the brain. This indication was supported by experiments with

noradrenaline blocking agents and inhibitors of the synthesis of dopamine and

noradrenaline.

HARVEY, J.A. and YUNGER, L.M. Relationship between telencephalic content of

serotonin and pain sensitivity. Serotonin and Behavior. Edited by J. Barchus

and E. Usdin. New York: Academic Press, 1973.

262
HENDERSON, A., NEMES, G., GORDON, N.B. AND ROOS, L. Sleep and narcotic

tolerance. Psychophysiology 7(2): 346-347 (September, 1970)

HENDLEY, E.D., TAYLOR, K.M. and SNYDER, S.H. 3H-normetanephrine uptake in

rat brain slices. Relationship to extraneuronal accumulation of norepinephrine.

European Journal of Pharmacology 12: 167-179 (1970)

3H-Normetanephrine accumulation in slices of rat brain was

characterized and contrasted with 3H-norepmephrine accumulation. Initial

rates of normetanephrine uptake were very rapid; accumulated amine was not

bound to particulate fractions and was easily washed out of the tissues. Unlike

norepinephrine uptake, normetanephrine accumulation was unaffected by

reserpine, was not stereospecific and was less affected by omission of glucose

or sodium than was norepinephrine uptake. The cerebral cortex was the region

of greatest normetanephrine accumulation whereas the corpus striatum

accumulated norepinephrine to highest tissue: medium ratios. Several features

of normetanephrine uptake in brain resembled both Uptake2 of norepinephrine in

heart and the extraneuronal uptake of norepinephrine in cocanized hearts. In

rat brains in which the catecholamine nerve terminals were destroyed by

intraventricularly administered 6-hydroxydopamine. endogenous norepinephrine

was markedly reduced; 3H-norepinephrine accumulation by slices was decreased,

and displayed characteristics more like normetanephrine uptake than like

norepinephrine uptake in control animals.

HERNDON. B.L., BAEDER, D.H. and RINGLE, D.A. Antagonism of morphine

analgesia by morphine-pellet implanted rabbit serum. Federation

Proceedings (in press)

Studies reported by us earlier and confirmed in another laboratory

have shown that repeated s.c. implantation of rabbits with pellets of morphine

and certain other narcotics evokes production of a serum component that

shows increased drug binding ability. This component has the characteristics

of an immunoglobulin.

In the study reported here, rabbit anti-morphine pellet serum (antiMP) was given i.v. to rats at a dose level equal to 20% of their blood volume.

For comparison, two other groups of rats were given either an antiserum

against a morphine-protein conjugate or serum from placebo pellet-implanted

rabbits. The effects on morphine analgesia in these three rat groups were

tested on a hot plate following a 5 mg/kg dose of morphine s.c. Anti-MP

serum and the antiserum to the morphine-protein conjugate both significantly

attenuated the analgesic response to morphine on the first day after serum

treatment. Subsequent tests on the same animals up to 6 weeks after serum

injection showed no differences in response among the three rat groups after

the second day, although a measurable level of rabbit gamma globulin

remained in the serum of most rats one month after injection.

263
HILL, H.F. and HORITA, A. Inhibition of ( + )-amphetamine hyperthermia by blockade

of dopamine receptors in rabbits. Journal of Pharmacy and Pharmacology 23:

715 (1971)

HILL, H.F. and HORITA, A. A pimozide-sensitive effect of apomorphine on body

temperature of the rabbit. Journal of Pharmacy and Pharmacology 24: 490 (1972)

HILLER, J.M., PEARSON, J. and SIMON, E.J. Distribution of stereospecific binding

of the potent narcotic analgesic etorphine in the human brain: Predominance in

the limbic system. Research Communications in Chemical Pathology and

Pharmacology 6(3): 1052-1061 (November, 1973)

Homogenates of human brain tissue obtained at autopsy exhibit stereospecific binding of the potent narcotic analgesic 3H-etorphine. Analysis of binding levels

in 39 anatomic sites shows a wide range of regional variation but good consistency

for the same area in different brains. Most sites with the highest binding activity

lie within the limbic system. Evidence in the literature supporting the significance

of the limbic system in responses to opiates is examined in the light of these findings.

HILLER, J.M. and SIMON, E.J. Inhibitions by levorphanol of the induction of acetylcholinesterase in a mouse neuroblastoma cell line. Journal of Neurochemistry

20: 1789-1792 (1973)

HIRSCHHORN, I.D. and WINTER, J.C. Mescaline and lysergic acid diethylamide (LSD)

as discriminative stimuli. Psychopharmacologia 22: 64-71 (1971)

The observation that a particular drug state may acquire the properties of a

discriminative stimulus is explicable on the basis of drug-induced interoceptive

cues. The present investigation sought to determine (a) whether the hallucinogens

mescaline and LSD could serve as discriminative stimuli when either drug is paired

with saline and (b) whether discriminative responding would occur when the paired

stimuli are produced by equivalent doses of LSD and mescaline. In a standard twolever operant test chamber, rats received a reinforcer (sweetened milk) for correct

responses according to a variable interval schedule. All sessions were preceded by

one of two treatments; following treatment A, only responses on lever A were reinforced and, in a similar fashion, lever B was correct following treatment B. No

responses were reinforced during the first five minutes of a daily thirty-minute

session. It was found that mescaline and LSD can serve as discriminative stimuli

when either drug is paried with saline and that the degree of discrimination varies

with drug dose, When equivalent doses of the two drugs were given to the same

animal, no discriminated responding was observed. The latter finding suggests that

mescaline and LSD produce qualitatively similar interoceptive cues in the rat.

HITZEMANN, R.J., HO, I.K., CHO, T. M. and LOH, H.H. Narcotic tolerance and dependence and serotonin turnover. Science 178: 645-647 (1972)

264
HITZEMANN, R.J. and LOH, H.H. Effect of morphine on the transport of dopamine into

mouse brain slices. European Journal of Pharmacology 21: 121-129 (1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

HO, B.T., ESTEVEZ, V.S. and ENGLERT, L.F. Effect of repeated administration on

the metabolism of ( - )-delta-9-tetrahydrocannabinols in rats. Research

Communications in Chemical Pathology and Pharmacology 5(1): 215-218

(January, 1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

HO, I.K. Effect of pharmacological manipulation on pentobarbital response.

Proceeding of the Western Pharmacological Society (in press)

The present studies describe the effect of pharmacological manipulations

which alter the functional state of putative neurotransmitters or neurohormones

on the responses of pentobarbital. As judged by sleeping time, the results show

that aminooxyacetic acid (an inhibitor of GABA transaminase), alpha-methyl

tyrosine (an inhibitor of tyrosine hydroxylase) and pargyline (an inhibitor of

monoamine oxidase) potentiated the pentobarbital effect on sleeping time. However, p-chlorophenylalanine (an inhibitor of tryptophan hydroxylase) antagonized

the effect.

HO, I.K. LOH, H.H. and WAY, E.L. Cyclic adenosine monophosphate antagonism of

morphine analgesia. The Journal of Pharmacology and Experimental Therapeutics

185: 336-346 (1973)

The administration of cyclic adenosine 3', 5'-monophosphate (cAMP) intracerebrally or intravenously antagonized morphine analgesia in nontolerant and

tolerant mice. The cAMP surrogates dibutyryl cAMP, a phosphodiesteraseresistant cAMP analog, and theophylline, a phosphodiesterase inhibitor, acted

in a similar manner. The antagonism of morphine effects by all three compounds

persisted for at least 24 hours and may have lasted for 48 hours. Elevation of

brain biogenic amines by monoamine oxidase inhibition with pargyline reversed

the antagonistic effects of cAMP on morphine analgesia. Increasing brain

dopamine with L-dopa did not prevent cAMP antagonism of morphine analgesia.

Increasing brain serotonin with tryptophan not only failed to reverse the effect of

cAMP, but also appeared to enhance the cAMP response. However, elevation of

norepinephrine with dihydroxyphenylserine did reverse the antagonistic effect

of cAMP. It is concluded, therefore, that norepinephrine is more important for

the reversal of cAMP antagonism of morphine analgesia than either dopamine or

serotonin.

265
HO, I.K., LOH, H.H. and WAY, E.L. Effects of cyclic 3', 5'-adenosine monophosphate

on morphine tolerance and physical dependence. The Journal of Pharmacology and

Experimental Therapeutics 185(2): 347-357 (1973)

The administration of cyclic 3', 5'-adenosine monophosphate (cAMP) antagonized the analgetic response of morphine in both nontolerant and tolerant mice and

also accelerated the development of tolerance to and physical dependence on morphine induced by morphine pellet implantation. Tolerance enhancement by cAMP was

evidenced by the increased amount of morphine to produce analgesia and acceleration

in dependence by the decrease in the amount of naloxone to induce precipitated withdrawal jumping after cAMP pretreatment. Further evidence that cAMP accelerated

dependence development on morphine was evidenced by the fact that cAMP increased

the loss in body weight that occurred after abrupt morphine withdrawal. Cycloheximide prevented the accelerating effect of cAMP on tolerance and physical dependence development.

HO, I.K., LOH, H.H. and WAY, E.L. Influence of GABA on morphine analgesia, tolerance

and physical dependence.

16: 4-7 (1973)

Proceedings of the Western Pharmacological Society

HO, I.K., SUTHERLAND, V. C. and LOH, I-L H. A model for the rapid development of

tolerance to barbiturates. Research Communications in Chemical Pathology and

Pharmacology 6(1): 33-46. (July, 1973)

For abstract, see Section I. Methodology of Drug Research.

HO, I.K., YAMAMOTO, I., LOH, H.H. and WAY, E.L. Enhancement of pentobarbital

responses after morphine addiction. The Pharmacologist 16(2): 193 (1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

HODGSON. J.R., BRISTOW, R.L. and CASTLES, T.R. Repression of RNA transcription

during the development of analgesic tolerance to morphine. Nature 248(5450):

761-763 (April 19, 1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

266
HOLLISTER, A.S., BREESE, G.R. and COOPER, B.R. Comparison of tyrosine

hydroxylase and dopamine-beta-hydroxylase inhibition with the effects of various

6-hydroxydopamine treatments on d-amphetamine induced motor activity.

Psychopharmacologia 36: 1-16 (1974)

The significance of central noradrenergic and dopaminergic neural systems

for the locomotor stimulant effects of d-amphetamine were investigated in rats

with depletions of norepinephrine, dopamine, or both catecholamines produced by

treatment with either reserpine. L-alpha-methyl-tyrosine (alpha-MPT), 6-hydroxydopamine (6-OHDA), or the dopamine-beta-hydroxylase inhibitor 1-phenyl-3 (2-

thiazolyll-2-thiourea (U-14,624). In animals pretreated with reserpine, amphetamine-stimulated locomotor activity was blocked by alpha-MPT but not by U-14,624

when amphetamine was given 1 h after these catecholamine synthesis inhibitors. In

rats with chronic depletions of brain norepinephrine, dopamine, or both

catecholamines produced by different 6-OHDA treatments, both amphetaminestimulated motor activity and sterotyped behavior were antagonized by treatments

reducing dopamine or both catecholamines but not in animals in which brain

norepinephrine was reduced. Results are consistent with the view that the locomotor stimulation and stereotyped behaviors produced by d-amphetamine are dependent upon functional dopaminergic neural systems in-brain.

HOLLISTER, L.E. Cannabidiol and cannabinol in man. Experientia

(1973)

29: 825-826

HOLLISTER, L.E. Human pharmacology of marihuana: What next? Psychopharmacology

Sexual Disorders and Drug Abuse. Edited by T. A. Ban, J.R. Boissier, G.J. Gessa,

H. Heimann, L. Hollister, H.E. Lehmann, I. Munkvad, H. Steinberg, F. Sulser,

A. Sundwall and 0. Vinar. Amsterdam, the Netherlands: North-Holland Publishing

Company, 1973. Pp. 705-706.

HOLLISTER, L.E. Interactions in man of delta-9-tetrahydrocannabinol. Clinical

Pharmacology and Therapeutics 15(1): 18-21 (1974)

The interaction of alphamethylparatyrosine (AMPT) and delta-9-tetrahydrocannabinol (THC) was studied in three separate experiments, two giving THC

orally, one adminstering it intravenously. Pretreatment with doses of 2.0 to 4.0 gm

of AMPT produced no major qualitative or quantitative change in the effects of THC.

Some accentuation of the total intensity of THC was apparent in each of these experiments, but one could not be certain whether this difference was due to additive

pharmacologic effects or diminished catecholamine concentrations in brain. It

would appear that mental effects of THC are not mediated primarily through

catecholamines, but rather by the balance between the concentrations of these

amines and others, such as acetylcholine or serotonin.

HOLLISTER, L.E. Tetrahydrocannabinol isomers and homologues: Contrasted effects

of smoking. Nature 227(5261): 968 (August, 1970)

267
HOLLISTER, L.E. and GILLESPIE, H.K. Delta-8- and delta-9-tetrahydrocannabinol.

Clinical Pharmacology and Therapeutics 14(3): 353-357 (1973)

Delta-8-tetrahydrocannabinol (THC) has activity in man similar to that of its

double-bond isomer, delta-9-THC. Its relative potency to the other isomer, as

judged following both oral and intravenous administration, is 2.3. Intravenous

administration of ethanolic solutions of cannabinoids in clinically active doses is

feasible and desirable for experimental purposes. A range of doses of 1 to 6 mg

of delta-9-THC intravenously produced a wide spectrum of cannabis-like effects.

Relatively simple clinical techniques clearly detect cannabis-like activity in man,

making both qualitative and quantitative comparisons of unknown materials with

delta-9-THC feasible.

HOLLISTER, L.E., KANTER, S.L. and DRONKERT, A. Antidiureses in man following

lysergic acid diethylamide and mescaline. Behavioral Neuropsychiatry 2: 50 (1970)

An antidiuretic effect following oral doses of 1. 5 to 2 mcg/kg of lysergic acid

diethylamide (LSD) was produced in 10 of 14 subjects. As compared with a control

day during which a water load was administered, LSD decreased urine formation,

decreased free water clearance, and increased urine osmolality. These changes

occurred promptly and lasted four hours or more. Determination of serum

osmolality and sodium content, or urinary excretion of sodium and chloride, was

of no help in demonstrating an antidiuretic effect. Similar changes in urine formation were noted after doses of 5 to 6 mg/kg of mescaline, effects being more

constant and profound. Attempts to relate the degree of antidiuresis with another

measure of physiologic stress, the rise in plasma free fatty acids, or clinical

indicators of stress as reported by subjects, were unsuccessful.

HOLLISTER, L.E., MacNICOL, M.F. and GILLESPIE, H.K. An hallucinogenic

amphetamine analog (DOM) in man. Psychopharmacologia 14: 62-73 (1969)

The amphetamine analog, 2, 5-dimethoxy-4-methylamphetamine (DOM), was

studied in 18 volunteer subjects given single doses ranging from 2 to 14 mg. The

former was a threshold dose, with definite psychotomimetic effects being evident

from doses over 5 mg. The clinical syndrome greatly resembled that of the LSDmescaline-psilocybin series of drugs, including its time-course. Somewhat more

sedation was produced by DOM than would have been expected from the others,

despite concomitant evidence of peripheral sympathetic stimulation. Just as with

the other drugs, DOM increased plasma free fatty acids, decreased phosphorus

and creatinine clearance, decreased circulating eosinophils and had little effect on

catecholamine excretion. Performance of psychometric tests was impaired. Chlorpromazine treatment concurrently was found to attenuate the reaction. Tolerance

rapidly developed when the drug was used chronically by patients.

268
HOLLISTER, L.E., MOORE, F., KANTER, S. and NOBLE, E. Delta-l-tetrahydiocannabinol, synhexyl and marijuana extract adminstered orally in man:

Catechoiamine excretion, plasma cortisol levels and platelet serotonin content.

Psychopharmacologia 17: 354-360 (1970)

Measurements of catecholamine excretion, plasma cortisol and platelet

serotonin concentration were done in the course of experiments in which human

volunteers were given sizable oral doses of delta-tetrahydrocannabinol, synhexyl

or marijuana extracts. A transient rise in epinephrine excretion was observed

following THC but seemed best explained by the anticipatory stress of the experiment or the rapid onset of unfamiliar symptoms. A decreased turnover of

catecholamines or a shift in the degradative pathways of catecholamines from the

oxidative to the reductive route was suggested by the decrease in VMA excretion

following synhexyl. Plasma cortisol was unchanged except in the presence of

clinically obvious psychological distress on the part of the patient. Platelet

serotonin was unchanged.

The lack of major effects of marijuana-like drugs on these and other clinical

measurement of stress corroborates the clinical observation that drugs of this type

seem to be less stressful than the usual psychotomimetics. The pronounced euphoriant and sedative effect of marijunana may ameliorate the stress of the psychotomimetic experience.

HOLLISTER, L.E., RICHARDS, R.K. and GILLESPIE, H.K. Comparison of tetrahydrocannabinol and synhexyl in man. Clinical Pharmacology and Therapeutics

9(6): 783-791 (November-December, 1968)

A synthetic isomer of tetrahydrocannabinol (1-delta'-3,4-transtetrahydrocannabinol), believed to be identical to the most active naturally occurring THC,

was compared with a semisynthetic THC-like compound, synhexyl. Sixteen

volunteer subjects received THC in doses ranging from 341 to 946 mu-g per

kilogram (median 581). Thirteen subjects received synhexyl in doses. ranging from

‘633 to 2,666 mu-g per kilogram (median 1.370). Clinical syndromes from the 2

drugs were similar, although synhexyl was slower in onset and only about one third

as potent. The clinical effects resembled those of psychotomimetics such as LSD,

at least at the higher doses. These drugs differed from LSD in the following

respects: sedation was prominent; euphoria was longer lasting; dreamlike sequences more pronounced; and physiological and biochemical effects were somewhat different, especially in the absence of sympathomimetic effects.

HOLLISTER, L.E. and TINKLENBERG. J.R. Subchronic oral doses of marihuana extract.

Psychopharmacologia 29: 247-252 (1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

269
HOLTZMAN, S.G. and JEWETT, R.E. Interactions of morphine and nalorphine with

physostigmine on operant behavior in the rat. Psychopharmacologia 22: 384-395

(1971)

Morphine and nalorphine were tested alone and in combination with physostigmine (0.0625 mg/kg) in rats trained under a continuous avoidance schedule

with an escape contingency. When tested alone, nalorphine increased avoidance

rate in doses up to 32 mg/kg but exerted no other effects. Morphine, 1 mg/kg,

increased avoidance response rate while higher doses produced a graded depress ion of all behavior. In the presence of physostigmine. nalorphine produced a

well-defined graded depression of avoidance responding and increased the number

of shocks received by the animals over a 16-fold dose range. Physostigmine

failed to potentiate the prominent depressant effects of morphine in the same test

situation. The finding that in the presence of cholinesterase’inhibition nalorphine

acts as a depressant of operant behavior in the rat supports existing evidence

that cholinergic mediation should be considered as a factor in some of the actions

of strong analgesics.

HOLTZMAN, S.G. and JEWETT, R.E. Some actions of pentazocine on behavior and brain

monoamines in the rat. The Journal of Pharmacology and Experimental

Therapeutics 181(2): 346 (1972)

The effects of pentazocine, a weak narcotic-antagonist analgesic, were

studied on operant behavior (continuous avoidance schedule), locomotor activity

and brain nonoamines in the rat. Operant behavior was increased in a graded

manner by 2 to 16 mg/kg of pentazocine and decreased by 32 mg/kg. Both

stimulant and depressant effects were antagonized by the potent narcotic antagonist naloxone (8 mg/kg). Pentazocine, 8 to 64 mg/kg, produced a graded increase

in locomotor activity which was not prevented by as much as 16 mg/kg of naloxone.

Stimulation of locomotor activity was blocked by alpha-methyltyrosine, an inhibitor

of catecholamine synthesis. The total brain content of norepinephrine, dopamine,

and serotonin was reduced by pentazocine; turnover rates were not affected. The

depletion of the catecholamines was 2 -3 times greater than that of serotonin.

Morphine, in doses as high as 256 mg/kg, caused a much smaller reduction in

brain norepinephrine than did pentazocine and elevated brain levels of dopamine.

Naloxone (16 mg/kg) failed to block the effects of pentazocine on brain monoamines

but did block those of morphine. These findings have been interpreted as follows:

1) the actions of pentazocine on operant behavior appear to be independent of its

effects on brain monoamines; 2) stimulation of locomotor activity by pentazocine

may be related to the release of brain monoamines; and 3) some of pentazocine’s

agonistic effects are mediated by mechanisms distinct from those which mediate

the actions of morphine.

270
HOLTZMAN. S.G. and JEWETT, R.E. Stimulation of behavior in the rat by cyclazocine:

Effects of naloxone. The Journal of Pharmacology and Experimental Therapeutics 187(2): 380 (1973)

The actions of cyclazocine, a potent analgesic with mixed agonist and

narcotic antagonist properties, were evaluated on two distinct types of behavior

in the rat: lever pressing maintained under a continuous avoidance schedule and

locomotor activity. The effects of cyclazocine on the total brain content of norepinephrine, dopamine and serotonin were also examined. Dose-response curves

were determined for cyclazocine alone, then redetermined with concomitant

administration of naloxone at two dose levels. d-Amphetamine was also tested

alone and with naloxone on avoidance behavior. Cyclazocine increased avoidance

responding and locomotor activity in a graded manner over a broad range of doses.

Both behaviors were disrupted by the highest doses of cyclazocine. Cyclazocine

lowered brain catecholamine levels slightly. Naloxone, inactive in all procedures,

attenuated the stimulant and disruptive effects of cyclazocine on avoidance behavior,

but failed to block cyclazocine’s effects on locomotor activity and brain catecholamine levels. Naloxone reduced the rate-increasing effect of d-amphetamine on

avoidance responding and enhanced the disruption of avoidance-behavior produced

by a high dose of that drug. These findings are consistent with the view that the

agonistic component of action of some narcotic antagonists is mediated by several

mechanisms, at least one of which is not blocked by naloxone. The interaction

between naloxone and d-amphetamine emphasizes the need for further evaluation

of possible interactions between narcotic antagonists and psychoactive drugs of

classes other than the opioid.

HORITA, A. Pharmacological aspects of the unnatural amino acids and amines.

Federation Proceedings 30(3): 857-858 (May-June, 1971)

HORITA, A. and CARINO, M.A. Modification of the toxic actions of 1-tryptophan by

pargyline and p-chlorophenylalanine. Biochemical Pharmacology 19: 1521 (1970)

HORITA, A., CLINESCHMIDT, B.V. and McMONIGLE, J.J. The role of metabolism in

the action of some monoamine oxidase inhibitors. Excerpta Medica International

Congress Series No. 180. Present Status of Psychotropic Drugs. Amsterdam,

the Netherlands: Excerpta Medica Foundation, 1968.

HORITA, A. and HAMILTON, A.E. The effects of DL-alpha-methyltyrosine and L-dopa

on the hyperthermic and behavioral actions of LSD in rabbits.

12: 471-476 (1973)

Neuropharmacology

Lysergic acid diethylamide (LSD) in relatively small doses produces in

rabbits a dose-related hyperthermia and behavioral excitation.

After a 24 hr pretreatment with DL-alpha-methyl-p-tyrosine (alpha-MT),

the LSD hyperthermia is no longer dose related. With lower doses of LSD it is

potentiated, and with higher doses attenuated. The behavioral actions of LSD are

attenuated at all dose levels.

The administration of L-dihydroxyphenylalanine (L-DOPA) restores the

behavioral action of LSD in alpha-MT-pretreated rabbits. Prior administration of

the dopamine-beta-hydroxylase inhibitor, sodium diethyldithiocarbamate (DEDC)

was ineffective in blocking the restorative action of L-DOPA.

Analyses of brainstem catecholamines indicate that under the conditions

of this study alpha-MT markedly depletes brain norepinephrine (NE) and dopamine

(DA). L-DOPA restores DA and partially restores NE levels to control values. In

animals pretreated with DEDC the effect of L-DOPA treatment on brainstem DA is

enhanced with only slight increases in NE levels.

271
HORITA, A. and HAMILTON, A.E. On the hyperthermic action of 2, 5-dimethoxy-4-methylamphetamine (DOM). Proceedings of the Western Pharmacological Society 15:

104 (1972)

In earlier studies we described the hyperthermic action of d-amphetamine

in rabbits as differing from that produced in rats because of the lack of antagonism

by beta-blocking agents, while the antidopamine compound, pimozide, was highly

effective in attenuating this response. These and other evidence indicated the

involvement of a dopaminergic link in the amphetamine-induced hyperthermia in

the rabbit.

In the present report we describe the nature of the temperature response

of rabbits to the hallucinogenic amphetamine derivative, 2.5-dimethoxy-4-methylamphetamine (DOM). In doses above 0.05 mg/kg DOM exerts a dose-dependent

pyretogenic effect which is characterized by a peak response at 2-3 hr and with a

duration of some 8-10 hr. This is in contrast to the effect of d-amphetamine

which peaks at 0.5-1.0 hr and lasts for only 2-3 hr. Above 1.0 mg/kg DOM exerts

in some animals lethal hyperthermia with temperatures rising to above 430-440.

In addition to the hyperthermia, animals with sublethal doses of DOM exhibit some

changes in gross behavior, such as piloerection, increased respiration, and vasoconstriction of ear vessels, but it produces none of the increased behavioral or

locomotor activity as seen with amphetamine.

When animals pretreated with pimozide (4 mg/kg, 3 hr previously) are

injected with 0.5 mg/kg of DOM the hyperthermia is only slightly decreased from

that of control DOM rabbits. However, rabbits pretreated with cinanserin

HCl (5-10 mg/kg, 30 min previously) exhibit a greatly attenuated response to DOM.

These preliminary results indicate that, while the amphetamine-induced

hyperthermia in rabbits is mediated via a dopaminergic mechanism, the response

seen with DOM resembles that produced by LSD and other indole amine hallucinogens. This interpretation is consistent with the findings of Wolbach et al. on the

development of a cross-tolerance between the psychotomimetic actions methoxylated phenethylamines and LSD, which in turn suggests a common site of action for

the two types of drugs.

HORITA, A. and HAMILTON, A.E. Potentiation of the central actions of 5-hydroxytryptophan in rabbits by DL-alpha-hydrazino-alpha-methyldopa. Journal of Pharmacy

and Pharmacology 22: 389 (1970)

HORITA, A. and HILL, H.F. Hallucinogens, amphetamines and temperature

regulation. The Pharmacology of Thermoregulation Symposium,

San Francisco, California. 1972. New York: Karger, 1972.

HORITA, A., NAIR, X. and HAMILTON, A.E. L-alpha-methyl-alpha-hydrazino-beta-

(3,4-dihydroxyphenyl)propionic acid: Relative lack of antidecarbocylase activity

in adrenals. Science 176: 931 (May, 1972)

In rats previously treated with a monoamine oxidase inhibitor, the administration of 5-hydroxytryptophan results in increases in concentrations of 5-hydroxytryptamine in kidney, brain. and adrenal glands. When the peripheral L-aromatic

amino acid decarboxylase inhibitor, L-alpha-methyl-alpha-hydrazino-beta-(3,4-

dihydroxyphenyl)propionic acid (HMD) is administered prior to 5-hydroxytryptophan,

the concentration of 5-hydroxytryptamine in kidneys does not rise, that of the brain

increases slightly, and that of the adrenal rises markedly. This indicates that

although the adrenal gland is a peripheral organ, it does not respond in the typical

manner to the antidecarboxylase action of HMD. These results suggest that HMD

does not gain free access into the adrenal medulla and that a possible “bloodadrenal barrier” may exist to this compound.

272
HOSKO, M.J. and HARDMAN, H.F. Effect of delta-9-THC on cardiovascular responses

to stimulation of vasopressor loci in the neuraxis of anesthetized cats. The

Pharmacologist 13: 296 (1971)

HOURY, S. and MECHOULAM, R. Benzoxocin and benzoxonin derivatives. Novel

groups of terpenophenols with central nervous system activity. Journal of

Medicinal Chemistry 17(3): 287-293 (1974)

HUANG, P. and SMITH, A.A. Single dose tolerance to meperidine. Committee on the

Problems of Drug Dependence. Washington, D.C.: National Academy of Sciences,

National Research Council, 1970.

HUDICK, J.P., WAJDA, I.J. and LAJTHA, A. Isotopic labelling of cholinergic nerveendings and the effect of drugs. The Pharmacologist 16(2): 541 (1974)

Regional and subcellular studies of choline acetyltransferase of rat brain

(Wajda et al., J. Neurochem. 21, 1385, 1973) indicated that this enzyme provides

a useful marker for cholinergic nerve-endings and that such organelles from corpus

striatum (S) have a higher sedimentation density than those from cerebral cortex

(Cx). We have now confirmed these results by specific labelling of cholinergic

synaptosomes with H

3

- or C

14-choline. High affinity choline uptake coincided in

S and Cx with the particles characterized as cholinergic synaptosomes, while the

low affinity uptake did not have this regional distribution. The specific distribution obtained with high affinity labelling was abolished by hemicholinium-3. The

choline uptake systems were further characterized by their kinetic parameters

and by their ability to convert accumulated choline to acetylcholine. Morphine

treated rats showed slight lowering of Km and Vmax in both S and Cx (P is greater

than 0.01). Our data support the idea that high affinity choline uptake labels

specifically the cholinergic nerve-endings, and hence is another biochemical

marker for these particles.

HUDICK, J.P., WAJDA, I.J. and LAJTHA, A. Regional variations in rat brain synaptosomal transport processes for choline and the effect of morphine. Transactions

of the American Society for Neurochemistry, New Orleans, Louisiana, March

10-14, 1974.

Recently it was shown that brain synaptosomes possess both low and high

affinity choline uptake systems. Acetylcholine formation and Na+

 dependency were

associated exclusively with the’ high affinity system. The present report is concerned

with regional differences in the low and high affinity choline transports in both normal and morphine treated rats. The three regions studied were: striatum (S),

cortex (Cx), and hypothalamus (Hy). Although in all three areas the apparent

kinetic parameters for choline uptake increased with higher substrate concentrations,

the substrate dependence was more pronounced in Hy than in S and Cx. With high

choline concentration (10-100 mu-M), deletion of Na+ from the incubation medium

resulted in a lower Vmax in S and a slightly higher Vmax in Cx and Hy.

increased by the absence of Na+

The Km was

170% in S, 129% in Cx, and 44% in Hy. The percentage of conversion of accumulated choline to acetylcholine was used as a marker

for the high affinity system. With 2 mu-M choline the conversion was 55% in S, 33%

in Cx, and 20% in Hy. Absence of Na+

 and presence of 100 mu-M substrate reduced

such conversion to less than 10%. Data obtained using rats killed one hour after

injection of 30 mg/kg of morphme revealed a small but significant lowering of Km

273
Hudick, J.P., Wajda, I. J. and Lajtha, A. Regional variations . . . continued

and Vmax in Cx with 1.0-10.0 mu-M choline. Taking into account the possible

variable conditions of different synaptosomal preparations, a conclusive interpretation of this finding awaits further experimentation. The high affinity choline

uptake system studied by us is more concentrated in striatum than in the other

two parts of the brain. This regional distribution correlates with our earlier

report that choline acetyltransferase activity is three fold higher in the striatum.

The high affinity transport process appears to reflect a specific accumulation

of choline by cholinergic neurons.

HUG, C.C., JR. Characteristics and theories related to acute and chronic tolerance

development. Chemical and Biological Aspects of Drug Dependence. Edited by

S. Mule and H. Brill. Cleveland, Ohio: Chemical Rubber Company Press, 1972.

Pp. 307-358.

HUGHES, J. Isolation of an endogenous compound from the brain with pharmacological

properties similar to morphine. Brain Research (in press)

HUGHES, J., KOSTERLITZ, H.W. and LESLIE, F.M. Assessment of the agonist and

antagonist activities of narcotic analgesic activities of narcotic analgesic drugs

by means of the mouse vas deferens. British Journal of Pharmacology 51: 139-

140 (1974)

HUNT, H.F. Unconditioned stimulus functions of drugs: Interpretations, I. Chapter 5

of Stimulus Properties of Drugs. Edited by T. Thompson and R. Pickens. New

York: Appleton-Century-Crofts, 1971.

INCIARDI, J.A. and CHAMBERS, C.D. Patterns of pentazocine abuse. Drug Abuse:

Current Concepts and Research. Edited by W. Keup. Springfield, Illinois:

Charles C. Thomas, 1972.

Pentazocine, an effective analgesic marketed under the trade name

Talwin, exerts an euphorogenic effect and, contrary to popular belief, is addictive. The greatest potential for abuse falls within the medical-medicine context;

physician overprescription. pharmacists overfilling prescriptions, and inadequate

control of institutional drug supplies are common avenues of availability for the

narcotic medicine abuser. This ready availability in a legal market and the

professional and lay confusion concerning the addiction liability of the drug have

contributed to the increasing incidence of abuse and addiction.

ISAAC, W. A study of the relationship between the visual system and the effects of d-amphetamine. Physiology and Behavior 6: 157-159 (1971)

The observed stimulant effect of d-amphetamine as measured by cage

activity in the nocturnal animal is at least partially due to the drugs reducing the

activity suppressing effect of illumination. The drug had its greatest effect in

combination with a lesion of the superior colliculus.

274
ISAAC, W. and TROELSTRUP, R. Opposite effect of illumination and d-amphetamine

upon activity in the squirrel monkey (saimiri) and owl monkey (aotes).

Psychopharmacologia 15: 260-264 (1969)

The effect of d-amphetamine upon locomotor activity in the monkey is

not uniform and seems related to the noctural-diurnal tendencies of the subject.

It increases activity of the nocturnal subject and decreases the activity of the

diurnal subject.

ITIL, T. and FINK, M. Electroencephalographic effects of trifluperidol. Diseases of

the Nervous System 30: 524-540 (19691

The EEG patterns of trifluperidol, a novel psychoactive agent of the

butyrophenone class were determined in acute intravenous and chronic oral

administration to psychiatric patients and normal volunteers. The effects were

dose related, with increased alpha activity, and increased synchronization

occurring at low doses and increased slow wave spike activity and persistence

of fast activity at higher dosages.

The EEG patterns are related more to the piperazine phenothiazines than

the aliphatic phenothiazine compounds, and the clinical efficacy of these compounds

is seen as directly related to the amount and type of central changes induced.

ITIL, T., SHAPIRO, D., HICKMAN, C., FINK, M. and KIREMITCI, N. The differentiaITO, A. and SCHANRERG, S.M. Central nervous system mechanisms responsible for blood

pressure elevation induced by p-chlorophenylalanine. The Journal of Pharmacology

and Experimental Therapeutics 181(1): 65 (1972)

tion of tranquilizers by quantitative EEG. Electroencephalography and Clinical

Neurophysiology 24: 288 (1968)

For abstract, see Section I. Methodology of Drug Research.

An elevation in blood pressure was produced in rats after either intracisternal (1-10 mg/kg) or i.p. (100-200 mg/kg) injections of p-chlorophenylalanine. The eievation was dose-related. Pulse and respiration rates showed no

significant changes. The pressor response was preceded by selective depletion

of serotonin in the brain and was blocked by simultaneous or subsequent treatment

with 5-hydroxytryptophan. Data from these and from experiments in which the

brain stem was transected sequentially suggest that the pressor response to pchlorophenylalanine is mediated by depletion of serotonin in the brain stem and

that “serotonergic” structures in the rostra1 medulla may exert an important

role in central tonic regulation systemic blood pressure in rats.

275
ITO, A. and SCHANBERG, S.M. Lack of significant central component in beta-adrenergic

chronotropic effect in vagotomized rats. Japanese Heart Journal 14(5): 432-

439 (September, 19731

The locus of the negative chronotropic response to propranolol was

studied in bilaterally vagotomized and respiration-controlled rats. Following

results were obtained: 1) The heart rate reduction on intravenous (i.v.) injection

of propranolol was most potent for L-, next for DL- and not significant for Disomer; 2) The response to i.v. DL-propranolol was not affected by the medullospinal transection nor by pretreatment with hexamethonium bromide; 3) Intracisternal (i.C.) administration of DL-propranolol elicited a dose-relating decrease

which was, however, not antagonized by i.C. addition of DL-isoproterenol which

caused an increase only inconsistently and not related with dose of the preceding

propranolol: and 4) I.C. DL-propranolol did not eliminate the positive chronotropic

effect of i.v. injection of DL-isoproterenol. Results indicate a lack of significant

central component in the beta-adrenergic negative chronotropic response to i.v.

applied propranolol, and suggest the heart rate decrease on the centrally administered propranolol arising in a mechanism other than its beta-adrenergic blocking

property.

ITO, A. and SCHANBERG. S.M. Maintenance of tonic vasomotor activity by alpha and

beta adrenergic mechanisms in medullary cardiovascular centers. The Journal

of Pharmacology and Experimental Therapeutics 189(2): 392 (1974)

A dose-related decrease in blood pressure and heart rate occurred in

vagotomized rats after intracisternal (i.c.) injection of phentolamine, an alpha

adrenergic antagonist. The site of action of these effects was determined to be

localized to the central nervous system. The depressor response was reversed

by alpha adrenergic agonist, norepinephrine or phenylephrine, and augmented by

the beta adrenergic agonist, isoproterenol. These agonists, however, had no

effect on the phentolamine-induced bradycardia. Phenoxybenzamine, an irrever -

sible alpha adrenergic antagonist, administered i.c. also caused a decrease in

blood pressure and heart rate but these effects were not reversed by norepinephrine.

The i.c. injection of norepinephrine without antagonist pretreatment caused a

transient increase in blood pressure while isoproterenol caused a decrease. A

beta adrenergic antagonist, propranolol, administered i.c. caused a pressor

response in small doses and a depressor response in large doses but only a doserelated decrease in heart rate. The propranolol-induced pressor response was

reversed by isoproterenol and enhanced by norepinephrine. Data from sequential

transections of the brain stem and from direct application of phenylephrine, norepinephrine or isoproterenol on the brain stem surface after transections suggest

that the pressor response elicited by alpha adrenergic agonists originates in a

region of the medulla localized between the inferior cerebellar peduncle and the

caudal end of the obex. The beta adrenergic depressor response, however, appears

less localized and to originate from a more diffuse region. These results suggest

that alpha adrenergic pressor and beta adrenergic depressor mechanisms are

involved reciprocally in tonic blood pressure control mechanisms located in the

medulla oblongata of rats. Although the i.c. administration of phentolamine or

propranolol also depresses heart rate, the data do not suggest a simple adrenergic

mechanism. These studies show clearly that receptor mechanisms for heart rate

control in the central nervous system are different from those involved in the regulation of blood pressure.

276
IWATSUBO, K. and CLOUET, D.H. The effects of narcotic analgesic drugs on the levels

and the rates of synthesis of cAMP in six areas of rat brain. Federation Proceedings

32: 536 (1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

IWATSUBO, K., GOLD, G. J. and CLOUET. D. H. Dopamine-sensitive adenylate cyclase

of the caudate nucleus of rata treated with morphine or haloperidol. The

Pharmacologist 16(2): 270 (1974)

The effects of opiates and neuroleptics on dopamine (DA) sensitive adenylate

cyclase (DA-AC) were examined in vitro and in vivo. Various opiate agonists and

antagonists at 3 to 300 micromoles had no effect on DA-AC in vitro, while haloperidol in concentrations greater than 3 micromoles completely inhibited the DA

response. The administration of morphine or haloperidol in vivo produced significant increases in DA-AC. DA-AC was also increased in rats made tolerant to

morphine by pellet implantation. The data are seen to support the hypothesis that

while neuroleptics block the DA receptor directly, morphine blocks dopaminergic

transmission by some other mechanism, and that the blockade of transmission

produces enhanced receptor activity as well as increased DA turnover.

JACOBS, G.R. and BURKS, T.F. Intestinal motor effects of a unique analgesic agent.

Journal of Pharmaceutical Sciences 63(5): 787 (May, 1974)

The effects of 2, 3.5, 6,11,11b-hexahydro-11, 11b-dimethyl-14-

indolizino (8,7,b)indole hydrochloride on intestinal motility were investigated,

The indole derivative altered contractile activity in each preparation

studied. Intestinal contractions in situ in anesthetized dogs were stimulated,

but variable mild stimulatory or inhibitory effects occurred in cats and monkeys.

Spontaneous contractions of monkey intestine were inhibited in vitro.

Dose-related increases in motility were produced in dog intestine in vitro,

although the experimental compound was considerably less potent than morphine

as an intestinal stimulant. The stimulatory effects of the indole derivative

in dog intestine were antagonized by atropine and by cyproheptadine.

Indolazinoindole also inhibited propulsion of a test meal in mice in vivo.

JACQUET, Y. and LAJTHA, A. A concurrent hyper/hypo-reactive syndrome following

morphine microinjection in the midbrain central gray. Journal of Pharmacology

5(Supplement 2): 46 (1974)

Microinjection of morphine into a site in the periaqueductal gray

matter (PGM) of the rat resulted in a concurrent hyperlhypo-reactive syndrome

not previously observed with systemic injection of morphine. At a moderate

dose (5 mu-g), this syndrome was manifested by backward circling in response

to auditory/visual stimuli and airpuffs, and simultaneously, moderate analgesia

to hemostat pinch to the 4 limbs, tail and ears. At a high dose (10 mu-g),

rats showed an explosive hyper-reactivity, making violent and repetitive 2-ft

high leaps to auditory/visual stimuli and airpuffs; simultaneously, there was

profound hypo-reactivity to noxious pinch, pinpricks and cold stimuli. This

hypo-reactivity was such as to allow surgery in a fully conscious rat without

signs of pain.

This site is part of the central gray “pain pathway” shown to terminate

partly in the posterior hypothalamus (PH). This PH site was shown in a

previous study to yield analgesia following morphine microinjection.

277
JACQUET, Y. and LAJTHA, A. Development of tolerance to morphine following intracerebral

injection in the pariaqueductal gray of the rat. Proceedings of the Society for

Neuroscience, Fourth Annual Meeting, St. Louis, Missouri, October 20-24, 1974.

Morphine injected via fine-gauge cannula in the rostral periaqueductal gray

(PAG) of the rat resulted in profound analgesia accompanied simultaneously by

an explosixe hyper-reactivity to sudden auditory and visual stimuli. Both effects

were dose-dependent, and could be blocked temporarily by prior intracerebral

(IC) naloxone, or reversed temporarily by subsequent IC naloxone. This PAG

site showed rapid tolerance development to a toxic dose of morphine. An initial

dose of 20 mu-g of morphine bilaterally resulted in a 57% mortality rate, whereas

if preceded by I - 3 injections of moderate doses of morphine, the mortality

rate was cut to 0. Tolerance was also shown to the analgesic action of IC etorphine

( 1 mu-g bilaterally) given on 2 successive days. Cross tolerance to the analgesic

action of morphine occurred between IC morphine and intraperitoneal (IP)

administrations of morphine, as well as between IC morphine and subsequent

IP levorphanol. These results indicate that 1) the PAG is a major site of morphine

action, and 2) tolerance is a central, and not peripheral phenomenon.

JACQUET, Y.F. and LAJTHA, A. Morphine action at central nervous system sites

in rat: Analgesia or hyperalgesia depending on site and dose. Science

182: 490-492 (1973)

Morphine was injected via fine-gauge cannulas permanently implanted

in various subcortical sites in the rat brain. In this way the blood-brain barrier

was avoided and precise quantities of the drug were delivered to the intended

sites. Ten micrograms of morphine in the posterior hypothalamus resulted in

significant analgesia, while the same dose injected into the medial septum, the

caudate, or the periaqueductal gray matter yielded hyperalgesia. The morphineproduced hyperalgesia at the last-mentioned site was accompanied by stereotyped

violent circular leaps, an effect of morphine not previously reported. Thus intracerebral injections of morphine differ significantly from systemic injections and

produce either analgesia or hyperalgesia. depending on site and dose.

JACQUET, Y. F. and LAJTHA, A. Paradoxical effects after microinjection of

morphine in the periaqueductal gray matter in the rat. Science 185: 1055-1057

(1974)

Paradoxical, concurrent hyper- and hyporeactivity of a profound

nature to specific stimuli occurred when 10 micrograms of morphine was microinjected bilaterally into the periaqueductal gray matter of the rat brain. Both

effects at this site were dose-dependent. The hyperreactivity (to previously neutral

auditory and visual stimuli) was obtained only with intracerbrally injected morphine and never with intraperitoneally injected morphine or with other opiates

administered either way. Rapid tolerance to toxic doses of morphine developed at

this site, as well as cross tolerance of the hyporeactivity to painful stimuli

between routes (intraoerebral to intraperitoneal) of morphine administration.

Both the hyper- and hyporeactivity were fully reversible by intracerebral injection

of naloxone in the periaqueductal gray. Thus, the periaqueductal gray appears to

be a major pathway for morphine action.

278
JAFFE, J., DAHLBERG, C.C., LURIA, J., BRESKIN, S., CHOROSH, J. and LORICK, E.

Speech rhythms in patient monologues: The influence of LSD-25 and dextroamphetamine.

Biological Psychiatry 4(3): 243-246 (1972)

A comprehensive review of research dealing with drug effects on speech

noted a relative paucity of studies in which speech rate was the dependent

variable (Waskow, 1967). We have shown that the average durations of sound

and silence in 5-min samples of extemporaneous speech are: (i) reliably

quantifiable by a completely automated apparatus, (ii) behaviorally stable

parameters of individual speakers; and (iii) systematically modifiable when

subject, task, and environmental variables are manipulated (Jaffe and Feldstein.

1970; Jaffe and Breskin, 1970a. 1970b). We now assess the effects of LSD and

dextroamphetamine (DA) on these temporal characteristics of speech.

JAFFE, J., DAHLBERG, C.C., LURIA, J. and CHOROSH, J. Effects of LSD-25

and dextroamphetamine on speech rhythms in psychotherapy dialogues.

Biological Psychiatry 6(1): 93-96 (1973)

We have previously reported the effects of LSD-25 and dextroamphetamine

(DA) on the sound-silence pattern of extemporaneous monologues (Jaffe et al.,

1972). A monologue consists of a sequence of vocalizations interrupted by

pauses. The major finding was that, with respect to placebo (P), the average

pause duration was lengthened by LSD and shortened by DA, whereas mean

vocalization duration was not affected significantly. This modification of pause

duration is one major mechanism by means of which speech rate is controlled.

The monologues were recorded in isolation, and immediately prior to psychotherapy dialogues in a double-blind study of the drug effects on the treatment

process. It is thus reasonable to ask if the effects of the drugs on the dialogues

are the same as those occurring in the monologues; the answer is in the affirmative.

JANDHYALA, B.S., MALLOY, K.P. and BUCKLEY, J.P. Effects of delta-gtetrahydrocannabinol (delta-9-THC) on pulmonary circulation. Federation

Proceedings 34(3): 744 (1975)

It has been reported that delta-9-THC accumulated in large

concentrations in lung tissue and can produce hypoxic hypoxia in

spontaneously breathing animals. The present study was designed

to investigate the effects of delta-9-THC, on pulmonary circulation and

possible consequences on right ventricular performance in anesthetized

mongrel dogs. Delta-9-THC (2.5 mg/kg i. v.) produced a decrease

in heart rate (HR), pulmonary blood flow (PBF) and transient changes

in right ventricular stroke volume (RVSV). The decrease in PBF was

not accompanied by a reduction in pulmonary artery pressure evidently

due to a marked increase in pulmonary vascular resistance (PVR).

Increased PVR could also account for gradual and consistent increases

in right ventricular stroke work (RVSW) despite reduced PBF. When

changes in HR were prevented by a pacemaker there was still a

significant reduction in PBF accompanied by a marked increase in PVR.

However, in the preparations in which HR was constant there was a

reduction in RVSV. RVSW also decreased despite a marked increase

in PVR. These changes could only be explained on the basis of

decreased venous return following delta-9-THC. Results of this

investigation are consistent with the conclusion, that in subjects with

normal cardiac rhythm, delta-9-THC could enhance RVSW (pressure-work)

due to marked increase in pulmonary vascular resistance.

279
JESPERSEN, S. and SCHEEL-KRÜGER, J. Antagonism by methysergide of the

5-hydroxytryptamine-like action of toxic doses of fenfluramine in dogs.

Journal of Pharmacy and Pharmacology 22: 637-638 (1970)

In summary a large dose of fenfluramine given to dogs caused symptoms

which were grossly similar to those reported after administration of 5-HTP,

indicating that 5-HT plays an important role in the reactions. The symptoms

improved after administration of the 5-HT antagonist methysergide, which

also seemed to antagonize the fenfluramine-induced anorexia.

Methysergide might be of value in the treatment of fenfluramine

overdosage.

JESPERSEN, S. and SCHEEL-KRÜGER, J. Evidence for a difference in mechanism

of action between fenfluarmine- and amphetamine-induced anorexia. Journal

of Pharmacy and Pharmacology 25: 49-54 (1973)

The influence of drugs, active on 5-hydroxytryptamine (5-HT)

mechanisms, has been examined on the anorexigenic activity of

fenfluramine and (+)-amphetamine in rats trained to consume their

daily food ration during 6 h. Chlorimipramine, which inhibits the

re-uptake mechanisms in central 5-HT neurons, and the 5-HT blocking

drugs methergoline and methysergide were used. Fenfluramine, 7.5 mg kg-1,

and amphetamine, 2.5 mg kg-1, given h before feeding reduced the food

intake during the following 2 h to approximately 40% compared with control

days. Pretreatment with metherpoline in the optimal dose (1 mg kg-l)

produced only a weak but significant antagonism to amphetamine anorexia,

whereas the fenfluramine anorexia was strongly antagonized by methergoline

in all doses tested (0.3, 1 and 3 mg kg-1). Methysergide (0.1, 0.3, 1 and 3

mg kg-1) showed no significant antagonism against amphetamine or fenfluramine anorexia. Chlorimipramine produced a strong antagonistic effect

to the fenfluramine anorexia, but showed no antagonism against amphetamine.

In contrast the highest dose of chlorimipramine (20 mg kg-1) potentiated

amphetamine anorexia. The present results together with other evidence

discussed support the conclusion that 5-HT mechanisms are involved in fenfluramine

anorexia, whereas amphetamine anorexia seems mainly correlated with catecholamine

dependent mechanisms.

JOHNSON, C.L. and GREEN, J.P. Molecular orbital studies on tryptamines active

on the LSD receptor of the rat fundus strip. International Journal of Quantum

Chemistry: Quantum Biology Symposium 1: 159-167 (1974)

JOHNSON, J.C. and CLOUET, D.H. Studies on the effect of acute and chronic

morphine treatment on catecholamine levels and turnover in discrete brain

areas of rats. Federation Proceedings 32: 757 (1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

280
JONAS, W. and SCHEEL-KRÜGER, J. Amphetamine induced stereotyped behavior

correlated with the accumulation of 0-methylated dopamine. Archives

internationales de Pharmacodynamie et de Therapie 177: 379-389 (1969)

For abstract, see Section II. Drug Chemistry and Metabolism.

JONAS, W. and SCHEEL-KRÜGER, J. Pharmacological studies on tetrabenazine induced

excited behaviour of rats pretreated with amphetamine or nialamide. Archives

internationales de Pharmacodynamie et de Therapie 206: 47-65 (1973)

Tetrabenazine (50 mg/kg) injected 1 h after various doses of

amphetamine (0.25-10 mg/kg) produced a 5-10 times potentiation of the

amphetamine-induced gross behavioural effects in rats: locomotion, rearing

and stereotyped activities. However, the amphetamine-tetrabenazine excitation

was shortlasting, 6-36 min dependent on the amphetamine dose. Tetrabenazine

(50 mg/kg) injected after cessation of the amphetamine excitation (i.e. 4 h

after 5 mg/kg amphetamine) was also able to reinduce a shortlasting and typical

amphetamine-like stimulation lasting 12-18 min. Neuroteptic drugs with dopamine

receptor blocking properties haloperidol, perphenazine and spit-amide produced

in very small doses complete inhibition of all behavioural effects in the amphetaminetetrabenazine reversal test, whereas noradrenaline receptor blocking drugs aceperone

and phenoxybenzamine in very high doses only produced partial inhibition of the

locomotor and rearing activities. Scopolamine increased the tetrabenazine reversal

effect. A single, relatively low, dose of alpha-methyltyrosine (100 mg/kg)

produced no inhibition of the amphetamine-tetrabenazine excitation, whereas high

repeated doses of alpha-methyltyrosine ( 2X350 mg/kg) or reserpine (7.5 mg/kg)

produced complete inhibition of the amphetamine-tetrabenazine excitation.

The present studies indicate that the strong potentiation effect of tetrabenazine

in amphetamine pretreated rats is dependent on a tetrabknazine-induced release

of the catecholamines from a reserpine sensitive storage pool to an extragranular

pool available for amphetamine release. The excitation produced by nialamidetetrabenazine was found very longlasting but not as strong and intense in

appearance as after amphetamine. The nialamide-tetrabenazine excitation was

potentiated by scopolamine, completely antagonized by the dopamine antagonist

spiramide and partially antagonized by the noradrenaline antagonists, aceperone

and phenoxybenzamine.

JONES, R. Significance and characteristics of drug dependence: Characteristics

of drug dependence to cannabis. Chemical and Biological Aspects of Drug

Dependence. Edited by S. J. Mule and H. Brill. Cleveland, Ohio:

Chemical Rubber Company Press. 1972. Pp. 65-81.

JONES, R.T. and STONE, G.C. Psychological studies of marijuana and alcohol in man.

Psychopharmacologia 18(1): 108-117 (1970)

Regular users of marijuana (cannabis sativa) were given smoked and

orally administered marijuana, a placebo, or alcohol. They were unable to

distinguish between smoked marijuana and the tetrahydrocannabinol-free

placebo. The oral administration of tincture of cannabis produced primarily

dysphoric symptoms and was similar to alcohol in this respect. The smoked

marijuana altered pulse rate, time estimation, and EEG, but had no effect

on a measure of field dependent or on a digit symbol substitution task. Both

drugs appeared to be mild intoxicant in a laboratory setting. Consideration

of the dose, prior experience with drugs, setting, and possible cross

tolerance of marijuana and alcohol are important in evaluating the

significance of the clinical effects.

281
KALLMAN, M.W. and ISAAC, W. The effects of age and illumination on the dose-response

curves for three stimulants. Psychopharmacologia (in press)

KANG, S. and GREEN, J.P. Correlation between activity and electronic states of

hallucinogenic amphetamines. Nature 226(5246): 645 (May 16, 1970)

KANG, S. and GREEN, J.P. Steric and electronic relationships among some hallucinogenic

compounds. Proceedings of the National Academy of Sciences 67(1):

62-67 (September, 1970)

For abstract, see Section II. Drug Chemistry and Metabolism.

KANG, S., SESSA, G. and GREEN, J.P. Spectroscopic observations of synaptosomal

membranes: The effect of morphine. Research Communications in Chemical

Pathology and Pharmacology 5(2): 359 (March, 1973)

KARLER, R., CELY, W. and TURKANIS, S.A. The anticonvulsant activity of

cannabidiol and cannabinol. Life Sciences 13: 1527 (1973)

The anticonvulsant activity of delta-9-tetrahydrocannabinol was

compared with that of two other naturally occurring cannabinoids.

cannabidiol and cannabinol, in a maximal electroshock test in mice. The

drugs were administered as an emulsion of sesame seed oil, Tween 80

and saline to mice i.p. The results indicate that all three cannabinoids are

effective anticonvulsants. The time for peak effect is about 2 hr. In terms

of relative potencies, cannabidiol and delta-9-THC are similar but both

of them are more active than cannabinol.

KARLER, R., CELY, W. and TURKANIS. S.A. Anticonvulsant activity of delta-9-

tetrahydrocannabinol and its 11-hydroxy and 8-alpha, 11-dihydroxy metabolites

in the frog. Research Communications in Chemical Pathology and Pharmacology

9(3): 441-452 (November, 1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

KARLER, R. CELY, W. and TURKANIS. S.A. Anticonvulsant properties of delta9-tetrahydrocannabinol and other cannabinoids. Life Sciences 15: 931 (1974)

Anticonvulsant doses of delta-9-tetrahydrocannabinol (delta-9-THC)

markedly lower body temperature in mice at an ambient temperature of 22°

C, but there is little such effect at 30° C. The anticonvulsant properties of

delta-9-THC are as follows: The drug abolishes hind-limb extension in a maximal

electroshock (MES) test, elevates both the MES (extensor) and 6-Hz-electroshock

thresholds, exerts no effect on the 60-Hz-electroshock threshold, and enhances

minimal seizures caused by pentylenetetrazol. All anticonvulsant properties

studied, with the exception of the 60-Hz-electroshock threshold, were unaffected

by the hypothermia resulting at 22° C. Additional experiments with delta-9-THC

indicated that chronic treatment results in the development of tolerance,

as determined by the MES test with rats. The four principal naturally occurring

cannabinoids, delta-9-THC, delta-8-THC, cannabinol and cannabidiol, display

anticonvulsant activity, as does the major, primary metabolite of delta-9-THC,

11-hydroxy-delta-9-THC. Of all agents investigated in mice, the synthetic

cannabinoids, dimethylheptylpyran and its isomers, are the most potent

anticonvulsants. The results of a study of the relative motor toxicity and

anticonvulsant activity of the cannabinoids demonstrate that these properties

are at least partially separable among the various agents.

282
KARLER, R., CELY, W. and TURKANIS, S.A. A study of the development of tolerance

to an anticonvulsant effect of delta-9-tetrahydrocannabinol and cannabidiol.

Research Communications in Chemical Pathology and Pharmacology 9(1): 23

(September, 1974)

Tolerance to delta-9-tetrahydrocannabinol, cannabidiol, diphenylhydantoin and phenobarbital was studied with a maximal. electroshock test

in mice. Tolerance to all four drugs developed very rapidly. Hexobarbital

sleep times of animals tolerant to delta-9-tetrahydrocannabinol and phenobarbital

were unchanged; whereas cannabidiol tolerance was accompanied by an increase,

and diphenylhydantoin tolerance by a decrease in sleep time. In addition, crosstolerance between the two cannabinoids and diphenylhydantoin and phenobarbital

was demonstrable. These results suggest that the mechanism of tolerance to

the cannabinoids’ nticonvulsant effect in mice is probably dependent upon an

adaptation of the central nervous system.

KARLER, R., CELY, W. and TURKANIS. S.A. A study of the relative anticonvulsant

and toxic activities of delta-9-tetrahydrocannabinol and its cogeners.

Research Communications in Chemical Pathology and Pharmacology 7(2):

353 (February, 1974)

The relative anticonvulsant and toxic activities of delta-9-tetrahydrocannabinol

were compared with those of cannabidiol and dimethylheptylpyran. Anticonvulsant

activity was determined in a maximal electroshock test and toxicity in a bar-walk

test. The data were expressed in terms of protective indices (TD50/ED50). The

results indicate that the anticonvulsant and toxic properties of these cannabinoide

are separable. The order of relative toxicity was dimethylheptylpyran greater

than delta-9-tetrahydrecannabinol greater than cannabidiol.

KAUFMAN, J.J. Quantum chemical and theoretical techniques for the understanding of

psychoactive drugs and narcotic agents. Proceedings of the International

Conference on Computers in Chemical Research and Education. Ljublajana,

Yugoslavia (in press)

KAUFMAN, J.J. and KERMAN. E. Quantum-chemical and theoretical techniques for

the understanding of the action of drugs which affect the central nervous system.

Jerusalem Symposia on Quantum Chemistry and Biochemistry 6: 524-547 (1974)

A method (sensitivity 1-2 ng/ml) for the estimation of methadone-3H

(sp. act. 5 mu-Ci/ma) from biological materials provided recoveries of 95-99%.

Following a 10 mg/kg s.c. injection to male Wistar rats, peak plasma levels of

1.1-1.2 mu-g/ml were obtained at 30 min. to 1 hr. The levels declined to 10

ng/ml at 24 hr. and were barely detectable at 48 hr. Peak brain conc. at

30 min. to 1 hr. ranged between 3.8-4.5 mu-g/g. Extensive localization of drug and

metabolites occurred in lung (66.7 mu-g/g), duodenum (34.2 mu-g/g). kidney

(19.7 mu-g/g), liver (18.6 mu-g/g) and heart (11.7 mu-g/g) hr. after injection.

Extractable radioactivity was detected in brain and other tissues 3 weeks after

injection. Excretion of methadone and metabolites in urine and feces was slow,

and prolonged with approx. 25-30% of the dose accounted for in 48 hr. The

distribution profile after oral administration (10 mg/kg) was qualitatively

similar to that after s.c. injection, however, peak plasma and brain levels were

approx. 1/10 and 1/25 of those obtained after s.c. administration, respectively.

Methadone and metabolites persisted in the duodenum and other tissues ‘for

more than 1 week. Besides 2-ethylidene-1,5-dimethyl-3.3-diphenyl pyrrolidine,

evidence for the formation of 1 nonconjugated and 3 glucuronide conjugated

urinary metabolites was obtained on column and thin layer chromatography.

283
KAUFMAN, J.J., KERMAN. E. and KOSKI, W.S. Quantum chemical, other theoretical

and physicochemical studies on narcotics and narcotic antagonists to understand

their mechanism of action. International Journal of Quantum Chemistry -

Symposia Issue 1: 289 (1974)

The topological and topographical requisites for effective narcotic and

narcotic antagonist action are outlined. Quantum chemical calculations by several

methods have been carried out for these drugs. CNDO/2 and PCILO results

are compared for morphine and nalorphine, both for the free bases and the

protonated forms. CNDO/2 results are presented for some additional

narcotics and narcotic antagonists: naloxone, cyclazocine and methadone. The

CNDO/2 calculated electron densities on the nitrogens are very close in the

free bases of the N-methyl and the N-ally1 congeners and they are also very

close in the protonated forms of these compounds, contrary to the assumption

usually held by chemists that the electron density on the nitrogen is lower in

the allyl compound which is what makes it a weaker base. Also, as we first

showed many years ago for pyridine aldoximes the positive charge in the N-protonated

species is not localized on the nitrogen but spread over many of the neighboring

atoms. Both of the above results on the charge distributions on the nitrogens

were experimentally given credence by the ESCA results of Carlson and

Saethre.

KAUFMAN, J.J. and KOSKI, W.S. Physicochemical, quantum chemical and other

theoretical techniques for the understanding of the mechanism of action of CNS

agents: Psychoactive drugs, narcotics and narcotic antagonists and anesthestics.

Drug Design, Vol. V. Edited by E. J. Ariens. New York: Academic Press,

1971.

KAUFMAN, J.J., SEMO, N.M. and KOSKI, W.S. Microelectrometric titration

measurement of the pKa's, partition and drug distribution coefficients of

narcotics and narcotic antagonists and their pH and temperature dependence.

Journal of Medicinal Chemistry (in press)

The pKa's, partition coefficients and drug distribution coefficients

(apparent partition coefficients) have been investigated for a number of narcotics

and where possible for their congener narcotic antagonists. These studies were

carried out by a microelectrometric titration technique as a function of temperature

and pH. This method enables one to determine not only the dissociation

constants to deconvolute overlapping pKa's, but also to determine the

solubilities and oil-water distribution of these various drugs.

KAYMAKCALAN, S. and DENEAU, C.A. Some pharmacological effects of synthetic

delta-9-THC. The Pharmacologist 13(2): 247 (1971)

THC produced analgesia in Sprague Dawley rats (ED50 10.1 mg/kg

s.c.) as determined by the hot-plate technique. A single s.c., dose of 10 mg/kg

produced tolerance which persisted for more than 1 month. The analgesic

effect of a combination of THC and morphine in rats was greater than additive. In

cats, vocalizations resulting from i.p. injections of phenylquinone or acetic acid

were reduced 65-85% with 1 mg/kg THC s.c. 1 mg/kg THC s.c. reduced the

motor activity of cats but enhanced the excitatory effect of morphine. SKF 525A

increased (not statistically significant) the analgesic effect of THC in rats and

hepatectomized rats showed a significantly greater effect than sham-operated

controls indicating that THC itself, and not a metabolite is, the active drug. A

single dose of 10 mg/kg THC s.c. reduced I

125 uptake by the rat thyroid by 27%

at 4 hours but repeated doses of THC (10 mg/kg qbh) did not affect 24-hour

I

125 uptake. THC produced hypothermia in rats, cats, dogs and monkeys and

bradycardia in cats. dogs and monkeys.

284
KELLY, R.J. and BURKS, T.F. Relative vasoconstrictor potencies of norepinephrine,

alpha-methylnorepinephrine and octopamine. Archives internationales de

Pharmacodynamie et de Therapie 208(2): 306 (April. 1974)

Blood pressure responses to l-norepinephrine, l-alpha-methylnorepinephrine and dl-octopamine were measured in anesthetized dogs. Alpha-methylnorepinephrine was 0.3 as potent as norepinephrine in raising blood pressure,

octopamine was 0.02 as potent. These potency ratios applied under control

conditions, after cholinergic blockade and after beta adrenergic blockade.

Vasoconstrictor responses were measured in dog isolated mesenteric arteries.

Again, alpha-methylnorepinephrine was 0.3 as potent as norepinephrine,

octopamine was only 0.002 as potent as norepinephrine. Both alpha-methylnorepinephrine and octapamine responses were antagonized by phentolamine and

enhanced by cocaine. The slight difference in potency between alpha-methylnorepinephrine and norepinephrine may be insufficient to explain completely the

hypotensive properties of alpha-methyldopa. Octopamine could, however,

serve as a false adrenergic neuro-transmitter substance.

KENNEDY, D.K., GRUBB, M.N. and BURKS, T.F. Antagonism of methadone’s

intestinal effects by cyproheptadine. Gastroenterology 66: 396-402 (1974)

The narcotic agonist methadone increases the amplitude of intestinal

phasic contractions and can retard intestinal propulsive activity. Like

morphine, methadone may produce its intestinal effects by release of local

5-hydroxytryptamine (5-HT). The ability of the 5-HT receptor blocking

agent cyproheptadine to antagonize the intestinal effects of methadone

was evaluated in vitro and in vivo. In vascularly perfused segments of dog

isolated intestine, cyproheptadine decreased the stimulatory effect of

methadone and 5-HT, but not the effect produced by bethanechol, a cholinergic

agonist. Atropine decreased responses to methadone, 5-HT, and bethanechol

because one component of 5-HT action is mediated by intramural cholinergic

nerves. Cyproheptadine also antagonized the methadone-induced reduction in

transit of test meals in mice. The LD50 of methadone was not altered by

cyproheptadine. The ability of a 5-HT blocking agent to antagonize the

intestinal effects of methadone suggests a potentially useful means of

overcoming one of the troublesome side effects of the narcotic drugs;

KERR, F. W. Morphine self-administration in dependent monkeys: Reduction by

hypothalamic lesions. IRCS International Research Communications System

(73-12) 7-1-6

KERR, F.W. The role of the lateral hypothalamus in morphine dependence.

Narcotics and the Hypothalamus. Edited by E. Zimmermann and R. George.

New York: Raven Press, 1974. Pp. 23-24.

285
KERR, F.W. Tolerance to morphine and the bloodbrain-CFS barrier. Federation

Proceedings 33: 528 (1974)

Tolerance to the CNS effects of morphine and other opiates has

never been satisfactorily explained. In this study adult Sprague Dawley

rats were used. The lethal dose of morphine by intraventricular injection

in naive rats was established to be 1 mg. (L.D. 50 was approximately 0. 5

mg while 0.25 mg was compatible with survival) 24 rats were made

tolerant to increasing doses of morphine till at 1 month they were receiving

100 mg twice daily intraperitoneally. Ventricular cannulae were then placed

stereotaxically into the left lateral cerebral ventricle and secured with acrylic.

24 hours later they received either 1 mg or 2 mg of morphine intraventricularly.

These doses of drug were lethal in all cases in which the injection entered

the ventricular system. Pantopaque ventriculography was done in every instance

to confirm correct placement.

These results suggest that tolerance is due to increasing effectiveness

of the blood brain barrier rather than to changes occurring in the neurons

themselves.

KERR, F.W. and POZUELO, J. Suppression of physical dependence and induction of

hypersensitivity to morphine by stereotaxic hypothalamic lesions in addicted

rats and a new theory of addiction. Drug Addiction: Experimental Pharmacology

Vol. 1. Edited by J. M. Singh, L. H. Miller and H. Lal. Mount Kisco, New York:

Futura Publishing Company, 1972.

The basic mechanisms underlying opiate tolerance and addiction have not

as yet been elucidated despite intensive efforts by numerous investigators

employing a wide variety of behavioral, biochemical and immunological

techniques. many of which have been reviewed recently.

The role of the central nervous system in narcotic addiction is paramount,

and it is generally believed that dependence is a result of widespread involvement

of cortical and subcortical centers. The alternative possibility, that opiates

might exert their addictive effects on quite limited nuclear areas of the CNS,

is the subject of this investigation.

The hypothesis to be tested was that narcotic addiction might be an

expression of disordered function of centers which control intake of solids or

liquids and thus comparable to a pathological type of hunger or thirst. Since

the centers which regulate these functions are located in the hypothalamus

the hypothesis could be subjected to experimental investigation along the lines

to be described.

An extensive review of the literature has failed to reveal any previous

report of suppression of physical dependence on opiates: a preliminary report

on this work has been made.

286
KERR, F.W., TRIPLETT, J.N., JR., and BEELER, G.W. Reciprocal (push-pull)

effects of morphine on single units in the ventromedian and lateral hypothalamus

and influences on other nuclei: With a comment on methadone effects during

withdrawal from morphine. Brain Research 74: 81-103 (1974)

The effects of morphine and of its antagonists naloxone and nalorphine

on multiple single units recorded simultaneously in the ventromedian nucleus

(VMN) and in the lateral hypothalamic area (LHA) and certain other neuronal

groups were investigated in naive and morphine dependent adult Sprague-Dawley

rats using pulse height analysis techniques and computer generated firing frequency

histograms.

Morphine produced diametrically opposite effects on VMN and LHA in

both naive and dependent animals: with the exception of a few units, neurons

recorded from the VMN were excited by morphine and. conversely, those in

LHA were inhibited; the antagonists naloxone and nalorphine produced clearcut reversal of these effects. During withdrawal phases in addicted animals,

firing rates in the LHA were greater than rates recorded in the same area

of naive animals; no significant differences between firing rates in the VMN of naive

and addicted animals were observed.

Methadone effects were investigated in morphine dependent rats in

withdrawal; both VMN and LHA neurons were excited by methadone and the

effect of morphine on these nuclei was reversed.

The possible implications of these observations for localization of

mechanisms in opiate dependency and for the concept of methadone blockade

are discussed.

KHALSA, J.H. and DAVIS, W.M. Effects of chronic alpha-methyltyrosine on the

locomotor activity response to morphine and amphetamine in rats.

The Pharmacologist 15(2): 219 (1973)

Two groups (36 each) of male Wistar rats weighing ca. 230 g.

were treated ip with either L-alpha-methyl-p-tyrosine (AMT; 50 mg/kg.

suspended in saline) or saline (SAL) twice daily for 15 or 18 days. Rats

from each group were treated with either SAL, morphine sulfate (MS;

5 mg/kg, ip), or d-amphetamine sulfate (AS; 1 mg/kg, ip) 4 h after the a.m.

dose of AMT on days 1, 3, 6, 9, 12, 15 and 18 of AMT treatment and at 28, 52

or 96 h after the last AMT dose. Locomotor activity was recorded for 2 h

immediately after SAL, MS or AS. Tolerance developed to the blocking

action of AMT on MS-induced hypermotility within the first 6 days. Such

tolerance was not seen toward the AMT antagonism of AS-induced hypermotility.

After AMT was discontinued, motility was significantly higher in AMT-MS

rats than in SAL-MS rats following a single further dose of MS, suggesting

an induction of CNS supersensitivity to the stimulatory action of MS.

However, such supersensitivity to the action of AS following withdrawal

of AMT, as reported by Beuthin et al. (J. Pharmacol. exp. Ther. 181: 446, 1972)

for rats receiving chronic oral AMT, was not observed by us.

287
KHALSA, J.H. and DAVIS, W.M. Inhibition of motility response to morphine

or d-amphetamine and of feeding behavior in rats by U-14,624.

Federation Proceedings 33: 564 (1974)

We have extended our previously reported study with chronic

alpha-methyltyrosine, a tyrosine hydroxylase inhibitor by using a dopamine-beta-hydroxylase inhibitor, U-14,624 (U), 1-phenyl-3-

(2-thiazolyl)-2-thiourea. Chronic treatment of two groups of rats

(36 each) with U (25 mg/kg ip once daily) prevented the hypermotility induced

in rats by morphine sulfate (MS; 5 mg/kg, ip) when tested at 6 hrs. after

U on days 1, 3, 6, 9, 12, 15, or 18. Tolerance developed to the blocking effect

of U on hypermotility induced by d-amphetamine sulfate (AS: 1 mg/kg. ip)

within 9 days. Such tolerance was not seen towards the U-antagonism of

MS-induced hyperactivity. Withdrawal from chronic U treatment produced

no supersensitivity to the CNS stimulant actions of either MS or AS at

30, 56, 78 or 102 hrs. after the last dose of U. Single ip or po doses of U

(25 mg/kg) did not inhibit feeding behavior or spontaneous locomotor

activity. However, doses of 50 or 75 mg/kg either ip or po, which

inhibited locomotor activity also reduced food intake significantly for 3

days after a single treatment.

KHAZAN, N. Declining levels of electrocorticogenesis and their response to morphine

in the morphine dependent rat. Federation Proceedings 29(2): 781 (1970)

In pursuing earlier studies on EEG-EMG correlations of

behavior during morphine addiction in the rat (Khazan, et al., J. Pharmacol.

Exp. Therap., 155: 521, 1967), electrocorticogenesis. the integrated or

mean voltage output of the electrocorticogram, was investigated along with

longitudinal EEG-EMG tracings. Morphine sulphate, 1.25 mg/kg. was

automatically injected, i.v., every hour for 24 hours. The dose was increased

each succeeding day to 2.5, 5, 10 and 20 mg/kg per hour respectively. This

preparation induced a state of morphine dependence in these rats. It was

found that an almost immediate and progressive increase of the levels of

electrocorticogenesis followed morphine injections, accompanied by a marked

decrease in viciousness and irritability of the rat. When morphine

injections were discontinued, a progressive fall in the EEG electrogenesis

occurred which was then followed by arousal, irritability and “wet dog”

withdrawal symptoms. It is assumed that along with the development of

“behavioral” tolerance and physical dependence to morphine, an “EEG”:

suppressant mechanism develops to counteract the acute EEG -deactivation

effects of morphine and which then dominates in the morphine dependent

rat. Thus, with a quantitative approach to the study of the longitudinal EEG

output, the existence of low levels of electrocorticogenesis in the morphine

dependent rat following morphine withdrawal was revealed.

KHAZAN. N. EEG correlates of morphine dependence and withdrawal in the rat.

Drug Addiction: Experimental Pharmacology Vol. 1. Edited by J.M. Singh,

L.H. Miller and H. Lal. Mount Kisco, New York: Futura Publishing

Company, Inc. 1972. Pp. 159-172.

For abstract, see Section I. Methodology of Drug Research.

288
KHAZAN, N. EEG-EMG studies of morphine-like narcotics and antagonists.

Journal de Pharmacologic 5(Supplement): 506 (1974)

Adult female rats were implanted with chronic electrodes to

record the cortical EEG and the temporalis muscle EMG, as well as with i.v.

cannulas for drug administration. The induction of EEG slow bursts by

morphine, methadone and l-alpha-acetyl-methadol. and also by the morphine

antagonist, nalorphine. was demonstrated. In contrast, the “pure” morphine

antagonists, naloxone and naltrexone, which blocked morphine’s EEG and

behavioral effects, failed to induce these same changes when given alone.

The longitudinal monitoring of EEG-EMG and sleep-awake activity of the

control. dependent. and abstinent rat enabled thorough characterization of

tolerance and physical dependence. the drug-seeking behavior, and immediate

and protracted abstinence. The study of the EEG and behavioral correlates

of acute and long-term effects of morphine and methadone provided further

support for analogous states of dependence and abstinence produced by these

narcotics. This animal model should be helpful in the evaluation of the efficacy

and duration of action of narcotic antagonists in blocking relapse in the postaddict rats self-administering morphine.

KHAZAN, N. Electrophysiological correlates of the action of drugs in the brain.

Introduction to Psychopharmacology. Edited by R.H. Rich and K.E. Moore.

New York: Raven Press, 1971.

1970.

KHAZAN, N. Longitudinal EEG study of the effects of morphine injections and withdrawal

in the morphine dependent rat. Committee on the Problems of Drug Dependence.

Washington, D.C.: National Academy of Sciences, National Research Council,

We previously reported on electroencephalographic (EEG).

electromyographic (EMG), and behavioral correlates of the rat during cycles of

dependence to morphine, self-injected on a fixed ratio schedule. EEG “slow

bursts” of four to seven Hz were noted during the development of morphine tolerance

and physical dependence, when rats received hourly injection of the drug. The

animals then learned to bar press for morphine self-injection. Inter-injection

intervals lasted about two to, three hours at FR 20 schedule. During this stage

of self-maintained addiction, the EEG “slow bursts” appeared immediately

after morphine injection, becoming more frequent within 20 to 30 minutes

and disappearing before the following injection. Furthermore, the longitudinal

EEG-EMG collected elicited prolonged episodes of sleep interrupted by

frequent and unusually long rapid-eye-movement (REM) sleep which predominated

prior to morphine self-injection, followed by wakefulness thereafter, and upon

withdrawal, no EEG “slow bursts” appeared.

Recently, we constructed a modified experimental set-up whereby

EEG-EMG tracings. from five freely moving rats with chronically implanted

electrodes and iv cannulae. could be collected simultaneously and analyzed

for the EEG-frequency and energy content. We have undertaken the present

investigation in an attempt to expand our earlier findings on the EEG-EMG and

behavioral aspects of morphine dependence and withdrawal in the rat.

289
KHAZAN, N. and BROWN, P. Differential effects of three tricyclic antidepressants

on sleep and REM sleep in the rat. Life Sciences 9(Part I): 279-284 (1970)

The closely related dibenzazepine antidepressants desipramine

(Pertofran), imipramine (Tofranil) and trimipramine (Surmontil), have

been reported to possess different drug profiles while retaining their

antidepressant property. Desipramine shows the highest degree of psychomotor

activation with almost no sedative anti-anxiety component, whereas trimipramine

has the richest anxiety reducing property with no psychomotor activation.

Both of these properties are moderately displayed by imipramine.

In addition, trimipramine shows no anti-reserpine effect, while this activity is

easily demonstrated by both imipramine and desipramine.

The differences in the pharmacociynamic and clinical drug profiles

of the above antidepressants, and the currently disputed role of Rapid Eye

Movement (REM) sleep in depression, prompted the present comparative

study of their effects on REM sleep.

KHAZAN, N. and BROWN, P. REM sleep blocking effects of imipramine and

trimipramine in the rat. The Pharmacologist 11: 780 (1969)

Imipramine (Tofranil) and trimipramine (Surmontil) are closely

related dibenzazepines. Unlike imipramine, trimipramine was shown to be

ineffective in reversing the reserpine syndrome and, clinically was described

as an antidepressant with psychomotor sedative “anxiolytic” component. This

study was carried out in an attempt to investigate further the REM sleep

suppressant properties of psychotropic drugs. Rats with chronic cortical and

neck muscle electrodes were used. EEG-EMG tracings were collected from

the freely moving rats for a period of 5 to 10 hours. Imipramine and trimipramine

were given i.p. in doses of 5. 10 and 20 mg/kg. Saline treated rat showed an

average of 1.5 to 2 REM sleep episodes per hour. Imipramine treatment

resulted in a significant suppression of REM sleep episodes while sleep-awake

alternation was left intact. On the other hand, trimipramine showed no

blocking effect on REM sleep even at the highest dose. Thus, imipramine

which has been shown to have relatively high anti-reserpine activity and weak

anti-anxiety activity, suppresses REM sleep, whereas, trimipramine,

which has low anti-reeerpine activity and high anti-anxiety activity, does not

suppress REM sleep.

KHAZAN, N. and COLASANTI, B. Decline in the mean integrated electroencephalogram

voltage during morphine abstinence in the rat. The Journal of Pharmacology

and Experimental Therapeutics 177(3): 491 (1971)

Direct, voltage-integrated and frequency-analyzed cortical electroencephalograms (EEG’s) as well as integrated electromyograms were obtained

from control, morphine-dependent and abstinent rats prepared with chronically

implanted cortical electrodes and i.v. cannulas. Morphine sulfate, 1.25 mg/kg

was injected automatically every hour for 24 hours during the first day. This

dose was increased on successive days to 2.5, 5, 10 and 20 mg/kg/hr. resulting

in the induction of a state of morphine dependence in the rats. When morphine

injections were discontinued, the behavioral manifestations of the abstinence

syndrome became evident. During this period, a decline in the mean integrated

EEG voltage prevailed throughout the sleep-awake cycle. This drop of the EEG

voltage output reached levels 35 to 70% below those of control. The lowered

290
Khazan, N. and Colasanti, B. Decline in the mean . . . continued

voltage output of the awake state EEG endured for two to three days. The

reduction of the EEG voltage output of the sleep’ state, however, was more

pronounced and longer lasting, with recovery reached by the fourth or fifth

day of abstinence. Morphine injections given during the abstinence

syndrome produced an immediate rise in the low voltage output: this

rise was accompanied by a marked decrease in the irritability and arousal

of the abstinent rat. It is suggested that the lowered voltage output of the

EEG during morphine abstinence is the product of a central nervous system

mechanism developed to counteract the acute effects of morphine as to

synchronization of the EEG.

KHAZAN, N. and COLASANTI, B. Differential pharmacodynamics of morphine injection

in naive and postaddict rats; EEG correlates. Federation Proceedings

30: 277 (1971)

High voltage EEG slow bursts have been reported to follow morphine

administration in experimental animals and in man. The present study has been

undertaken to explore the possible existence of “long-term” morphine effects

in post-addict rats in comparison with naive rats in EEG terms. Adult

female Sprague-Dawley rats prepared with chronically implanted cortical and

temporal muscle electrodes and i.v. cannulae were used. Morphine injections

of 10 mg/ kg were given i.p. to naive rats and to post-addict rats at successive

intervals following morphine withdrawal. These intervals extended in a

few cases up to one year. In the naive rat, high voltage EEG slow bursts

associated with stuporous behavior appeared almost immediately after injection

and prevailed for 60 to 90 minutes. This phase was followed by continuous EEG

and behavioral arousal for another period of 60 to 90 minutes, after which

sleep appeared. In contrast, morphine challenge to post-addict rats was

followed by an EEG and behavioral arousal for as long as 180 minutes, the

degree of which was less pronounced at the longer intervals following withdrawal.

The EEG and behavioral arousal of the post-addict rat in response to morphine

challenge is reminiscent of similar responses in human post-addicts already

reported and may further emphasize the pharmacodynamic factors in morphine

addiction.

KHAZAN, N. and COLASANTI, B. EEG correlates of morphine challenge in post-addict

rats. Psychopharmacologia 22: 56 (1971)

Adult female Sprague-Dawley rats were prepared with chronically

implanted cortical and temporal muscle electrodes and i.v. cannulae. Morphine

injections of 10 mg/kg were given i.p. to naive rats and to post-addict rats at

successive intervals following morphine withdrawal. These intervals extended

in a few cases up to one year. In the naive rat, high voltage EEG slow

bursts associated with stuporous behavior appeared almost immediately after

injection and prevailed for 60-90 min. This phase was followed by continuous

EEG and behavioral arousal for another period of 60-90 min. after which sleep

appeared. In contrast, morphine challenge to post-addict rats was followed by an

EEG and behavioral arousal for as long as 180 min, the degree of which was less

pronounced at the longer intervals following withdrawal. The EEG and behavioral

arousal of the post-addict rat in response to morphine challenge is reminiscent

of similar responses in human post-addicts already reported and may further

emphasize the pharmacodynamic factors in morphine addiction.

291
KHAZAN, N. and COLASANTI, B. Protracted rebound in rapid eye movement sleep

time and electroencephalogram voltage output in morphine dependent

rats upon withdrawal. The Journal of Pharmacology and Experimental

Therapeutics 183(1): 23 (1972)

Rats prepared with chronic electrodes for recording the direct and

voltage-integrated cortical electroencephalogram (EEG) as well as the

integrated electromyogram were made dependent on morphine by its

administration through chronic indwelling i. v. cannulas. Injections of

morphine sulfate were given automatically at an initial dose of 1.25 mg/kg/hr

for 24 hours. This dose was increased on successive days to 2.5, 5, 10

and 20 mg/kg/hr respectively. After maintenance of the rats on the highest

dose for two days, the injections were discontinued. EEG and electromyogram

recordings monitored continuously revealed a suppression of rapid eye movement

(REM) sleep during morphine administration at the progressively increasing

doses; on the second day of the 20 mg/kg/hr dose, however, the

duration of REM sleep returned to the control base-line value. The mean

EEG voltage output of REM sleep episodes within these two days showed a

slight but significant reduction. Within the first four to six hours after the

withdrawal of morphine, the duration of REM sleep was significantly enhanced.

After this initial elevation, both the duration and the mean EEG voltage output

of REM sleep episodes declined to minimal levels during the remainder of the first

day of withdrawal and remained below the control base-line values up to the

third day. A significant rebound then occurred in both pamareters, during which the

REM EEG voltage output was significantly elevated until the sixth or ninth day

after withdrawal, while the rebound in REM time remained evident up to the

12th day. The increases in REM sleep time during this period of morphine

abstinence extended to twice the REM rebound normally expected to follow

REM deprivation by other means.

KHAZAN, N. and ROEHRS, T. EEG responses to morphine test dose in morphine

and methadone treated rats. The Pharmacologist 15: 168 (1973)

We have reported that EEG responses to a test dose of morphine

are markedly different in rats previously exposed to morphine from those

in naive rats. In the present study, methadone is evaluated in a similar

manner. After implantation with chronic electrodes for recording of the EEG

and EMG, two groups of five rats each were given an i.p. dose of either 10 mg/kg

morphine or 2 mg/kg methadone, respectively. A second injection at the same

dose level was administered one week later. A third group of five rats were

simultaneously treated with isotonic saline. Ten days after the last injection,

all rats were given an i.p. test dose of 10 mg/kg morphine. In the salinetreated rats, this morphine injection induced high voltage EEG slow bursts in

association with stuporous behavior appearing almost immediately and prevailing

for 60 to 90 minutes Such administration to the rats having prior exposure to

either morphine or methadone, however, resulted in a significant shortening of

this period of EEG slow bursts and the stuporous phase by 50 to 75%. These EEG

findings suggest comparable and long-lasting CNS effects produced by these

narcotics.

KHAZAN, N. and ROEHRS, T. Methadone dependence and abstinence: EEG study in

the rat. Drug Addiction: Neurobiology and Influences on Behavior, Vol III.

Edited by J. H. Singh and h. Lal. New York: Stratton Intercontinental

Medical Book Company, 1974.

The present EEG study was undertaken to compare states of dependence

and abstinence in methadone and morphine treated rats and to assess the

possible existence of a protracted REM sleep rebound in the methadone abstinent

rat similar to that which has been reported tn the morphine withdrawn animal.

292
KIMIZUKA, H. and ABOOD, L.G. Interfacial adsorption of psychotomimetic drug using

liquid scintillation. Journal of Pharmaceutical Sciences 62(5): 740-745

(May, 1973)

For abstract, see Section I. Methodology of Drug Research.

KIPLINGER, G.F. and MANNO, J.E. Dose-response relationships to cannabis in

human subjects. Pharmacological Reviews 23(4): 339 (1971)

KLAUSNER, H.A., WILCOX, H.G. and DINGELL, J.V. Investigation of the plasma

binding of tetrahydrocannabinol and other drugs by zonal ultracentrifugation.

Presented at the Fifth International Congress on Pharmacology, San

Francisco, California. 1972.

KNAPP, S. and MANDELL, A.J. Narcotic drugs: Effects on the serotonin biosynthetic

systems of the brain. Science 177: 1209-1211 (1972)

The effects of short- and long-term administration of morphine on

the activity of two measurable forms of rat brain tryptophan hydroxylase were

studied. Morphine administration produced an immediate decrease and a

long-term increase in the nerve ending (particulate) enzyme activity but did

not change the cell body (soluble) enzyme activity. Cocaine administration

demonstrated a short-term decrease in measurable nerve ending enzyme

activity that was due to the inhibition of the high affinity uptake (the Michaelis

constant, Km, is 10-5 molar) of trytophan, the serotonin precursor. Cocaine

did not affect the low affinity uptake (Km= 10-3 molar) of tryptophan. Both the

uptake of the precursor and the enzyme activity appeared to be drug-sensitive regulatory

processes in the biosynthesis of serotonin.

KNAPP, S., MANDELL, A.J. and GEYER, M.A. Effects of amphetamines on regional

tryptophan hydroxylase activity and snaptosomal conversion of tryptophan

to 5-hydroxytryptamine in rat brain. The Journal of Pharmacology and

Experimental Therapeutics 189(3): 676-689 (1974)

For abstract, see Section II. Drug Chemistry and Metabolism,

KOPELL, B.S., TINKLENBERG, J.R. and HOLLISTER, L.E. Contingent negative

variation amplitudes: Marihuana and alcohol. Archives of General Psychiatry

27: 809 (1972)

In a double-blind study, the amplitude of the contingent negative

variation (CNV) was assessed in 12 normal men given placebo and quantified

“social” doses of 1-delta-9-transtetrahydrocannabinol (THC) and alcohol

(ethyl alcohol). Using subjects as their own controls, it was found that

THC selectively enhanced the amplitude as compared to placebo while

alcohol depressed it.

KOPELL, B.S. and WITTNER, W.K. The effects of chlorpromazine and methamphetamine

on visual signal-from-noise detection. Journal of Nervous and Mental Disease

147(4): 418 (1968)

293
KOSERSKY, D.S., DEWEY, W.L. and HARRIS, L.S. Antipyretic, analgesic and

anti-inflammatory effects of delta-9-tetrahydrocannabinol in the rat.

European Journal of Pharmacology 24(1): 1 (1973)

The effects of body temperature produced by graded doses of

delta-9-tetrahydrocannabinol (THC) and phenylbutazone (PB) were compared

in both normal and pyretic rats. Dose related hypothermic responses were

produced in normal animals given THC. THC reduced elevated temperatures

in yeast-induced pyretic rats to near normal levels at doses which exhibited

little hypothermic activity in normal rats. The oral antipyretic potency of

THC was twice that of PB. The oral anti-inflammatory efficacy of THC

was compared with PB and acetylsalicylic acid. THC was ineffective in inhibiting

carrageenin-induced edema of the rat paw following acute or chronic

administration.

KOSTERLITZ, H.W., LESLIE, FM. and WATERFIELD, A.A. Narcotic agonist and

antagonist potencies of a homologous series of N-alkyl-norketobemidones

measured by the guinea pig ileum and mouse vas deferens methods.

Journal of Pharmacology 27: 73-78 (1975)

For abstract, see Section I. Methodology of Drug Research.

KOSTERLITZ, H.W. and WATERFIELD, A.A. An analysis of the phenomenon of

acute tolerance to morphine in the guinea-pig ileum. British Journal of

Pharmacology (in press)

KOSTERLITZ, H.W. and WATERFIELD, A.A. In vitro models in the study of structure

activity relationships of narcotic analgesics. Annual Review of Pharmacology

(in press)

KUBENA, R.K., PERHACH, J.L., JR., and HERBERT, B., III. Corticosterone

elevation mediated centrally by delta-1-tetrahydrocannabinol in rats.

European Journal of Pharmacology 14(1): 89-92 (1971)

For abstract, see Section II. Drug Chemistry and Metabolism.

KUPFER, D.J. and BOWERS, M.B., JR. REM sleep and central monoamine oxidase

inhibition. Psychopharmacologia 27: 183 (1973)

Our preliminary observations on the relationship of sleep and lumbar

CSF acid monoamine metabolite levels suggested a greater decrease in

lumbar CSF HVA as compared to 5HIAA following clinical doses of phenelzine

in the presence of virtually total REM suppression. This report on nine

psychiatric patients confirms these findings in a larger sample and thus

supports an inhibitory role for dopamine or other catecholamines in REM

sleep mechanisms. The drug-withdrawal results indicate that the four patients

with REM rebound showed increases in HVA levels compared to treatment levels,

while the single patient with no REM rebound also had no increase in HVA levels.

294
LABRECQUE, G. and DOMINO, E.F. Tolerance to and physical dependence on morphine:

Relation to neocortical acetylcholine release in the cat. The Journal of

Pharmacology and Experimental Therapeutics 191: 189-200 (1974)

LAHIRI, P.K., LADDU, A.R. and HARDMAN, H.R. Effect of delta-9-THC on the

heart rate of the dog. Federation Proceedings 31: 505 (1972)

LAL, H. and PURI, S.K. Morphine-withdrawal aggression: Role of dopaminergic

stimulation. Drug Addiction: Experimental Pharmacology, Vol 1.

Edited by J. M. Singh, L. H. Miller and H. Lal. Mount Kisco, New York:

Futura Publishing Company, 1972.

The effect of THC, i.v., was studied in conscious (C) and in

anesthetized (A) dogs. In C dogs graded doses of THC ranging from 0.012-

2.0 mg/kg, produced a dose dependent bradycardia. A significant

reduction in HR was observed with doses of 0.05-2.0 mg/kg. In both C

and A groups THC (2 mg/kg) reduced HR equally. The effect of THC was

reduced by pretreatment (PT) with propranolol (P) 2.0 mg/kg but more

so after atropine methyl nitrate (AMN) 0.5 mg/kg. The effect was abolished

after PT with a combination of AMN and P. Similar abolition of effect was

observed after Cl transection of spinal cord. In the isolated supported

heart preparation (ISHP) THC was ineffective.

It is a matter of common knowledge that, epidemiologically, heroin

addiction is related to crimes of violence. However. neither is a cause-and-effect

relationship established; nor is it known whether the violence is incidental to the

methods of procuring heroin or is elicited by neuronal changes caused by heroin

addiction. In order to obtain answers to these questions, we studied aggressive

behaviors in animals made dependent on morphine. This paper will summarize

the data from our laboratory which show that intense aggression can be obtained

in animals during morphine-withdrawal and further suggest that aggression during

morphine-withdrawal is due to the hyperactivity of central dopaminergic receptors.

The role of dopaminergic stimulation in eliciting aggressive behaviors was

suggested in a previous study with non-addicted mice.

LALLEY, P.M. and BAKER, W.W. Local analysis of endogenous cholinergic

tremor mechanisms in the caudate nucleus. The Pharmacologist

9: 253 (1967)

Our group described the cholinergic mechanisms in tremor

resulting from intracaudate injection of carbachol in chronic cats;

this tremor was readily suppressed by locally administered

catecholamines. TO gain insight into the endogenous mechanisms,

acetylcholine (ACh) activity was augmented by intracaudate injection

of DFP or echotheopate (ECHO). Both anticholinesterase induced

tremor of variable intensity and duration which was antagonized by local

injections of epinephrine or dopamine. In contrast to carbachol, DFP

(25-60 mu-g) and ECHO (15-30 mu-g) tremor activity was accompanied

by local electrographic discharges which projected to functionally related

areas. Tremor persisted for days to weeks after a single dose of DFP;

tremorogenic susceptibility to small doses of ACh (10 mu-g) could be

demonstrated even after overt motor activity had declined. Variations

in the intensity and persistence of tremor appear related to fluctuating

levels of intrinsic ACh. Additional factors capable of influencing

local cholinergic activity will be considered. We conclude that critical

imbalances in local metabolic processes regulating the dynamids of ACh,

as well as catecholamines, both can result in tremor.

295
LANG, D.W., DARRAH, H.K., HEDLEY-WHYTE, J. and LAASBERG, L.H. Uptake

into brain proteins of 35S-methionine during morphine tolerance. The Journal

of Pharmacology and Experimental Therapeutics (in press)

LEE, H.K. and WANG, S.C. Mechanism of morphine-induced miosis in the dog.

The Journal of Pharmacology and Experimental Therapeutics (in press)

It was observed that dogs under 50% nitrous oxide and succinylcholine

exhibited a moderately large pupil, maintained a good pupillary light reflex, and

had a relatively high sensitivity to the miotic effects of morphine. A cumulative

dose of 1 mg/kg i.v. of morphine caused marked and sustained miosis in these

animals. Morphine 1 mg was found to have no pupillary effect by intra-ocular

administration. Optic nerve section and cervical sympathectomy did not

interfere with the miotic response in either acute or chronic preparations.

Conversely, a cumulative i.v. dose of 30 mg/kg of morphine failed to cause

pupillary constriction when oculomotor innervation had been interrupted. In

addition, morphine, 0.2 to 0.6 mg/kg i.v., caused marked miosis in dogs

whose occipital lobes or cerebral hemispheres had been removed. These

findings suggest that morphine acts on a subcortical region causing constriction

of the pupil. The possible location was ascertained by unit recording with microelectrodes. It was observed that pupilloconstrictor neurons in the visceral

nuclei of the oculomotor nuclear complex responded to morphine 0.2 mg/kg i.v.,

by increased frequency of discharge. Other neurons in the pupillary light reflex

pathway showed depressed activity. Levallorphan, 0.05 mg/kg i.v., but not

phenylephrine (locally applied to the conjunctival sac) antagonized all of the

actions of morphine on the pupillo-constrictor neurons. The present findings

demonstrate that the miosis induced by morphine is accomplished by an

excitatory action of the narcotic on the visceral nuclei of the oculomotor

nuclear complex.

LEVINE, R., ZAKS, A., FINK, M. and FREEDMAN, A.M. Levomethadyl acetate:

Prolonged duration of opioid effects, including cross-tolerance to heroin in

man. Journal of the American Medical Association 226(3): 316 (October, 1973)

One way to reduce diversion of methadone is to substitute a longacting opioid such as levomethadyl acetate hydrochloride. In male volunteers,

levomethadyl acetate was given three times weekly in increasing dosages,

and blockade to 25 mg intravenously given heroin at 72 hours was determined.

Levomethadyl acetate hydrochloride, 70 mg, was necessary to suppress

subjective discomfort of withdrawal, and 80 mg or more to blockade

pupillary effects. For clinical trials, levomethadyl acetate hydrochloride,

80 mg, three times a week is suggested as a substitute for methadone.

296
LEVY, J.A., MUNSON. A.E., HARRIS, L.S. and DEWEY, W.L. Effects of delta-8-

and delta-9-tetrahydrocannabinol on the immune response in mice. The

Pharmacologist (in press)

Skin graft survival (BDF skin on WYLAR mice) was determined

following treatment with delta-9-tetrahydrocannabinol (THC) bound to

bovine serum albumen (BSA). Delta-9-THC (25-200 mg/kg) was administered

daily by gavage for 7 days prior to and until rejection of skin grafts. Graft

survival for BSA-controls was 16.2 + 0.8 (SEM) days. Delta-9-THC increased

graft survival time 21% to 42% over controls. In studies to determine the

effect of delta-8- and delta-9-THC on IgM response to sheep erthrocytes

(sRBC), drugs were administered orally with and for 7 days following i.p.

injection of 0.1 ml of 20% suspension of sRBC. 200 mg/kg delta-9-THC

reduced the hemagglutanin titer 72% as compared to controls. Similar results

were obtained for delta-8-THC. Treatment of mice with delta-9-THC (25-

200 mg/kg) daily for 7 days did not alter the functional activity of the

reticuloendothelial system as measured by the vascular clearance of colloidal

carbon. Phagocytic indices were .057 + .007 (SEM) for vehicle control

and .049 + .005 for 200 mg/kg delta-9-THC.

LIN, C.H., BRAVERMAN, S., KEINATH, S., TRESK, R. and ADLER, M.W.

Anticonvulsant action of acute morphine administration in rats. Federation

Proceedings (in press)

LIN, S.C., SUTHERLAND, V. C. and WAY, E.L. Brain amino acids in morphine tolerant

and non-tolerant rats. Proceedings of the Western Pharmacological Society

16: 8-13 (1973)

LINTS, C.E. and HARVEY, J.A. Altered sensitivity to foot shock and decreased

brain content of serotonin following brain lesions in the rat. Journal of

Comparative and Physiological Psychology 67: 23-31 (1969)

Rats with lesions in the ventrolateral tegmentum which ablated

50% of the medial lemniscus, the presumed primary projection system

for pain, demonstrated a decreased sensitivity to electric shock as

measured by an 84% elevation of the mean jump threshold. Lesions in

the medial forebrain bundle, septal area, or dorsomedial tegmentum

increased sensitivity to electric shock and decreased brain concentrations

of serotonin. The septal area and dorsomedial tegmentum are strongly

interconnected via the medial forebrain bundle by both ascending and

descending fibers. It was concluded that lesions in this anatomical

system increased sensitivity to electric shock by virtue of their

effects on telencephalic serotonin and that serotonin normally functions

to inhibit effects of a painful stimulus.

LINTS, C.E. and HARVEY, J.A. Drug-induced reversal of brain damage in the rat.

Physiology and Behavior 4: 29-31 (1969)

Lesions in the medial forebrain bundle of the rat produced both an increased

sensitivity to electric-foot shock and a decrease in the telencephalic content of

scrotonin. Administration of DL-5-hydroxytryptophan reversed the effects of the

lesion on shock sensitivity. Only L-5-hydroxytryptophan, the immediate precursor

of scrotonin in brain, was effective. Equimolar dosages of either D-5-hydroxytryptophan or L-dihydroxyphenylalanine had no effect. It was suggested that

sensitivity to a painful stimulus is in part determined by the telencephalic content

of serotonin.

297
LIU, C-T. and ADLER, F.L. Immunological studies on drug addiction. I. Antibodies

reactive with methadone and their use for detection of the drug. Journal of

Immunology 111: 472 (1973)

LOMAX, P., GROSS, S.J. and CAMPBELL, C. Immunological blockade of the

hypothermic effect of delta-9-tetrahydrocannabinol in the rat. Pharmacology and

Thermoregulation. Edited by E. Schenbaum and P. Lan. White Plains,

New York: Abert J. Phiebig, 1973. Pp. 488-490.

LOWNEY, L.I., SCHULZ, K.. LOWERY. P.J. and GOLDSTEIN, A. Extraction of

a mouse brain proteolipid with opiate receptor properties. Committee on the

Problems of Drug Dependence. Washington, D.C.: National Academy of

Sciences, National Research Council, 1974.

LOWNEY, L.I., SCHULZ, K., LOWERY. P.J. and GOLDSTEIN, A. Partial

purification of an opiate receptor from mouse brain. Science 183: 749-753

(1974)

A proteolipid isolated from a lipid extract of mouse brain demonstrates

stereospecific binding properties for levorphanol. It is present only in neuronal

tissue and most abundant in the rhombencephalon. One component saturates at

a concentration corresponding to ma ximum pharmacologic effect in vivo. The

estimated mass is 60,000 daltons per bound opiate molecule.

LYON, M. Rostra1 forebrain lesions in relation to central stimulant and

neuroleptic drug action. Journal de Pharmacologic 5 (Supplement II):

61 (1974)

The relevance of ventrobasal (s. rhinalis) cortex to preservative

responding associated with frontal lesions in rats was assessed by:

(1) neurological examination; (2) water-reinforced, two-lever alternation;

(3) tilt-cage, shock-escape with extra responses punished. D-amphetamine

(2.0 mg/kg) and dopamine (DA) receptor-blocker Spiramide (0,025-0.075

mg/kg) were used posoperatively with tilt animals to assess lesion

effects upon DA -activated systems. Results indicated that, without drugs,

ventrobasal and dorsolateral frontal lesions are not differentiated by

neurological examination or tilt-cage testing, but they may differ on

two-lever alternation. However, in the tilt-cage only the ventrobasal operates

(1) under d-amphetamine gave signif. more punished (extra) responses

than sham operates, (2) under d-amphetamine plus Spiramide (0.075 mg/kg)

reduced responses and shock-free time signif. below control levels.

Neural systems dependent upon DA transmission may be more closely

related to ventrobasal than to dorsolateral frontal cortex.

McAULIFFE, W.E. and GORDON, R.A. A test of Lindesmith’s theory of addiction:

The frequency of euphoria among long-term addicts. American Journal of

Sociology 79(4): 795-840 (January, 1974)

For abstract, see Section I. Methodology of Drug Research.

McCLUNG, R., DAFNY, N. and BURKS, T.F. Effects of morphine and naloxone on

CNS field in unanesthetized rats. Federation Proceedings (in press)

For abstract, see Section I. Methodology of Drug Research.

298
McMAHON, E.M., ANDERSEN, D.K., FELDMAN, J.M. and SCHANBERG, S.M.

Methamphetamine-induced insulin release. Science 174: 66-68 (1971)

Administration of methamphetamine or amphetamine to rats and

mice produces a rapid increase in the level of immunoassayable plasma insulin

not attributable to hyperglycemia. While in the mouse this release of insulin

is followed consistently by a profound hypoglycemia, in the rat this response

is variable. Studies in vitro demonstrate that insulin is released by a direct

effect of methamphetamine on the pancreas.

McMAHON, T., FELDMAN, J. and SCHANBERG, S.M. Further studies of methamphetamineinduced insulin release. Toxicology and Applied Pharmacology (in press)

McMILLAN, D.E. and DEWEY, W.L. On the mechanism of tolerance to delta-9-THC.

Current Research in Marihuana. Edited by M.F. Lewis. New York: Academic

Press, 1972.

McMILLAN, D.E., DEWEY, W.L., TURK, R.F., HARRIS, L.S. and MCNEIL, J.H., JR.

Blood levels of 3H-delta-9-tetrahydrocannabinol and its metabolites in tolerant

and nontolerant pigeons. Biochemical Pharmacology 22: 383-397 (1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

McMILLAN, D.E., FORD, R.D., FRANKENHEIM, J.M., HARRIS, R.A. and HARRIS, L.S.

Tolerance to active constituents of marihuana. Archives internationales de

Pharmacodynamie et de Therapie 198: 132 (1972)

A marked pharmacological tolerance develops to the repeated

administration of a number of behaviorally active cannabinoids. This

tolerance is characterized by a rapid development and by the magnitude of

the effect. Cannabinoid tolerance occurs in a number of species and cross

tolerance among the cannabinoids appears to be widespread. Although the

degree of tolerance development to the cannabinoids resembles that seen with

morphine. we did not observe cross tolerance between morphine and delta-gTHC.

MAICKEL, R.P., BRAUNSTEIN, M.C., McGLYNN, M., SNODGRASS, W.R. and

WEBB, R. W. Behavioral, biochemical, and pharmacological effects of chronic

dosage of phenothiazine tranquilizers in rats. The Phenothiazines and Structurally

Related Drugs. Edited by I.S. Forrest, C.J. Carr and E. Usdin. New York:

Raven Press, 1974.

For abstract, see Section I. Methodology of Drug Research.

MAICKEL, R.P., LEVINE, R.M. and QUIRCE, C.M. Differential effects of d- and

1-amphetamine on spontaneous motor activity in mice. Research Communications

in Chemical Pathology and Pharmacology 8(4): 711-714 (August, 1974)

For abstract, see Section I. Methodology of Drug Research.

299
MAICKEL, R.P. and MALONEY, G.J. Effects of barbital on deprivation-induced water

consumption by rats. Physiology and Behavior 8: 1175-1178 (1972)

I.P., evoked an increase in water consumption. The pretreatment time,

Treatment of water-deprived rats with barbital in doses of 20-160 mg/kg

especially with the largest dose, was critical. Pretreatment of 15 minutes or

less caused an increase in water consumption despite a decreased motor activity;

a 45 min pretreatment time decreased water consumption. while increased

drinking was observed with 8 or 20 hr pretreatments. The content of sodium

in sodium barbital had a significant stimulatory effect on drinking at the 5 min

pretreatment time.

MAICKEL. R.P., ROMPALO, A.M. and COX, R.H., JR. Differential effects of

monoamine oxidase inhibitors. Research Communications in Chemical

Pathology and Pharmacology 8(4): 727-730 (August. 1974)

For abstract. see Section I. Methodology of Drug Research.

MANDELL, A.J. Frontiers in the neurobiology of euphoria. American Handbook of

Psychiatry, Vol. VI. Edited by S. Arieti, D.A. Hamburg and H.K. H. Brodie.

New York: Basic Books, 1972.

For abstract, see Section I. Methodology of Drug Research.

MANDELL, A.J. Neurobiological barriers to euphoria. American Scientist 61(5):

565-573 (September-October, 1973)

The brain seems well equipped to counter chemical perturbation

whether the agent is exogenous (a psychoactive drug) or endogenous (a

natural amine gone awry).

MANDELL, A.J. Neurochemical aspects of narcotic addiction -- A conceptual review.

Proceedings of the Fourth International Conference on Methadone. Edited

by A. Goldstein. New York: NAPAN, 1972.

MANDELL, A.J., editor. New Concepts in Neurotransmitter Regulation. New York:

Plenum Press, 1973.

For abstract, see Section II. Drug Chemistry and Metabolism.

MANDELL, A.J., KNAPP, S. and HSU, L.L. Minireview. Some factors in the

regulation of central serotoenergic synapses. Life Sciences 14: 1-17 (1974)

For a number of years release, reuptake, vesicular storage, and

degradation via monoamine oxidase were the exclusive foci in chemical

studies of the regulation of central serotonergic synapses. This brief

review describes some other factors, including the brain levels of

tryptophan and uptake processes in the nerve ending relevant to the

substrate, the activity and amount of tryptophan hydroxylase in cell

bodies and nerve endings, and a potential regulatable parasynaptic

inactivation process, N-methylation. In chronic and acute drug studies

some of these factors appear to function to compensate for acute

perturbations in central serotonergic synaptic processes.

300
MANDELL, A.J., SEGAL, D.S. and KUCZENSKI, R. Metabolic adaptation to

antidepressant drugs -- A neurochemical paradox. Catecholamines and

Behavior. Edited by A. Friedhoff. New York: Plenum Press, 1974.

MANDELL, A.J., SEGAL, D.S. and KUCZENSKI, R. Metabolic adaptation to antidepressant drugs - Implications for pathophysiology and treatment in psychiatry.

Catecholamines and Behavior. Edited by A. J. Friedhoff. New York:

Plenum Press, 1974.

MANDELL, A.J., SEGAL, D.S., KUCZENSKI, R.T. and KNAPP, S. Amphetamineinduced changes in the regulation of neurotransmitter biosynthetic and receptor

functions in the brain. Pharmacology and the Future of Man, Vol. 1. San

Francisco: Karger, Basel, 1973. Pp. 95-105.

MANNO, B.R. and MANNO, J.E. 11-hydroxy-delta-9-tetrahydrocannabinol induced

changes in the perfused rat heart. Presented at the Meeting of the Society

of Toxicology, Williamsburg, Virginia, Spring, 1975.

For abstract, see Section I. Methodology of Drug Research.

MANNO, B.R. and MANNO, J.E. The marihuana dilemma: Has it been resolved?

Toxicology Annual. Edited by C. L. Winek. New York: Marcel Dekker.

Inc. (in press)

MANNO, B.R. and MANNO, J.E. Some cardiovascular actions of delta-9-tetrahydrocannabinol in the rat. Toxicology and Applied Pharmacology 25: 451 (1973)

For abstract, see Section I. Methodology of Drug Research.

MANNO, J.E. and MANNO, B.R. Cardiovascular actions of 11-hydroxy-delta-9-

tetrahydrocannabinol in the rat. Presented at the Meeting of the Society of

Toxicology, Williamsburg, Virginia, Spring, 1975.

Eleven-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC), dissolved

in a vehicle of 5% ethanol, 1.5% Tween-80 and water (Olsen, et al. (1973)

J. Pharm. Pharmac, 25, 344.) was administered intravenously or subcutaneously

to male, albino rats in doses of 0.025 mg/kg, 0.05 mg/kg and 0.15 mg/kg

Direct arterial blood pressure and heart rate were continuously monitored via

indwelling femoral arterial catheters from the unanesthetized, unrestrained

animals for 90 minutes after drug administration. A similar series of

experiments was conducted to investigate the effect of pretreatment with the

metabolic inhibitor, SKF-525A (beta-diethylaminoethyl diphenylpropylacetate)

administered 30 minutes before the 11-OH-THC.

The administration of 11-OH-THC by either the intravenous or subcutaneous

route did not produce any significant alteration in cardiovascular response in

animals not pretreated with SKF-525A. In animals that were pretreated with

SKF-525A there was an immediate positive chronotropic effect up to +10% of

control at the 0.05 mg/kg 11-OH-THC dose. There was a negative chronotropic

action at the 0.15 mg/kg dose that returned back to control values after the

intravenous dose. The positive and negative chronotorpic actions occurred when

the drug was administered either intravenously or subcutaneously. The data

indicate a biphasic action of 11-OH-THC on heart rate and support implication

of the compound in the marihuana induced tachycardia observed in man.

301
MANNO, J.E. and MANNO, B.R. The interaction of delta-9-tetrahydrocannabinol (THC).

pentobarbital and SKF-525A with the cardiovascular system of the rat.

Federation Proceedings 32: 755 (1973)

For abstract, see Section I. Methodology of Drug Research.

MANNO, J.E., MANNO, B.R. and KIPLINGER, G.F. Motor and mental performance

with marihuana: Relationship to administered dose of THC and its interaction

with alcohol. Behavioral Actions of Marihuana. Edited by L.L. Miller

New York: Academic Press (in press)

MARKS, M.J. and MEDZIHRADSKY, F. Characterization of the active transport of

benzomorphans in leukocytes. Proceedings of the Fifth International-Congress

on Pharmacology, San Francisco, July 23-28, 1972.

MARSHALL, I. and SMITH, C.B. The role of tyrosine hydroxylase in changes in

brain catecholamine synthesis after acute and chronic administration of

morphine to mice. Committee on the Problems of Drug Dependence.

Washington, D.C.: National Academy of Sciences, National Research

Council, 1973. P. 351.

MARTIN, B.R., DEWEY, W.L. and HARRIS, L.S. Subcellular distribution of 3Hdelta-9-tetrahydrocannabinol in brains of nontolerant and tolerant rats.

Proceedings of the Sixth International Congress of Pharmacology, Helsinki,

Finland, July 20-25 (in press)

For abstract, see Section II. Drug Chemistry and Metabolism.

MARTIN, B.R., DEWEY, W.L., HARRIS, L.S. and BECKNER, J. Marihuanalike activity of new synthetic tetrahydrocannabinols. Pharmacology Biochemistry

and Behavior (in press)

For abstract, see Section II. Drug Chemistry and Metabolism.

MARTIN, B.R., HARRIS, L.S., DEWEY, W.L., MAY, E.L. and WILSON, R.S.

Behavioral and pharmacological properties of 11-methyl- and

9-nor-delta-8-tetrahydrocannabinol. Federation Proceedings 33(3, Part I):

540 (March, 1974)

It has been demonstrated that delta-8-tetrahydrocannabinol (THC),

is rapidly metabolized to 11-hydroxy-delta-8-THC in the body, and it has been

postulated that this metabolite is responsible for the activity of delta-8-THC.

The pharmacological properties of 2 analogs of delta-8-THC, 11-methyl- and

9-nor-delta-8-THC were investigated. The former is probably not converted to

an 11-hydroxy metabolite, the latter cannot be. In the unanesthetized dog these

analogs produce a cannabinoid like effect on overt behavior. They produce prance

like placement of feet, static ataxia, hyperreflexia and a decrease in spontaneous

activity. This profile of behavior is the same as that seen after delta-8- or

delta-9-THC. In the anesthetized dog 9-nor-delta-8-THC is again as effective

as delta-8-THC in producing bradycardia and hypotension; as before. 11-methyldelta-8-THC is somewhat less effective. In mice delta-8-THC, 9-nor-delta8-THC, and 11-methyl-delta-8-THC have no effect on hexobarbital induced

sleeping time and exhibit no antinbciceptive activity as measured in the tail

flick or hot plate test. Each compound has some activity in the phenylquinone

writhing test, delta-8-THC being more active than either analog.

302
MASUR, J. and KHAZAN, N. Induction by cannabis sativa (marihuana) of rhythmic

spike discharges overriding REM sleep electrocorticogram in the rat. Life

Sciences 9: 1275-1280 (1970)

Cannabis sativa and delta-9-tetrahydrocannabinol (delta-9-THC)

have been shown to disrupt complex memory patterns in rhesus monkeys and to

interfere with visual discrimination in both monkeys and pigeons. These drugs

alter maze learning, bar pressing, and climbing rope performances, and after

chronic treatment in food-deprived rats, they induce aggressiveness. Administration

to mice of delta-9-THC is followed by a slight increase in whole-brain concentration

of 5-hydroxytryptamine. Cerebral norepinephrine concentration appears to

decrease after low doses and to increase after high doses.

Changes in the electroencephalogram (EEG) and in the sleep-awake

cycle have been reported to occur after administration of psychotropic drugs

to experimental animals and to man. Studies on the acute effects of Cannabis

indica resin on the EEG of the rabbit revealed initial stimulation and subsequent

depression, followed by a recovery phase during which repeated high voltage

sharp waves weremanifest. In humans deprived of REM sleep for two nights,

REM time tended to be decreased by marihuana extract, THC or synhexyl

(a synthetic analogue of THC), but the change was not significant. In normal

subjects. THC had no consistent effect on REM sleep time.

The present study describes acute and chronic marihuana-induced

changes in the electrocorticogram during longitudinal study of the sleepawake cycle in the rat.

MECHOULAM, R. Cannabinoid chemistry. Marijuana. Chemistry, Metabolism,

Pharmacology and Clinical Effects. Edited by R. Mechoulam. New York:

Academic Press, 1973. Pp. 1-88.

MECHOULAM, R. Chemistry and cannabis activity. Ciencia e Cultura

25(8): 742 (1973)

MECHOULAM, A. Marihuana chemistry. Review. Science 168: 1159 (1970)

MECHOULAM, R., BEN-ZVI. Z., AGURELL, S., NILSSON, I.M., NILSSON, J.L.G.,

EDERY, H. and GRUNFELD, Y. Delta-6-tetrahydrocannabinol-7-oic acid, a

urinary delta-6-THC metabolite: Isolation and synthesis. Experientia 29: 1193

(1973)

MECHOULAM, R., BEN-ZVI, Z. and GAONI, Y. Hashish XIII. On the nature

of the Beam test. Tetrahedron Letters 24: 5615 (1968)

For abstract, see Section II. Drug Chemistry and Metabolism.

MECHOULAM, R., BEN-ZVI, Z., SHANI, A., ZEMLER, H., LEVY. S., EDERY, H.

and GRUNEFELD, Y. Cannahinoids and cannabis activity. Cannabis and Its

Derivatives. Pharmacology and Experimental Psychology. Edited by

W.D.M. Paton and J. Crown. Fairlawn, New Jersey: Oxford University

Press, 1972.

303
MECHOULAM. R., BEN-ZVI, Z., VARCONI, H. and SAMUELOV, Y. Cannabinoid

rearrangements. Synthesis of delta-5-tetrahydrocannabinol. Tetrahedron Letters

29: 1615-1619 (1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

MECHOULAM, R., BEN-ZVI, Z., YAGNITINSKY, B. and SHANI, A. A new

tetrahydrocannabinolic acid. Tetrahedron Letters 28: 2339 (1969)

MECHOULAM, R., BRAUN, P. and GAONI, Y. Hashish XI. A stereospecific synthesis

of (-)-delta-l- and (-)-delta-1(6)-tetrahydrocahnabinol. Journal of the

American Chemical Society 89: 4552 (1967)

MECHOULAM. R., BRAUN, P. and GAONI, Y. Synthesis of delta-l-tetrahydrocannabinol

and related cannabinoids. Journal of the American Chemical Society 94: 6159

(1972)

For abstract, see Section II. Drug Chemistry and Metabolism.

MECHOULAM, R. and EDERY, H. Structure-activity relationships in cannabinoid series.

Marijuana. Chemistry, Metabolism, Pharmacology and Clinical Effects.

Edited by R. Mechoulam. New York: Academic Press, 1973. Pp. 101-133.

MECHOULAM, R. and GAONI, Y. Hashish X. The absolute configuration of

delta-l-tetrahydrocannabinol, the major active constituent of hashish.

Tetrahedron Letters 12: 1109-1111 (1967)

MECHOULAM. R. and GAONI, Y. Recent advances in the chemistry of hashish.

Progress in the Chemistry of Organic Natural Products (Fortschritte

der Chemie Organischer Naturstoffe). Edited by L. Zechmeister. New York:

Springer-Verlach-Verlag, 1967.

MECHOULAM, R., SHANI, A., EDERY, H. and GRUNFELD, Y. Chemical basis

of hashish activity. Science 169: 611-612 (1970)

A sample of hashish was extracted consecutively with petroleum

ether, benzene, and methanol. When tested intravenously in monkeys only

the petroleum-ether fraction was active. This material was further

fractionated. The only active compound isolated was delta-l-tetrahydrocannabinol.

Cannabinol, cannabidiol, cannabichromene, cannabigerol, and cannabicyclol

when administered together with delta-1-tetrahydrocannabinol do not cause a

change in the activity of the latter, under the experimental conditions used. These

results provide evidence that, except for delta-1-tetrahydrocannabinol, no

other major, psychotomimetically active compounds are present in hashish.

304
MECHOULAM, R., SHANI, A., YAGNITINSKY, B., BEN-ZVI, Z., BRAUN, P. and

GAONI, Y. Some aspects of cannabinoid chemistry. Botany and Chemistry

of Cannabis. Edited by C.R.B. Joyce and S.H. Curry. London: J. and A.

Churchill, 1970. Pp. 93-117.

MECHOULAM, R., VARCONI, H., BEN-ZVI, Z., EDERY, H. and GRUNFELD, Y.

Synthesis and biological activity of five tetrahydrocannabinol metabolites.

Journal of the American Chemical Society 94: 7930 (1972)

MECHOULAM, R. and YAGEN, B. Stereoselective cyclizations of cannabinoid 1, 5

dienes. Tetrahedron Letters 60: 5349 (1969)

MECHOULAM, R., YAGNITINSKY, B. and GAONI, Y. Hashish XII. Stereoelectronic

factor in the chloranil dehydrogenation of cannabinoids. Total synthesis of dlcannabichromene. Journal of the American Chemical Society 90: 2418 (1968)

MEDZIHRADSKY, F., MARKS, M.J. and CARR, E.A., JR. Energy-dependent

uptake of benzomorphans by leukocytes. Biochemical Pharmacology 21: 1625-1632

(1972)

For abstract, see Section Ii. Drug Chemistry and Metabolism.

MEDZIHRADSKY, F., MARKS, M.J. and METCALF, J.I. Cellular transport

of CNS drugs in leukocytes. Narcotic Antagonists. Edited by M.C. Braude,

L.S. Harris, E.L. May, J.P. Smith, and J.E. Villarreal. Advances in

Bibchemical Psychopharmacology, Volume 8. New York: Raven Press,

1973. Pp. 537-548.

Using leukocytes as model mammalian cells, the cellular transport of

various CNS drugs was studied. Morphologically intact and metabolically

active rat. leukocytes rapidly accumulated pentazocine against a concentration

gradient by a process which fulfills the criteria for an active transport.

The energy for the transport is derived from anaerobic metabolism

of glucose. The kinetics of the process are characterized by a rapid initial

uptake: 5 sec after addition of the drug 60% of the final cellular drug

concentration was reached; saturation was usually obtained between 2 and

3 min. When pentazocine was present in the medium at micromolar

concentrations, the cellular accumulation of the drug was fivefold. The maximum

velocity of the uptake was 0.12 mu-moles/g cells/5 sec and the concentration

of drug necessary to achieve half-maximum velocity (Km) was 40 mu-m.

The temperature coefficient of the transport process was constant at four

drug concentrations and three temperatures: a temperature change of

10° C affected the uptake by a factor of two. The transport of pentazocine

was competitively inhibited by analogue bcnzomorphans and its cellular

uptake was blocked by inhibitors of anaerobic glycolysis. The active

transport of pentazocine was independent of the presence of sodium and

not affected by ouabain. In addition to pentazocine, methadone and morphine

were also accumulated at a rapid rate into leukocytes. The cells showed

marked selectivity in their uptake of these compounds. The highest affinity

for the cellular accumulation, characterized by a Km of 10 mu-M, was

observed with methadone, whereas morphine was actively transported

inot leukocytes with a much lower affinity: its Km was 4 mM. Ouabain

had no effect upon the uptake of morphine and methadone. The results

suggest the existence in the plasma membrane of leukocytes of transport

systems responsible for the cellular accumulation of various CNS drugs.

305
MEDZIHRADSKY, F. and NANDHASRI, P.S. Effects of some analgesics and

antidepressants on the (Na+ + K

+

)-adenosine triphosphatase from cortices of

brain and kidney. Biochemical Pharmacology 21: 2103-2109 (1972)

For abstract, see Section II. Drug Chemistry and Metabolism.

MESHEL, E. and DENBER, H.C. Double-blind study of tybamate in psychotic

patients. Diseases of the Nervous System 28: 311-313 (1967)

MILLER, J.M. and COCHIN, J. Dose-related aspects of tolerance to the analgesic

effect of chronically administered morphine sulfate (MS) in mice. The

Pharmacologist 10: 189 (1968)

It is known that irregular and even infrequently repeated doses of

narcotic analgesics result in analgesic activity lower than that elicited by

an initial dose of the same size, and that the tolerance that develops is

influenced by dose size and schedule. In order to quantitate some of

these aspects of the altered response to chronic drug administration,

8 mg/kg and 6 mg/kg MS were administered SC to two groups of 12

male mice (ICR strain) 18 times over 26 days and again on day 63.

Analgesia was measured on various days during the 26 day period

and on day 63 by the hot plate method of Eddy and Leimbach (JPET

107: 385, 1953). Differences were seen in the rate of development, degree,

character and persistence of tolerance. A mean analgesic effect significantly

(P less than. 05) lower than the initial day’s effect was seen in the 8 mg/kg group

on the 5th day while it was not until day 25 that a comparable attenuation

was seen in the 6 mg/kg group. The day 63 test showed that the effect of

an 8 mg/kg dose was only 58% of the initial day’s level, while the 6 mg/kg

group no longer demonstrated significant tolerance. An interesting

observation was that from day 5 to the conclusion of the test a greater

analgesic effect was seen after 6 mg/kg MS than after 8 mg/kg.

MILLER, L.L., editor. Marijuana. Effects on Human Behavior. New York:

Academic Press, 1974.

For abstract, see Section I. Methodology of Drug Research.

MISRA, A.L. and MULE, S.T. Persistence of methadone-3H and metabolite in rat

brain after a single injection and its implications on pharmacological tolerance.

Nature 238: 155-156 (July 21, 1972)

MISRA, A.L, and MULE, S.J. Stereoselectivity and differential metabolism in vivo

of dextro and laevo -methadone-1-3H. Nature 241: 281-283 (January 26, 1973)

MISRA, A.L., MULE, S.J., BLOCH, R. and VADLAMANI, N.L. Physiological

disposition and metabolism of Levo-methadone-1-3H in nontolerant and

tolerant rats. The Journal of Pharmacology and Experimental Therapeutics

185(2): 287-299 (1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

306
MIZOCUCHI, K. and MITCHELL, C.L. An evaluation of the effects of morphine

on electrocortical recruitment in the cat and dog. The Journal of Pharmacology

and Experimental Therapeutics 166: 134-145 (1969)

The effects of morphine on recruiting responses in the cat and dog

have been studied with several stimulating sites. These sites were the thalamic

nuclei centrum medianum, medialis dorsalis, centralis medialis and ventralis

anterior. The recording sites were on the anterior sigmoid, posterior sigmoid,

anterior ectosylvian, posterior lateral and posterior suprasylvian gyri, as

well as in the nucleus ventralis anterior. The morphine dosage was 1, 2 and 4

mg/kg. It was found that recruiting responses generally were depressed in the

cat after morphine, although this was not statistically significant in all cases.

In the dog recruiting responses were likewise generally depressed, although a

tendency toward enhancement was sometimes seen. However, the most striking

effect of morphine on recruiting responses in the dog was an alteration in the

recruitment pattern (waxing and waning of the response). This was not observed

in the cat. Presumptive evidence is presented on which are based working

hypotheses concerning the effects of morphine on the diffuse thalamocortical

projection system.

MOLANDER, L. and RANDRUP, A. Investigation of the mechanism by which L-DOPA

induces gnawing in mice. Acta Pharmacologica et Toxicologica 34: 312-324

(1974)

Stereotyped behaviour including gnawing was elicited in mice by

L-DOPA given after various doses of the decarboxylase inhibitor Ro 4-4602.

The gnawing was estimated quantitatively. The effect of various drugs including

reserpine, FLA-63. spiramide and alpha-methyltyrosine on the gnawing

was studied and it is concluded that the gnawing is influenced by both dopamine

and noradrenaline in the brain. The relation of noradrenergic brain

mechanisms to gnawing seems to be complicated.

MORETON, J.E. and DAVIS, W.M. Effects of delta-9-tetrahydrocannabinol on locomotor

activity and on phases of sleep. The Pharmacologist 12(2): 258 (1970)

Rats injected daily s. c. with 25 mg/kg of synthetic delta-gtetrahydrocannabinol (THC) in olive oil and placed for 4 hrs in photocell

actometers showed initially a biphasic response of stimulation during the 1st

hour and depression during the 2nd. The excitant effect was no longer seen by

the 4th day. With continued doses through 20 days, tolerance developed to

the depressant effect by the 11th day, and lasted through at least the 9th day

after withdrawal. Mice injected i.p. for 23-26 days with 50 mg/kg of THC in a

2% Tween-65, 2% Arlacel-20, 1% olive oil, and saline suspension showed a

twofold reduction in locomotor inhibitory response to THC. Rats chronically

implanted with electrodes over the frontal cortex, and in the dorsal hippocampus

and neck muscles were given one 10 mg/kg dose of THC i.p. following control

recordings. THC caused a pronounced reduction in the level of paradoxical

sleep (PS) which required two days for complete recovery. In rats selectively

deprived of PS for 72 hrs, 10 mg/kg of THC caused a blockade of PS rebound.

307
MORETON, J.E. and DAVIS, W.M. Electroencephalographic study of effects of delta-gand delta-8-tetrahydrocannabinol and cannabis estract on sleep in the rat.

The Pharmacologist 13(2): 246 (1971)

The criteria for paradoxical sleep (PS) included activated ECoG.

hippocampal (HIP) theta rhythm, rapid eye movement (EM) and low EMG.

Daily 3h recordings were made from 3 days before to 6 days after the drugs.

in non-deprived (ND) rats and for 6 days afterwards in rats PS deprived (PSD)

for 72 h. Five and 10 mg/kg of synthetic delta-9 and delta-8-tetrahydrocannabinol

(delta-9-THC and delta-8-THC) and 10 mg/kg of cannabis extract i.p. PS,

slow sleep (SS) and wakefulness in ND rats. PS rebound was blocked in PSD

rats. Ten mg/kg delta-9-THC in studies utilizing recordings 24 h/d on the daily

schedule as above suppressed PS for 12 h in 2/3 ND rats. A non-significant rise

in PS occurred in the next 12h. In PSD rats 10 mg/kg suppressed PS for 6-9 h

and SS. Rebound did not occur in the next 12 h or subsequent 5 days. Ten

mg/kg delta-9-THC, daily for 20 days to rats permitted PS only during daily

15h EEG sessions, reduced PS for 3 days after which tolerance developed.

No PS rebound occurred in the 10 day post-drug period. Ten mg/kg on the 13th

withdrawal day tended to reduce PS. After THC, sleep characterized by HIP theta

rhythm, cortical spindles, low EM and or absent EM occurred. If such is

considered PS, then THC reduces PS in ND and has little effect in PSD rats.

MORETON, J.E. and DAVIS, W.M. Electroencephalographic study of the effects

of tetrahydrocannabinols on sleep in the rat. Neuropharmacology 12: 897-907

(1973)

This study examined the effects of tetrahydrocannabinols on sleep-wake

states, and especially on paradoxical sleep (PS), in rats bearing chronically

implanted EEG and EMG electrodes. Greatest attention was given to delta-gtetrahydrocannabinol (delta-9-THC) but delta-8-tetrahydrocannabinol and

marihuana extract distillate were also studied. These agents in i.p. doses

of 5 and 10 mg/kg reduced PS in rats non-deprived (ND) of PS, caused an apparent

dissociation of phasic and tonic events of PS in PS-deprived (PSD) rats, and

tended to decrease slow wave sleep and increase wakefulness. No PS rebound was

detected during 5 post-drug days in ND rats. In PSD rats the normal PS rebound

was replaced by a form of “incomplete PS” characterized by tonic hippocampal

theta thythm, absence of muscle activity and continuous cortical spindling

in the absence of normal phasic activity. The effect of 10 mg/kg of delta-9-

THC administered daily for 20 days was initially to suppress PS; this was

followed by rapid development of tolerance to effects on both sleep and behavior.

Partial tolerance remained upon retesting at the 13th withdrawal day. When

delta-9-THC was withdrawn no PS rebound occurred in rats. In preliminary

experiments in cats, single doses of delta-9-THC (10 mg/kg i.p.) caused a

clear-cut inhibition of PS in both ND and PSD cats which was followed by a

significant PS rebound on the first post-drug day.

308
MORETON, J.E., ROEHRS, T. and KHAZAN, N. Sleep-awake activity and selfinjection pattern of rats dependent on morphine, methadone, or L-alphaacetyl-methadol (LAAM). Federation Proceedings 33: 516 (1974)

We have reported on the EEG, EMG and sleep-awake activity of

dependent rats maintained by voluntary i.v. self-injections of morphine on a

fixed-ratio schedule of reinforcement (Khazan, Weeks, and Schroeder, JPET,

155, 521, 1967). The usual inter-injection interval was 2-3 hours. Sleep and

REM sleep predominated before an injection, and wakefulness with EEG slow bursts

followed the injection. In our present studies, when methadone (2 mg/kg/injection)

or LAAM (1 mg/kg/injection) was substituted for morphine (10 mg/kg/injection),

rats titrated the daily drug intake and maintained the dependence state. A

significant shift from inter-injection intervals of 2.5 ± 0.1 hours for morphine

to shorter intervals of 1.4 ± 0.1 hours was noted for methadone and to much

longer intervals for LAAM (8.8 ± 0.8 hours). While the drug-induced pattern of

distribution of sleep, REM sleep, and awake during these inter-injection intervals

was analogous, LAAM exhibited a relatively delayed onset of this effect. However.

EEG slow bursts that may represent a significant agonistic property emerged

with little delay following LAAM injections.

MUDGILL, L., FRIEDHOFF, A.J. and TOBEY, J. Effect of intraventricular administrations

of epinephrine. norepinephrine, dopamine, acetycholine, and physostigmine on

morphine analgesia in mice. Archives internationales de Pharmacodynamie et de

Therapie 210: 85 (1974)

Intraventricular epinephrine or norepinephrine antagonized the

analgesic effect of morphine on the rat tail flick response while dopamine

in equivalent doses had no effect. The effects of acetylcholine or physostigmine

were not definitive.

MULE, S.J. and CLOUET, D.H. Pharmacological and biochemical aspects of

opiate dependence. Psychopharmacologia 26: 116 (1972)

For abstract, see Section II. Drug Chemistry and Metabolism.

MUNKVAD, I. The mechanism of action of psychopharmacological agtens on

behaviour. Acta Pharmacologica et Toxicologica 35 (Supplement I):

11 (1974)

The problem of aggressiveness and abnormal social behaviour

can be elucidated from an anatomical, a behavioural, and a

biochemical point of view.

1) Anatomy: regions in the brain related to rage, aggressiveness,

fear and escape have been investigated for many years. Rage is

produced by lesions or electro-stimulation in many parts of the brain,

but a system in the central gray matter of the mid-brain and hypothalamus

seems to be of special importance. These are areas in which a high

concentration of noradrenaline is found.

Some experiments, however, indicate that forms of aggressive

features depend on dopamine in the basal ganglia. In this relation it

should be mentioned that direct bilateral intrastriathl injections of

L-Dopa after MAO-inhibition in rats are able to produce aggressive

behaviour.

The behavioural effects of treatment with L-Dopa in man underline

this statement, as agitation, restlessness, and aggressiveness in one form

or another is not a quite uncommon side-effect in Parkinsonian patients

treated with this drug.

309
Munkvad, I. continued

2) Behaviour: while lower doses of amphetamine (5 mg/kg) in mice

produce stereotypies, higher doses of this drug (15 mg/kg) add aggressive

activities during certain experimental circumstances and these

activities are counteracted by neuroleptics, especially the more specific

ones with high antidopaminergic action.

In rats aggressive behaviour can be produced by apomorphine,

but also by amphetamine combined with inhibitors of noradrenaline

synthesis, indicating a role of dopamine in relation to aggressiveness.

In monkeys the social behaviour is altered with small doses of

amphetamine and especially neuroleptics with strong anti-dopaminergic

action are able to normalize the animals to some degree. Here also

dopamine seems to play a role.

In man amphetamines can produce aggressive behaviour, and

neuroleptics, which all have antidopaminergic properties in various degree,

can normalize the abnormal behaviour including the stereotypies.

3) Biochemistry: in rats and other animals it is difficult to distinguish

behaviourally between different types of aggression and it is possible that

different biochemical mechanisms in various brain areas give rise to nearly

identical aggressive behaviour and attempt to “normalize” these different

forms of aggressiveness with neuroleptics depends on a very subtle alteration of

a balance between transmitters as noradrenaline, dopamine, serotonin

and acetylcholine, perhaps with “moderators” as e.g. gamma-aminobutyric

acid.

Neuroleptics in animals and also in man are able to modify abnormal social

behaviour (including aggressiveness), interfering with the balance between the

different transmitters in various parts of the brain, including the dopaminergic

system in corpus striatum.

MUNKVAD, I., PAKKENBERG, H. and RANDRUP, A. Aminergic systems in

basal ganglia associated with stereotyped hyperactive behavior and

catalepsy. Brain, Behavior and Evolution 1: 89-100 (1968)

The physiological action of the basal ganglia is still far from

being understood. The evidence indicates, however, a motor regulatory

role as well as a role in the integration of “higher” behavior.

Experiments from recent years have provided new knowledge

about the occurrence and distribution of biogenic amines in the basal

ganglia.

These aminergic systems seem to be associated with stereotyped

hyperactive behavior and catalepsy produced by amphetamine and

neuroleptic drugs.

It is suggested as a working hypothesis that the aminergic

systems in basal ganglia may play an important role in the adtipsychotic

effect of neuroleptic drugs and perhaps in the pathogenesis of

schizophrenia.

310
MUSHLIN, B. and COCHIN, J. Effects of irradiation on the development of tolerance to

morphine in the rat. Federation Proceedings 33:502 (1974)

A number of studies have been carried out in our laboratory characterizing the effects of cycloheximide, Freund’s adjuvant and dose interval on the

development of tolerance. In order to investigate the phenomenon of tolerance

further, we conducted a series of experiments in which we irradiated groups of

rats with gamma irradiation (1250 R), either before or during a regimen of morphine sulfate (MS) injections (15 mg/kg subcutaneously). Non-irradiated control

groups were tested concomitantly. The difference in the degree of tolerance

development between irradiated and control groups was compared by measuring

morphine effect using the hot-plate assay. Rats irradiated and then given daily

MS injections starting 24 hours after irradiation were not different from controls

with respect to tolerance development after 4 injections. Thus irradiation seemingly has no effect on the development of tolerance under these conditions. However, when rats were irradiated, given bone marrow transplants, and then weekly

injections of MS starting 6 days after irradiation, there was a significant delay in

the development of tolerance as compared with control animals. In another experiment, irradiation of animals that had previously received 4 weekly injections

of MS failed to affect subsequent development of tolerance induced by additional

weekly injections of MS.

MUSHLIN, B., GRELL, R. and COCHIN, J. Blockade of the development of tolerance

to morphine by concurrent naloxone administration. The Pharmacologist

16: 193 (1974)

The effects of concurrent morphine (MS) and naloxone (NAX) administration on the development of tolerance to MS in Wistar-Lewis rats were

examined., MS dosage was 15 and NAX 6 mg/kg s.c. Rats were assigned to 3

groups: MS only, receiving MS daily for 9 days; NAX only, NAX for 8 days and

MS on the ninth day; and MS-NAX, both NAX and MS for 8 days and MS only on

the ninth day. NAX was given 10 min before, and 50 and 110 min after MS; rats

not receiving MS were given saline. Animals were tested on the hot plate on

days 1 and 4, following the usual dose of MS or saline. On day 9, all rats

were injected with just MS and tested for analgesic response. In a second

experiment, NAX injections were given 30 and 10 min before, and 50 and 110

min after MS or saline. All injections were given weekly rather than daily.

Rats received 2 injections of MS or NAX or MS-NAX and all received only MS on

their last injection. Animals were tested on the hot plate after each MS or saline

injection. In neither experiment did NAX or MS-NAX treatment induce any

tolerance to MS, nor were there any differences between the analgesic response

of NAX or MS-NAX groups. Concurrent administration of NAX and MS appeared

to block both MS analgesia and tolerance development.

NAKAMURA, J., HENDERSON, G.L. and WINTERS, W.D. The behavioral and EEG effects of 1-alpha-acetylmethadol (LAAM) in the rat. Proceedings of the Western

Pharmacological Society 17: 155-158 (1974)

L-alpha-acetylmethadol (LAAM), a long-acting synthetic congener of

methadone, has recently undergone preliminary trials in the treatment of heroin

addicts. The 72-96 hour duration of action of LAAM allows the patient to receive

maintenance doses of the drug every third day instead of daily as with methadone.

The purpose of this study is to determine the gross behavioral and EEG

activity in rats after the administration of LAAM.

311
NAKAMURA, J. and MITCHELL, C.L. A comparison of the effects of morphine and pentobarbital on conditioned and non-conditioned bioelectrical potentials evoked within

the pyriform lobe. Archives internationales de Pharmacodynamie et de Therapie

206: 31-40 (1973)

The effects of morphine sulfate and pentobarbital sodium were studied

in cats on bioelectrical potentials evoked by stimulation of the pyriform cortex and

recorded in the entorhinal cortex. The effects of a 1000 msec conditioning stimulus

applied to radial nerve at 5 and 40 v, to tooth pulp at 5 and 100 v, to the reticular

formation at subthreshold, threshold and suprathreshold voltage intensities for

cortical activation and to radical nerve at threshold levels, were examined. The

conditioning with greatest effect in, raising blood pressure and activating the cortex

produced the greatest inhibition of the entorhinal response. Pentobarbital caused

a general depression of both conditioned and non-conditioned responses. In contrast, morphine had no effect on the integrity of the non-conditioned response,

However, it did antagonize the inhibitory effect of the more noxious levels of the

conditioning stimuli. It was suggested that the removal by morphine of the

specific inhibition of the entorhinal response after noxious conditioning stimuli

may be related at least in part to the mechanism of morphine analgesia.

NAKAMURA, J. and MITCHELL, C.L. The effects of morphine, pentobarbital and

chlorpromazine on bioelectric potentials evoked in the brain stem of the cat by

electrical stimulation of the gingiva and tooth pulp. The Journal of Pharmacology

and Experimental Therapeutics 178: 232 (1971)

The effects of morphine sulfate (1, 2 and 4 mg/kg), pentobarbital sodium

(2.5, 5 and 10 mg/kg), chlorpromazine hydrochloride (1, 2 and 4 mg/kg) and saline

(0.1, 0.2 and 0.4 ml/kg) on the responses evoked from the central tegmental

fasciculus, the dorsal tegmentum of the mesencephalon and the spinal trigeminal

tract by gingival and tooth pulp stimulation were studied. In the central tegmental

fasiculus, morphine had no significant effect on responses evoked by either type

of stimulus. Pentobarbital and chlorpromazine significantly depressed both responses. In the dorsal tegmentum. both responses were significantly depresse’d

by morphine, but this effect was not dose related. Pentobarbital significantly

depressed both responses in a dose-related manner. Chlorpromazine had no

effect on the response elicited by gingival stimulation but depressed that produced

by tooth pulp stimulation. In the spinal trigeminal tract, morphine had no effect

on the responses evoked by either mode of stimulation. Pentobarbital and

chlorpromazine slightly depressed the responses. The responses in the spinal

trigeminal tract increased with time in the absence of drug. Had saline not been

used to monitor the stability of the preparation an incorrect interpretation would

have been placed on the results obtained with the recordings from the spinal trigeminal tract. The proper assessment of drug effects on bioelectrical responses

is impossible without this control.

NAKAMURA, J. and MITCHELL, C.L. The effects of morphine, pentobarbital and saline

on bioelectrical potentials recorded in limbic structures of the cat evoked by radial

nerve and direct brain stimulation. Archives internationales de Pharmacodynamie

et de Therapie 200: 70-87 (1972)

The effects of morphine, pentobarbital and saline were studied in cats on

limbic and midbrain potentials recorded in 1) entorhinal cortex and mesencephalic

reticular formation evoked by radial nerve stimulation and in 2) septum, hippocampus

and entorhinal cortex after pathways were established from mesencephalic reticular

formation to entorhinal, septum to hippocampus. hippocampus to septum and entorhinal, entorhinal to hippocampus and piriform cortex to entorhinal. Morphine had

no effect on hippocampal or entorhinal excitability. However, morphine reduced

312
Nakamura, J. and Mitchell, C.L. The effects . . . on bioelectrical potentials recorded in

limbic structures . . . continued

sensory input into these areas since entorhinal responses evoked by radial nerve or

reticular stimulation were depressed but responses recorded from pathways within

the limbic areas were not. Pentobarbital, in contrast, depressed the general level

of excitability of both hippocampus and entorhinai cortex as well as the entorhinal

response evoked by radial nerve and reticular stimulation. It. was concluded that

morphine exhibits more specificity in its effect on limbic structures than that

shown by pentobarbital.

NASH, P., COLASANTI, B. and KHAZAN, N. Long-term effects of morphine on the electroencephalogram and behavior of the rat. Psychopharmacologia 29: 271-276

(1973)

Adult female Sprague-Dawley rats were given 10 mg/kg i.p. injections

of morphine sulfate twice weekly, at 84-h intervals, over a period of three weeks.

A control group of rats was simultaneously treated with equivalent volumes of

isotonic saline. The animals were then prepared with cortical and temporalis

muscle electrodes. Ten days after the last injection of morphine or of saline,

they were placed in individual cages for recording of the EEG and the EMG and

both groups were given i.p. a 10 mg/kg test dose of morphine. In the salinetreated rats, high voltage EEG slow bursts in association with stuporous behavior

appeared almost immediately after injection and prevailed for 60-90 min. This

phase was followed by continuous EEG and behavioral arousal for another period

of 60-90 min, after which sleep appeared. Administration of the 10 mg/kg test dose

of morphine to the rats having prior morphine exposure resulted in a much shorter

initial period of EEG and behavioral stupor and a longer secondary phase of EEG

and behavioral arousal. The duration of the entire morphine effect as determined

by the latency to sleep onset, however, was the same in the saline-treated and

morphine-treated groups of rats. These results support the assumption that, longterm alterations in the function of the CNS occur not only after morphine addiction, but also after only exposure to morphine.

NEWMAN, L.M., LUTZ, M.P., GOULD, M.H. and DOMINO, E.F. Delta-9-THC and ethyl

alcohol: Evidence for cross-tolerance in the rat. Science 175:1022-1023 (1972)

Rats trained in a one-way avoidance situation were made tolerant to the

depressant effects of delta-9-tetrahydrocannabinol. Ethy1 alcohol (3. 2 grams per

kilogram, infraperitoneally) did not greatly affect rats that were tolerant to

delta-9-tetrahydrocannabinol but depressed the behavior of nontolerant rats. Rats

made tolerant to ethyl alcohol were less affected by delta-9-tetrahydrocannabinol.

NICHOLSON, M.T., PACE, H.B. and DAVIS, W.M. Effects of marijuana and lysergic

acid diethylamide on leukocyte chromosomes of the golden hamster. Research

Communications in Chemical Pathology and Pharmacology 6(2):427 (September,

1973)

Female Syrian golden hamsters were given daily subcutaneous injections

of marihuana extract distillate (MED), containing 17.1% delta-9-tetrahydrocannabinol

(delta-9-THC), or dl-lysergic acid diethylamide (LSD) for 10 consecutive days.

Daily dosages of MED, in terms of delta-9-THC content, were 1.0, 10, and 100

mg/kg. LSD dosages were 0.1, 10, 100. and 1000 mu-g/kg. A ninth drug treatment was

the combination of MED at 100 mg/kg of delta-9-THC and 1000 mu-g/kg of LSD. None

of these treatments caused significant elevation of leukocyte chromosome breaks

above control levels.

313
NIELSEN, M. The effects of amitriptyline, desipramine, imipramine and protriptyline on the in vivo brain synthesis of 3H-noradrenaline from 3H-1-dopa

in the rat. Acta Pharmacologica et Toxicologica 35(Supplement I): 43

(1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

NIELSEN, M., EFLOV, L. and SCHEEL-KRUGER, J. The effect of amitriptyline,

mine and imipramine on the in vivo brain synthesis of 3H-L-dopa in the rat.

desipraPsychopharmacologia (in press)

NIELSEN, M., EPLOV, L. and SCHEEL-KRÜGER, J. Protriptyline induced

inhibition of the in vivo 3H-noradrenaline synthesis from 3H-L-DOPA

in the rat brain. Nanunyn-Schmiedebergs Archives of Pharmacology

285: 15-28 (1974)

NIELSEN, E.B. and LYON, M. Some possible mechanisms involved in amphetamine

or apomorphine induced hypodipsia. Journal de Pharmacologic 5(Supplement II):

72 (1974)

Hypodipsia produced by d-amphetamine or apomorphine must

be related in some, as yet unknown, way to deficits in cholinergic

initiation of drinking. Both dopamine (DA) and norepinephrine may

be implicated. Hypodipsia yielded by d-amphetamine (2.0 mg/kg)

or by apomorphine (0.8 mg/kg) was partially antagonized by specific

DA receptor-blockers (Pimozide and Spiramide) in doses which alone

produced no drinking loss. Injections of adrenergic blockers

aceperone (1.0 mg/kg) or phenoxybenzamine (10.0 mg/kgl, in rats

pretreated with d-amphetamine (2.0 mg/kg) restored drinking to ca.

75% of NaCl control levels, while without d-amphetamine these doses

had no effect. Like doses had no effect on hypodipsia following apomorphine

(0.4 mg/kg). The results suggest that d-amphetamine and apomorphine

affect drinking by different modes with apomorphine deficits being more

specifically DA-related, since adrenergic blocking did not antagonize

this type of hypodipsia.

NILAKANTAN, B. and RANDRUP, A. Phylogenetic approach to the study of brain

mechanisms involved in the action of amphetamine and other drugs.

Present Status of Psychotropic Drugs. Edited by A. Cerletti and F. Bove,

Amsterdam, the Netherlands: Excerpta Medica Foundation, 1969.

NILSSON, I.M., AGURELL, S., NILSSON, J.L.C., OHLSSON, A., LINDGREN, J.E. and

MECHOULAM, R. Metabolism of 7-hydroxy-delta 1(6)-tetrahydrocannaninol in the

rabbit. Acta Pharmaceutics Suecica 10:97 (1973)

For abstract, see Section II. Drug Chemistry and Metbolism.

314
NILSSON, J.L.G., NILSSON, I.M., AGURELL, S., BEN-ZVI, Z. and MECHOULAM, R. Synthesi

a potential urinary THC metabolite. Acta Pharmaceutics Suecica 9:215 (1972)

For abstract, see Section II. Drug Chemistry and Metabolism.

NYBACK, H., SCHUBERT, J. and SEDVALL, G. Effect of apomorphine and pimozide on

synthesis and turnover of labelled catecholamines in mouse brain. Journal of

Pharmacy and Pharmacology 22: 622-624 (1970)

OGLESBY, M.W., ROSENBERG, J. and WINTER, J.C. Behavioral and biochemical effects

of chronic administration of bromide in the rat. Psychopharmacologia 32: 85-92

(1973)

Bromide, a sedative in low doses and a psychotogen in high doses and a

psychotogen in high doses in man, was tested for behavioral and biochemical effects

in the rat. The kinetics of bromide excretion following chronic administration were

studied in the rat to determine drug regimens necessary to achieve stable, nonlethal levels of blood bromide. When administered daily to animals performing on

a variable-interval schedule of positive reinforcement, a low dose of bromide increased rates of responding while a high dose depressed response rates. Follow -

ing withdrawal of the drug after six weeks of administration, response rates returned to previously determined control levels. Chlorpromazine failed to antagonize bromide-induced rate depression. No change in the concentration of norepinephrine or 5-hydroxytryptamine was seen with any dose of bromide studied.

PACE, H.B., DAVIS, W.M. and BORGEN, L.A. Teratogenesis and marijuana. Annals of

the New York Academy of Sciences 191: 123-131 (December, 1971)

178-5-1786 (1974)

OVERTON, D.A. and WINTER. J.C. Discriminable properties of drugs and state dependent

learning. Federation-Proceedings 33(7):

PACE, H.B., HOLBROOK, J.M., TOMPOROWSKI, R.A. and DAVIS, W. M. Oral

methadone treatment of pregnant female rats: Effects on neonatal viability and

postnatal development. The Pharmacologist 16(2): 649 (1974)

Methadone hydrochloride in distilled water was administered p.o. to

pregnant female rats (Wistar-derived) during discrete periods of gestation, and

postpartum, to determine its effects on offspring viability and growth. Dosing

schedules used were: 15 mg/kg on days 8-14(I), days 15-20(II) or day 15 to

weaning (III). and 30 mg/kg on days 8-14(IV). Control females received, 1 ml/kg

of vehicle. Offspring were weighed individually within 4 h after birth and daily

until weaning. There were no differences among groups in the ave. wt. of pups

at birth or the number of pups dead at birth. Group IV pups showed significantly

lower values for ave. wt./pup and ave. litter size at weaning than controls.

Only 29% of live-born group IV pups survived past 48 h compared to 80% of controls. Most of these neonatal deaths occurred within 24 h. Groups II and III

also differed from control. having less pups alive at 48 h and at weaning. Group I

showed no significant deviations from control values. Reflex ontogeny of

methadone pups was somewhat delayed compared to controls.

315
PAKKENBERG, H., FOG, R. and NILAKANTAN, B. The long-term effects of perphenazine enanthate on the rat brain. Some metabolic and anatomical observations.

Psychopharmacologia 29: 329-336 (19’73)

Perphenazine enanthate 3.4 mg/kg per injection, was administered subcutaneously to rats every second week over a period of a year, a total of 31 mg

per animal being given. The animals were observed weekly and only a few

became cataleptic during brief periods. After treatment for one year, 3Huridine and 3H-lysine were administered intravenously and the labelling was

studied by microautoradiography. Labelling of the cortical cells in the treated

animals was found to be slightly greater than in the control animals. The converse was found in the basal ganglia in the case of uridine. None of these differences were significant.

In counting nerve cells in the cortex and in the basal ganglia, a significantly lower number of nerve cells was found in the basal ganglia in the treated

group.

Histological investigation of lungs, liver, spleen and kidneys showed only

insignificant changes in the tissues.

All the investigations mentioned were performed blind.

PAL, B.K., LOWNEY, L.I. and GOLDSTEIN, A. Further studies on the stereospecific binding of levorphanol by a membrane fraction from mouse brain.

Agonist and Antagonist Actions of Narcotic Analgesic Drugs. Edited by

H. W. Kosterlitz, H.O.J. Collier and J.E. Villarreal. Baltimore, Maryland:

Baltimore University Park Press, 1973. Pp. 62-69

1. The stereospecific binding of the opiate levorphanol by mouse

brain tissue in vitro is concentration dependent; about 3 x 1016 molecules per

brain were bound at the highest concentration studied.

2. The binding capacity is not extractable by Triton X-100 or sodium

lauryl sulphate. It is enhanced by EDTA and nearly abolished by calcium or

magnesium ions. It is unaffected by p-chloromercuribenzoate, beta-mercaptoethanol, or iodoacetic acid. Trypsin treatment increases it.

3. The material responsible for the stereospecific binding is completely

extactable into chloroform-methanol, and is recovered again in an ‘aqueous

residue’ obtained by water extraction of the organic phase. The material

has the general properties of a proteolipid.

PALMER, G.C., SULSER, F. and ROBISON, G.A. The effect of neurohumoral

and adrenergic agents on cyclic AMP levels in various areas of the rat

brain in vitro. Neuropharmacology (in press)

PANG, C.N., ZIMMERMANN, E. and SAWYER, C.H. Effects of morphine on the

proestrous surge of luteinizing hormone in the rat. Proceedings of the 87th

Annual Meeting of the American Association of Anatomists. Cleveland, Ohio,

April, 1974.

Barraclough and Sawyer (Endocrinology 57: 329, 1955) reported inhibition

of ovulation in the rat by administering morphine sulfate (MS) at the outset of the

critical period on the afternoon of proestrus. To further study this inhibition,

the influence of MS on the ovulatory surge of circulating luteinizing hormone (LH)

was investigated. Normally cycling Sprague-Dawley adult rats were given various

doses of MS intraperitoneally at 1400 on proestrus. Four hours later, jugular

venous blood was collected under rapid ether anesthesia and used for radioimmunoassay determination of plasma levels of LH. To verify ovulation, the

uterine tubes were examined the following day for the presence or absence of ova.

Compared with low levels of LH observed at 1400 in 8 untreated proestrous rats,

316
Pang, C. N., Zimmermann, E. and Sawyer, C. H. continued

saline (S)-injected controls showed highly elevated (p less than 0.01) values of

LH at 1800 that evening and all animals ovulated. Compared with S-treated animals,

those receiving 10 mg/kg MS showed apparently enhanced (p less than 0.05) levels

of LH and all rats in this group ovulated. In contrast, rats given 60 mg/kg MS

showed complete suppression (p less than 0.01) of LH discharge and failed to

ovulate. Rats given either 20 or 40 mg/kg MS showed intermediate levels of

LH which did not differ from that of S-treated controls but were less than that

of rats given 10 mg/kg (p less than 0. 05) and greater than that of rats given 60

mg/kg (p less than 0.05). Inspection of the data from individual animals revealed

that 3 of 6 rats receiving 20 mg/kg and 5 of 13 receiving 40 mg/kg MS showed

marked suppression of LH levels (159±54 ng/ml) and no tubal ova, whereas the

remainder of animals in these groups had high levels of LH (1523±167 ng/ml) and

7 or more tubal ova. These findings suggest that MS exerts dose-dependent

effects on secretion of LH with stimulation at low doses and inhibition at higher

doses. In addition. the data suggest that MS may block, in an all-or-none fashion,

brain mechanisms responsible for triggering the progestrous surge of MS in the

rat. Studies are underway to explore further these neuroendocrine effects of MS.

PAPESCHI, R. The effect of ECT on dopamine-dependent behaviour and DA turnover.

Psychopharmacologia 26: 45 (1972)

ECT given for seven days prior to the administration of reserpine,

or alpha-methyl-p-tyrosine accelerated the onset of catalepsy. The catalepsy

induced by reserpine or alpha-methyl-p-tyrosine is at least in part due to the

depletion of dopamine. There was a correlation between the scores on catalepsy

and the increase of HVA following reserpine. The onset of amphetamine-induced

stereotyped behaviour was also accelerated by preliminary application of ECT.

The effect of ECT on dopamine turnover was studied by means of synthesis

inhibitors.

PAPESCHI, R. An investigation on the behavioral and hypothermic effects of

yohimbine: Interaction with drugs affecting central and peripheral

‘monoamines. Archives internationales de Pharmacodynamie et de

Therapie 208: 61-80 (1974)

The hypothermia and the behavioral changes induced by

yohimbine in the rat were investigated by studying the interaction of

this alkaloid with various drugs which affect central and peripheral

monoamines. The results indicated that hypothermia mainly stems

from a peripheral blocking action of yohimbine on alpha adrenergic

receptors, but a central component, through stimulation of serotonin

receptors, may also exist. Although yohimbine seems to block

noradrenaline functions also centrally, it is unlikely that this

mechanism contributes to the hypothermia. The changes in body

temperature induced by yohimbine and by the interacting drugs

were not always correlated with those of motor activity. The implications

of the present findings for the thermoregulatory function of central and

peripheral monoaminergic neurons are discussed,

Yohimbine antagonized the aggressiveness and the increased

locomotion induced by various drug treatments, such as pargyline

Ro4-4602 + L-DOPA, thus suggesting that this alkaloid blocks central

noradrenaline mechanisms too; on the other hand, only the stereotyped

activity induced. by (+)-amphetamine was reduced by yohimbine,

whereas that following apomorphine or Ro-4602 + L-DOPA was

unaffected. This observation suggests that yohimbine may also disturb

the intraneuronal metabolism of brain dopamine, though being inactive

on dopamine receptors.

317
PAPESCHI, R. Relations of effects of neuroleptics in animals to pharmacological

parkinsonism in man. Psychopharmacologia 26(Supplement): 21 (1972)

Parkinsonian syndrome is characterized by akinesia, rigidity and

tremor and the same symptoms can be induced by neuroleptics in man.

Neuroleptics can also induce a neurodysleptic syndrome and akathisia.

Parkinson’s disease in man is believed to be due to a lesion of the

nigro-striatal pathway with low dopamine and HVA in striatum and CSF.

The symptom which better correlates with a decrease of HVA in CSF

is akinesia. There is evidence that also pharmacological syndromes

induced by phenothiazines and butyrophenones in experimental animals

are due to the blockade of dopamine receptors. Again in these syndromes

the most striking feature is the reduced motor activity, which can arrive

to catalepsy. Catalepsy can also be induced by other means interfering

with the nigro-straital pathway such as lesions or block of synthesis

of dopamine by alpha-methyl-p-tyrosine. However, in the latter case

the toxicity of the drug itself is also in part responsible for the syndrome.

Bulbocapnine and reserpine provide other examples of catalepsy related

‘to interference with dopaminergic mechanisms. However, cholinergic

stimulation can also provoke catalepsy. It is concluded that the main

symptom induced by neuroleptics in animals and in man which correlates

with the dysfunction of the dopaminergic nigro-straital pathway is the

reduction of motor activity.

PAPESCHI, R., RANDRUP, A. and LAL, S. Effect of ECT on dopaminergic and noradrenergic mechanisms. I. Effect on the behavioural changes induced by reserpine,

alpha-methyl-p-tyrosine or amphetamine. Psychopharmacologia 35: 149-158

(1974)

The preliminary application of one or 5-8 electroconvulsive shocks

(ECT) significantly increased the severity of the seadation and catalepsy induced

by reserpine or alpha-methyl-p-tyrosine (AMT). ECT X 7, prior to various doses

of d-amphetamine, significantly depressed the locomotor stimulation and the

rearing, and slightly antagonized the decrease of social interactions induced by

this drug. No consistent effect was found on amphetamine-induced stereotyped

activity. Locomotor activity was already depressed in the ECT group before

amphetamine.

The results suggest that ECT cannot affect such spontaneous and druginduced behaviour through an increased functional catecholamine turnover, but

rather through a decreased flow of nerve impulses in catecholaminergic neuronal

systems and/or through increased non-functional catecholamine turnover or other

non-specific neurological changes.

PATRICK, G.A., DEWEY, W.L. and HARRIS, L.S. Relationship of brain morphine concentration to tail-flick activity in pellet-implanted and acutely treated mice and

rats. Federation Proceedings 33(3): 474 (1974)

Brain morphine (M) levels were measured according to a modification

of the fluorometric method of Kupferberg et al. (JPET 145: 247, 1964) in

animals in which the tail-flick test was performed. In mice implanted subcutaneously with M pellets (75 mg), significant analgesia was observed 20 min.

after implantation though brain M was not measurable. Increased analgesia

paralleled increased brain M at 1 and 4 hours after implantation. By 24 hrs.

analgesia had begun to decline and was entirely absent at 72 hrs., though brain

M levels remained elevated through 78 hrs. When the M pellets were removed at

72 hrs., brain M declined steadily, returning to zero 6 hrs. later. These data

suggest that the encapsulation observed around the pellet does not greatly interfere with the absorption of M. Brain M levels were found to correlate with s. c.

318
Patrick, G.A., Dewey, W.L. and Harris, L.S. continued

doses of morphine sulfate (MS) and tail-flick activity in mice and rats. In mice

the brain M level at the ED-50 in the tail-flick test was approximately 100 ng/g

tissue, while in rats the brain M level at the ED-50 was found to be 140 ng/g

tissue. Following a single S. C. injection of 8 mg/kg of MS, mouse brain M

levels peaked at 30 mm. after injection, corresponding to peak analgesic effect.

In rats, an injection of 16 mg/kg S.C. produced peak brain M levels and peak

analgesia at 45 to 60 min. after administration.

PATRICK, G.A., DEWEY, W.L. and HARRIS, L.S. Studies on morphine tolerance and

dependence in mice and rats. Virginia Journal of Science 125: 102 (1974)

Chronic administration of morphine (M) to rodents leads to development

of the phenomena of tolerance and dependence. Tolerance is characterized by

decreased analgesic activity of M and dependence is characterized by a number of

signs upon withdrawl of M, among which loss of body weight is most reliable.

Mice were treated chronically by the implantation of a pellet containing M base,

while rats were treated by continuous infusion of morphine sulfate. The analgesic

effect of M was measured by means of the tail-flick test, and the concentration

of M was measured by a standard fluorometric technique. Brain M levels corresponded quantitatively to analgesic effect on acute M administration in regard

both to magnitude and to time course of effect. Tolerance development was

observed after 24 hours of chronic treatment, and pronounced tolerance and

dependence were apparent at 72 hours. Upon cessation of treatment in mice,

brain M levels returned to baseline within 6 hours while significant tolerance persisted for at least 24 hours. Following M withdrawal in rats, a 20 to 25% loss in

body weight was observed after 24 hours, however, this sign of dependence was

implanted at the beginning of the infusion regimen. This latter finding is of

theoretical and practical importance in the search for a better treatment of

narcotic addiction.

PATRICK, G.A., DEWEY, W.L., HARRIS, L.S., DAVES, E.D. and NEUMANN, J.H.

Relationship of brain morphine concentration to tail-flick activity and tolerance

and dependence development in chronically infused rats. The Pharmacologist

16(2): 71 (1974)

For abstract, see Section II. Drug Metabolism and Chemistry.

PATRICK, G.A., DEWEY, W.L., SPAULDING, T.C. and HARRIS, L.S. Relationship of

brain morphine levels to analgesic activity in acutely treated mice and rats and

in pellet-implanted mice. The Journal of Pharmacology and Experimental

Therapeutics (in press)

The relationship of brain morphine concentration, determined fluorometrically, to tail-flick activity was investigated following acute and chronic

morphine treatment of mice and acute treatment of rats. Brain morphine levels

were quantitatively related to analgesic effect on acute administration, with levels

of 100 and 140 ng/g tissue corresponding to the ED-50 in mice and rats, respectively. Over a 90-minute time course following acute s.c. injection, the analgesic

effect of morphine in the tail-flick test lagged slightly behind morphine brain level

in both species. In mice implanted s.c. with. morphine pellets, significant analgesia and appreciable morphine brain levels appeared as early as 20 to 30 min.

after implantation. Increased brain morphine corresponded to increased analgesia

at 1 and 4 hr. after implantation. Tolerance was evident by 24 hr. after implantation and was maximal at 72 hr. Brain morphine remained elevated up to 144 hr.

319
Patrick, G.A., Dewey, W.L., Spaulding, T.C. and Harris, L.S. continued.

after implantation even though substantial encapsulation of the pellet occured within

72 hr. If pellets were removed at 72 hr., brain morphine declined to control

levels within 6 hr., but significant tolerance persisted for at least 24 hr. after

pellet removal. These results demonstrate that morphine is being absorbed from

the pellet up to 6 days after implantation and that the decreased analgesic activity

observed in the latter times is due to tolerance to the narcotic and not to a

decrease in absorption from the pellet.

PEARSON, J., RICHTER, R.W., BADEN, M.M., SIMON, E., HILLER, J. and

GROVER-JOHNSON, N. Studies on sites of binding and effects of narcotics

in the human brain. Proceedings of the VII International Congress of

Neuropathology (in press)

PEDIGO, N.W., DEWEY, W.L. and HARRIS, L.S. Determination and characterization of

the antinociceptive activity of intraventricularly administered acetylcholine in

mice. The Journal of Pharmacology and Experimental Therapeutics (in press)

Antinociceptive activity of intraventricularly administered acetylcholine

was quantitated in mice by the tail-flick and phenylquinone tests. Acetylcholine

was administered intraventricularly under light ether anesthesia in a 5 ul volume

of sterile saline and mice were retested ten minutes later. A dose-response curve

was established for acetylcholine (LD50 7.3 ug) which was potentiated significantly

by intraventricular neostigmine and blocked by intraperitoneal atropine but not by

atropine methyl nitrate or mecamylamine. The antinociceptive effect of morphine

was potentiated by intraventricularly administered acetylcholine. The acetylcholine-induced antinociception was blocked by five narcotic antagonists in the

same rank order of potency in which they antagonized the effects of morphine.

However, the sterospecificity of two narcotic antagonists, pentazocine and cyclazocine, was reversed in blocking acetylcholine and morphine induced antinociception.

Tolerance was demonstrated with chronic intraventricular administrations of acetylcholine and cross tolerance in morphine-pretreated mice was observed. Animals

tolerant to acetylcholine were not tolerant to the antinociceptive effects of morphine.

The results of this study have established the phonomenon of acetylcholineinduced antinociception and demonstrated similarities between this phenomenon and

morphine-induced antinociception. These data implicate the possible involvement

of central cholinergic mechanisms in the antinociceptive action of morphine.

PEDIGO, N.W., DEWEY, W.L., HARRIS, L.S. and ACETO, M.D. Antinociceptive activity of

intraventricularly administered acetylcholine in mice. Federation Proceedings (in press)

Antinociceptive activity of intraventricularly (ivt.) administered acetylcholine (ACh) was quantitated in mice by the tail-flick (T.F.) and phenylquinone (P.P.Q.) tests. ACh was administered iv-t. under anesthesia in a 5 ul

volume of sterile saline. Peak antinociceptive activity was observed at 10 mm.

and only slight activity existed at 20 min. Ivt. injections of procaine and pentobarbital were inactive, while ivt. choline was only weakly active. Dose-response

curves were established for ACh (ED50 7.3 ug in T.F. and 5.1 ug in P.P.Q.).

ACh was potentiated significantly by ivt. neostigmine and blocked by i.p. atropine

but not atropine methyl nitrate or mecamylamine. The antinociceptive effect of

morphine (M) was potentiated by iv-t. ACh. The ACh effect was blocked by 5

narcotic antagonists in the same rank order of potency in which they antagonized

the effects of M. However, the steriospecificity of 2 narcotic antagonists,

pentazocine and cyclazocine, was reversed in blocking ACh and M induced antinociception. Tolerance was demonstrated with chronic ivt. administrations of ACh

and cross tolerance was observed in M-tolerant mice. Animals tolerant to ACh

were not tolerant to the effects of M. The results of this study have established the

phenomenon of ACh induced antinociception and demonstrated both similarities and

differences between this phenomenon and M-induced antinociception.

320
PETERSON, D.W. and SPARBER, S.B. Increased fixed-ratio performance and differential

d- and l-amphetamine action following norepinephrine depletion by intraventricular 6-hydroxydopamine. The Journal of Pharmacology and Expkrimental

Therapeutics 191(3): 349-357 (1974)

The intraventricular injection of 200 mu-g of 6-hydroxydopamine (6-

OHDA) into rats trained to respond on a fixed-ratio 30 (FR 30) schedule of food

reinforcement resulted in decreased response rates which returned to predrug

rates after 8 days. The response rates then gradually increased and remained

significantly greater for up to 156 days after the 6-OHDA treatment. Vehicleinjected control animals did not change their rates over this same period of time.

While the 6-OHDA treatment did increase reinforced responding, it did not increase

the number of unreinforced (extinction) responses or exploratory activity. The

dose of 6-OHDA used depleted hypothalamic and midbrain-striatal norepinephrine

(NE) measured 1 week later, but midbrain-striatal dopamine was unchanged, At

the end of the behavioral study, 5 months later, NE levels had partially recovered

and the extent of this recovery was positively correlated with the increased

response rates. The suppression of the FR responding by d-amphetamine was not

altered by the 6-OHDA treatment. When l-amphetamine was given to the same

rats, the behavioral suppression was significantly attenuated in the group that had

received 6-OHDA. These results suggest a relatively greater importance of NE

in some of the operant behavioral actions of l-amphetamine than of d-amphetamine.

PETERSON, G.R. and SHUSTER, L. Effects of morphine on choline acetyltransferase

and acetylcholinesterase in cultured mouse neuroblastoma. Proceedings of the

Western Pharmacological Society 16: 129-133 (1973)

The neuroblastoma system affords an opportunity to investigate neuronal

functions in vitro. Cultured neuroblastoma cells possess choline acetyltransferase

(ChAc) and acetylcholinesterase (AChE) activities, both of which are thought to be

regulatory enzymes in this system. In addition, there is evidence for the hypothesis that cholinergic mechanisms are involved in. the actions of narcotic drugs

on neurons.

PETERSON, G.R., WEBSTER, G.W. and SHUSTER, L. Effect of narcotics on enzymes of

acetylcholine metabolism in cultured cells from embryonic chick brains.

Neuropharmacology 13: 365-376 (1974)

The addition of 2•5 x 10-4 M morphine sulphate to cultures of cells dissociated from the brains of chick embryos brought about 25-50% increases in the

activities of neuronal choline acetyltransferase (ChA) and acetylcholinesterase

(AChE). Narcotic drugs also increased the activities of these two enzymes in the

brains of developing chicks in vivo.

The effects of morphine on the cultures were antagonized by naloxone but

not by propranolol. Both L(+)-dextrorphan and D(-)-levorphanol produced similar

increments in the enzyme activities of cultured cells.

The activities of ChA and AChE in cultured cells from embryos that had

been previously exposed to narcotics were unaffected, by the addition of morphine

to the cultures. Dissociated brain cells from treated embryos also exhibited

tolerance to the inhibition of leucine incorporation by high concentrations of

morphine.

321
PILLARD, R.C. Medical progress. Marihuana. New England Journal of Medicine 283: 294-

303 (August, 1970)

PIRCH, J.H. and OSTERHOLM, K.C. Influence of alpha-methyltyrosine on enhancement

of shuttle-box avoidance by marijuana and pentobarbital. Research Communications in Chemical Pathology and Pharmacology 8(2): 203 (June, 1974)

Marijuana extract administered orally at doses of 20 or 40 mg/kg of

delta-9-THC enhanced shuttle-box performance of poorly performing rats. A

similar effect was produced by 5 or 10 mg/kg of pentobarbital. given intraperitoneally. Pretreatment with alpha-methyltyrosine, 50 mg/kg, antagonized the

facilitative effect of marijuana but not that of pentobarbital. The results indicate that the facilitative effect of marijuana on shuttle-box performance involves

catecholamines and that the actions of marijuana and pentobarbital to enhance

shuttle-box avoidance are exerted through different mechanisms.

PRUITT, D.B., GRUBB, M.N., JAQUETTE, D.L. and BURKS, T.F. Intestinal effects of

5-hydroxytryptamine and morphine in guinea pigs, dogs, cats and monkeys.

European Journal of Pharmacology 26(2): 298-305 (May, 1974)

Intestinal introluminal pressure was measured in vivo in anesthetized

guinea pigs, dogs, cats and monkeys. In guinea pigs; but not in the other species,

the intestinal stimulatory effect of 5-hydroxytryptamine was antagonized by morphine. The 5-HT-blocking action of morphine in intestine seems to be unique to

the guinea pig.

PURI, S.K., COCHIN, J. and VOLICER, L. Effect of morphine sulfate on adenylate

cyclase and phosphodiesterase activities in rat corpus striatum. Life Sciences

(in press)

The effect of morphine sulfate (MS) on adenylate cyclase (AC) and phosphodiesterase (PDE) activities in the rat striatum was investigated. MS produced

a dose-dependent increase in basal AC activity and did not alter sodium fluorideinduced stimulation both in vivo (7.5-30 mg/kg, 1 hr pretreatment, i.p.) and in

vitro (1-100mu-M). In vitro, when submaximal effective concentrations of dopamine

and MS were combined, there was an additive effect. However, administration

of MS in vivo did not alter dopamine-induced stimulation of AC activity. MS, in

vitro and in vivo inhibited PDE activity in a dose-dependent manner only with the

high substrate concentration (3.3 x 10-3 M cyclic AMP). Preliminary results from

this study indicate that morphine affects the cyclic AMP system.

PURI, S.K., VOLICER, L. and COCHIN, J. Changes in the striatal adenylate cyclase (AC)

activity after acute and chronic morphine sulfate (MS) administration. The Pharmacologist 16(2): 269 (1974)

MS affects the striatal dopaminergic system in rat brain. Since dopamine

(DA)-sensitive AC has been found in the striatum, we investigated the effect of

acute and chronic administration of MS on AC activity. AC activity was measured

by the method of Krishna et al.

14C-ATP as a substrate.

(J. Phar. Exp. Therap. 163, 379, 1968) using

Acute MS administration (7.5-30mg/kg, i.p., 1 hr

pretreatment) produced a dose-dependent increase in AC activity. In vitro

addition of MS (0.1-100 mu-M) also stimulated AC in a dose-dependent manner.

MS, both in vivo and in vitro, did not alter NaF-induced stimulation of AC activity

and did not block DA-induced stimulation. Naloxone, an MS antagonist, increased

AC activity and failed to antagonize MS-induced stimulation. The rats made dependent on MS (maximum dose, 100 mg/kg, 3 times a day) showed an increase in

322
Puri, S.K., Volicer, L. and Cochin, J. continued

the basal AC activity. This activity remained elevated for 72 hrs and returned

to control 96 hrs after the last MS injection. Addition of DA in vitro, which

stimulated AC activity in non-dependent rats, did not stimulate AC activity

during withdrawal. These results suggest that both acute and chronic MS administration affect the AC system.

QUOCK, R.M. and HORITA, A. Apomorphine: Modification of its hyperthermic effect in

rabbits by p-chlorophenylalanine. Science 183: 539 (1974)

The hyperthermic response of rabbits to apomorphine. a dopaminergic

agonist, is abolished by prior treatment with p-chlorophenylalanine. If such 5-

hydroxytryptamine (5-HT)-depleted animals are administered a peripherally

acting decarboxylase inhibitor plus 5-hydroxytryptophan, central stores of 5-HT

are regenerated and the hyperthermic response to apomorphine is restored in

part. The effects of apomorphine in rabbits with elevated concentrations of 5-HT

are not different from those in control animals. The behaviorai effects of apomorphine appear to be constant in all groups of animals tested. It is suggested

that the hyperthermic effects of apomorphine in rabbits require the presence of

5-HT.

QUOCK, R.M. and HORITA, A. The interaction of naloxone with apomorphine induced

hyperthermia in rabbits. Proceedings of the Western Pharmacological Society

16: 68 (1973)

Apomorphine, a central dopaminergic agonist, has been demonstrated

in our laboratory to cause a dose dependent hyperthermic response in rabbits.

The fact that apomorphine, a non-analgesic derivative of morphine, also causes

some narcotic analgesic like responses led us to investigate whether the hyperthermia induced by apomorphine was a purely dopaminergic response or also

involved stimulation of some unidentified receptor sites acted upon by morphine.

The present report describes the interaction between the narcotic antagonist naloxone and apomorphine and of attempts to uncover the underlying mechanism of interaction.

RANDRUP. A. The neuroleptics. Pharmacology of Neuroleptive Drugs, Vol. 5.

Edited by J. Bobon and P. Janssen. New York: Karger, 1970. Pp. 23-33.

RANDRUP. A. and JONAS, W. Brain dopamine and the amphetamine-reserpine

interaction.

(July, 1967)

Journal of Pharmacy and Pharmacology 19: 483-484

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RANDRUP, A. and MUNKVAD, I. Biochemical, anatomical and psychological

investigations of stereotyped behavior induced by amphetamines. Amphetamines

and Related Compounds: Proceedings of the Mario Negri Institute for

Pharmacological Research, Milan, Italy. Edited by E. Costa and S. Garattini.

New York: Raven Press, 1970. Pp. 695-713.

Amphetamine elicits a highly stereotyped form of hyperactive

behavior when given to mammalian and avian species in doses of 1 to 20 mg/kg.

Experiments with rats have indicated that the stereotyped activity is produced by an

effect of amphetamine upon dopamine in cropus striatum. New evidence,

which supports this interpretation, is presented. This evidence includes

biochemical analysis of the interaction of reserpine with various amphetamines,

micro-injections of dopamine and p-hydroxyamphetamine into corpus striatum,

etc.

The stereotyped behavior of rats has been subjected to more detailed

psychological analysis and this has shown that amphetamine even in low doses

produces a selective stimulation: some activities (e.g., locomotion, rearing,

sniffing) are increased while others (e.g., grooming) are concurrently

decreased. With higher doses the activation becomes gradually more selective;

at 10 mg/kg the behavior consists only of continuous sniffing, licking or

biting of a small area and thus has a highly stereotyped character. Learned

behavior (lever-pressing for shock avoidance) may be blended into the

stereotypy. Selective stimulation leading to extreme stereotypy was also

observed in primate monkeys given amphetamine.

Amphetamines in larger doses in humans have produced psychoses

with schizophreniform symptoms including stereotypy. It is, therefore,

thought that study of abnormal behavior produced by amphetamine may be

of interest for psychosis research. It is also hoped that these studies may

contribute to the understanding of amphetamine addiction and of certain

features of normal behavior (e.g., regulation of behavioral variability

and excitation level).

RANDRUP, A. and MUNKVAD, I. Brain dopamine and amphetamine induced stereotyped

behaviour. Acta Pharmacolosia et Toxicologia 25 (4): 62 (1967)

RANDRUP, A. and MUNKVAD, I. Correlation between specific effects of

amphetamines on the brain and on behavior. Current Concepts on Amphetamine

Abuse. Edited by E.H. Ellinwood Jr. and S. Cohen. Washington, D.C.:

U.S. Government Printing Office, 1972.

Animal experiments on the pharmacological effects of amphetamines

have been performed in our laboratory for several years, This research was

originally inspired by the clinical reports about an “amphetamine psychosis,”

and it was hoped that our investigation would yield new information about the

brain mechanisms underlying such psychoses. From the outset we were

interested in possible correlations between the effects of amphetamines on the

central nervous system and their specific behavioral effects, particularly the

elicitation of abnormal behavior. The purpose of this presentation is to

review the correlations which have been uncovered thus far. Our own

data on brain effects are mostly biochemical, although some data on anatomic

localization are included.

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RANDRUP, A. and MUNKVAD, I. Evidence indicating an association between

schizophrenia and dopaminergic hyperactivity in the brain. Orthomolecular

Psychiatry 1: 2-7 (1972)

The evidence indicating an association between schizophrenia

and brain dopamine is of pharmacological nature. It emerges from

studies of two classes of drugs: amphetamines which can produce a

schizophrenic-form psychosis and neuroleptics which can antagonize

psychotic symptoms in schizophrenic patients.

RANDRUP, A. and MUNKVAD, I. Mechanisms by which amphetamines produce stereotypy,

aggression and other behavioural effects. VIII Congress Collegium International

Neuro-Psychopharmacologicum, Copenhagen. Praha: Avicenum Press, 1972.

The dopaminergic systems in the forebrain(nucleus caudatus, putamen and

some adjacent areas) appear to have effects, in mammals, on’many perhaps all

types of behaviour, and these effects tend in the extreme to change the whole pattern

of behaviour into a stereotyped, apparently aimless one. At the same time each type

of behaviour e.g. locomotion, aggressive and other social activities, drinking, etc.

appear to be influenced also by other brain systems. The behavioural effects of a

drug, which like amphetamines acts on several brain systems (dopaminergic, noradrenergic, serotonergic and possibly others) are therefore bound to be complicated.

For example: smaller doses of d-amphetamine cause increase in locomotion of rats

while larger doses cause inhibition. The increased locomotion can be stereotyped,

consisting in repetition of a fixed route in a restricted part of the cage. Brain dopamine plays a role in these locomotor effects, but locomotion is also influenced by

brain noradrenaline. Recent findings about the mechanisms by which amphetamines

produce their behavioural effects will be reviewed. Real and apparent contradictidns in the most recent publications about experiments with brain lesions will be

discussed; the ektent of lesions in the striatum and the slow recovery of behaviour

after such lesions seem to be important items in this context.

RANDRUP, A. and MUNKVAD, I. Mechanisms by which amphetamines produce stereotypy,

agression /sic/ and other behavioural effects. Psychopharmacologia 26(Supplement):

37 (1972)

For abstract, see Section II. Drug Chemistry and Metabolism.

RANDRUP, A. and MUNKVAD, I. Pharmacological studies on the brain mechanisms underlying two forms of behavioural excitations: Stereotyped hyperactivity and “rage.”

Annals of the New York Academy of Sciences 159: 928-938 (1969)

The effects of excitant or stimulant drugs are often measured by apparatus

recording “general activity” such as jitter cages, treadmills, or cages traversed

by light beams. By these methods, quantitative data are obtained and the effects

of various drugs and various doses can be compared. Stimulant drugs may, however, also differ qualitatively, with respect to the forms of behavior. Everett and

Wiegand (1962) stress the importance of these qualitative differences, giving a drastic

example of two drugs (5-hydroxytryptophane and 3,4-dihydroxyphenylalanine, DOPA),

both of which were reported to produce “excitement” or “central excitation” when

given after a monoamine oxidase inhibitor. The former of these drugs was, however, found to produce jerks, abduction of the limbs, tremor, and convulsions,

while the latter produced increasing degrees of organized motor activity, increased

irritability, and aggressiveness. Another example is found in a detailed study of

some amphetamine derivatives performed with cats by Muller-Calgan & Hotovy

(1961). In the doses used, amphetamine and a norcamphane derivative (H610) both

produced increased running, but while H610 also enhanced hopping, climbing. and

mewing, these activities were depressed by amphetamine.

325
Randrup, A. and Munkvad, I. Pharmacological studies on the brain. . . continued

In the present paper we shall describe two forms of strong drug-induced

excitation: stereotyped hyperactivity and “rage.” Evidence concerning the neural mechanisms underlying these forms of hyperactivity will also be presented and discussed.

RANDRUP, A. and MUNKVAD. I. Relation of brain catecholamines to aggressiveness

and other forms of behavioural excitation. Aggressive Behaviour. Edited by

S. Garattini and E.G. Sigg. Amsterdam, the Netherlands:. Excerpta: Medica Foundation, 1969

RANDRUP, A. and MUNKVAD, I. Roles of brain noradrenaline and dopamine in

pharmacologically induced aggressive behaviour. Symposium on Pharmacological

Agents and Biogenic Amines in the Central Nervous System. Edited by J. Knoll

and K. Magyar. Budapest, Hungary: Akademia Kiado, 1973. Pp. 131-139.

RANDRUP, A., and MUNKVAD, I. Stereotyped behavior. Section 25 of The International Encyclopedia

of Pharmacology and Therapeutics (in press)

RANDRUP, A. and MUNKVAD, I. Stereotype behavior produced by amphetamine and

other substances. Investigations on the mechanism of action. NeuroPsychopharmacology, Vol. 5. Edited by H. Brill, J.O. Cole, P. Deniker,

H. Hippius and P.B. Bradley. Amsterdam, the Netherlands: Excerpta

Medica Foundation, 1967. P. 1224.

Since our report to the fourth C.I.N.P. meeting about amphetamineinduced abnormal, stereotype behavior we have extended our studies of the underlying

neural mechanisms.

It was found that rats pretreated with alpha-methyl-p-tyrosine, which

inhibits the synthesis of DOPA, remained quiet after amphetamine, and that

the stereotype sniffing and biting activity could be restored by 1-DOPA in

relatively low dose (100-200 mg/kg s.c.). Stereotype behavior could also

be produced in untreated animals by 1-DOPA alone, but then a larger

dose was necessary (1200 mg/kg s.c.).

Catecholamines thus seem to play an important role in the mechanism

which produces stereotype behavior but neither alpha-nor-beta-adrenergic

receptors are involved, since blockade of these receptors does not inhibit

the amphetamine response. Possibly dopamine carries this activity.

Besides 1-DOPA other naturally occurring substances (5 HTP, tryptamine

and phenylethylamine) could also produce stereotype sniffing and biting activity

of rats. Acetylcholine, however, seems to inhibit this form of behavior,

since anticholinergic agents (1-hyoscyamine, scopolamine, benzhexol (artane),

caramiphen (parpanit, pentaphen) and benactyzine) were found to enhance the

amphetamine effect and reproduce stereotype activity, which had vanished

about 3 hours after amphetamine.

It is thus indicated that certain disturbances of equilibrium between

various monoaminergic mechanisms in the brain result in excitation and

stereotypy instead of normal varied activity.

The anatomical location of these monoaminergic mechanisms is now

also being studies. For this purpose we use intracerebral micro-injections

and electrophysiological methods; the preliminary results of this work will

be reported.

326
RANDRUP, A., MUNDVAD, I., FOG, R. and AYHAN, I.H. Catecholamines in activation

stereotypy and level of mood. Catecholamines and Behavior. Edited by A. J.

Friedhoff. New York: Plenum Press, 1974.

RANDRUP, A., MUNKVAD, I. and SCHEEL-KFÜGER, J. Mechanisms by which

amphetamines produce stereotypy, aggression and other behavioral

effects. Proceedings of the Symposia-held at the VIII Congress of the

Collegium Internationale Neuro-Psychopharmacologicum, Copenhagen,

Denmark, August 14-17, 1972. Edited by T.A. Ban, J.R. Boissier, G. J. Gessa,

H. Heimann, L. Hollister, H.E. Lehmann. I. Munkvad, H. Steinberg, F. Sulser,

A. Sundwall and 0. Vinar. Amsterdam, the Netherlands: North Holland

Publishing Company, 1973.

For abstract, see Section I. Methodology of Drug Research.

REICHMAN. L.B., SHIM, C.S., BADEN, M. and RICHTER, R. Development of tolerance to street heroin in addicted and nonaddicted primates. American Journal

of Public Health 63(9): 801-803 (1973)

Protocols of acute and chronic heroin administration to babonns were

tested to evaluate the effects of sporadic and continual drug usage on the handling

of an acute administration of various doses of street heoin. Animals were observed

during initial doses, during repeat dosage after a short lapse of time and during a

repeat dosage after a longer period of abstinence. The results indicate that acute

challenges with large and varying doses of heroin are well tolerated by the chronically addicted animal. A repeat dose of heroin on the same day as an initial dose

showed either no cumulative effect, or much less effect than the first dose. The

implications are that one dose of heroin can protect the user from the untoward

effects of an inadvertently large dose. This could be a mechanism for protection

of the addict against the potentially fatal effects of the large variations in heroin

content of the street bags he injects. The study further suggests that many acute

reaction deaths are not due to true pharmacologic heroin overdosage, but to

other factos, such as the effect of quinine, bacteria, sugars, colloids or an

immunologic reaction.

RENAULT, P.F., SHUSTER, C.R., HEINRICH, R. and FREEMAN, D.X. Marihuana:

Standardized smoke administration and dose effect curves on heart rate in humans.

Science 174: 589-591 (November, 1971)

For abstract, see Section I. Methodology of Drug Research.

327
RIBLET, L.A. and MITCHELL, C.L. The effect of cervical spinal section on the ability

of morphine to elevate the jaw jerk threshold to electrical stimulation of the

tooth pulp in cats. The Journal of Pharmacology and Experimental Therapeutics

180: 610-615 (1972)

The tooth pulp was stimulated in normal, full spinal section and hemisectioned preparations with either a single monophasic square wave pulse of 0.5-

msec duration or a train of four such pulses at 64 Hz. The effect of morphine

(2 mg/kg i.v.) upon the threshold voltages required to elicit the jaw jerk response

was different in the three preparations. In animals with intact spinal cords,

morphine was effective in elevating the jaw jerk threshold. In contrast, morphine

had no effect in animals with full spinal section. In addition, in animals in which

the cord was hemisectioned, morphine was less effective against tooth pulp stimulation on the side ipsilateral to the site of hemisection than on the contralateral

side. These findings suggest that morphine may exert its effect on tooth pulp

thresholds either directly or indirectly through a depressant action upon the caudal

portion of the spinal nucleus of the trigeminal nerve.

RICHTER, J.A. and GOLDSTEIN, A. Effects of morphine and levorphanol on brain

acetylcholine content in mice. The Journal of Pharmacology and Experimental

Therapeutics 175(3): 685-691 (1970)

For abstract, see Section II. Drug Chemistry and Metabolism.

RICHTER, J.A. and GOLDSTEIN, A. The effects of morphine-like compounds on the light

responses of the brine shrimp Artemia salina. Psychopharmacologia 17: 327-337

(1970)

Methods for the measurement of the light responses of Artemia nauplii

and adults are described. Although no effects of levorphanol were found on the

positive phototaxis of nauplii, this compound inhibited and partially reversed the

negative phototaxis of adults. Levorphanol was also effective in adults after

removal of the compound eyes, indicating that it probably acts on the median eye

or its central connections in adults.

Methadone and dextrorphan (the inactive stereoisomer of levorphanol)

caused similar effects in adults, but morphine was inactive. Pentobarbital

inhibited the negative movement but induced very little positive phototaxis. Attempts

to reverse the effect of levorphanol with nalorphine pretreatment were unsuccessful.

Attempts to develop tolerance to levorphanol were also unsuccessful; the shrimp

died, apparently as a result of an increasing effect of the drug with time.

RICHTER, J.A. and GOLDSTEIN, A. Tolerance to opioid narcotics, II. Cellular tolerance

of levorphanol in mouse brain. Proceedings of the National Academy of Sciences

66(3): 944-951 (July, 1970)

For abstract, see Section II. Drug Chemistry and Metabolism.

328
RINGLE, D.A. and HERNDON, B.L. Binding of morphine by serum proteins of morphinetreated rabbits. Federation Proceedings 32: 2853 (1973)

The possibility that some aspects of tolerance to morphine are immunologic in nature has been considered by a number of investigators. Part of the

evidence suggesting an immunologic response to morphine is the occurrence of

a humoral factor after treatment with morphine. We have studied the effects of

long-term pretreatment with morphine on morphine binding by serum and serum

fractions in rabbits. Binding of morphine was measured by Sephadex gel elution

and equilibrium dialysis methods using C

14-labeled morphine. Results of our

investigations on rabbits have demonstrated an increase in morphine binding by

sera following morphine treatment with degree of binding related both to length

of pretreatment and to method of dosage. Dosage by chronic s.c. pellet implantation of morphine free base was more effective than daily s.c. morphine sulfate

injections. Preliminary findings have indicated that the increased binding is

associated with the globulin fractions prepared by ammonium sulfate precipitation. The results of these studies suggest that rabbits are capable of responding

immunologically to morphine through the production of an immunoglobulin directed

against the morphine configuration. Similar studies of this binding phenomenon in

other species as well as characterization of the morphine binding component are

now in progress.

RINGLE, D.A. and HERNDON, B. L. In vitro morphine binding by sera from morphinetreated rabbits. The Journal of Immunology 109: 174 (1972)

ROCHLIN, M., MILLER, J.W. and SPARBER, S.B. Studies on the central effects of

d and l phenoxybenzamine (PBZ). Federation Proceedings 33: 551 (1974)

A comparison was made between the ability of the enantiomers of PBZ

to block the uptake of -7-1 -Norepinephrine (

3H-NE) by rat brain hypothalamic

and striatal slices, as well as inhibit the suggested alpha adrenergically mediated

eating response to food satiated animals to in aventricularly administered NE.

Whereas both isomers inhibited the uptake of 3H-NE to equal extent in both areas

of rat brain (I50 6 x 10-5M), a selective effect of the isomers was noted for

blockade of the eating response. Doses of d-PBZ from 0.75 mu-g to 3 mu-g into

the lateral ventricle two hours before NE (10 mu-g) inhibited the eating response

the following hour in a dose related manner. Three mu-g produced a complete

blockade. A dose of 5.5 mu-g of the 1-PBZ inhibited the eating response only

to 55% of control eating. Time response studies with d-PBZ (1.0 mu-g) indicated

its maximal blocking effect on the eating response occurred two hours after intraventricular administration. The eating response to NE returned within 1 to 2

days after d-PBZ. These data support the contention that alpha-type receptors

within the CNS are differentially affected by d and 1 isomers of PBZ in a manner

similar to that reported for vas deferens (Miller et al., 1971).

329
ROEHRS, T. and KHAZAN, N. REM sleep rebound and EEG correlates in methadone

dependent rats upon withdrawal. The Pharmacologist 15: 167 (1973)

Rats prepared with chronic electrodes for recording of the EEG and EMG

were made dependent on methadone by its administration through chronic

indwelling i.v. cannulas. Methadone was administered at an initial dose of 0.15

mg/kg/hr and increased on successive days. reaching 2 mg/kg/hr on the ninth

or tenth day. Discontinuation of the injections then precipitated the abstinence

syndrome. The primary EEG manifestation of abstinence was a decline in the

voltage output of the entire sleep-awake cycle, a phenomenon that correlated with

the behavioral hyperirritability of the abstinent rat. The duration of slow wave

sleep (SWS) and REM sleep were significantly enhanced within the first six to ten

hours after withdrawal. Both SWS and REM sleep then declined to minimal, levels

and returned to base-line values by the third day. After this decline, a significant

and protracted REM rebound occurred extending up to the twelfth day of abstinence

studied. These EEG and behavioral findings provide further evidence of an analogous state of abstinence produced by methadone and morphine.

ROIZIN, L., HELPERN, M., BADEN, M.M., KAUFMAN, M. and AKAI, K. Toxosynpathies (a multifactor pathogenic concept). Drug Abuse: Current Concepts and

Research. Edited by W. Keup. Springfield, Illinois: Charles C. Thomas, 1972.

Pp. 97-116.

For abstract, see Section II. Drug Chemistry and Metabolism.

ROPPOLO, J.R., WERNER, G., WHITSEL, B.L., DREYER, D.A. and PETRUCELLI,

L.M. Phencyclidine action on neural mechanisms of somesthesis. Neuropharmacology 12(5): 417-431 (1973)

The effect of phencyclidine on the activity of neurons in somatic sensory

areas I and II was determined in Rhesus monkeys. In the behaviorally significant

dose range of 200-300 mu-g/kg, phencyclidine augmented the neural responses to

natural, cutaneous stimuli in somatic sensory area II consistently and drastically.

With neurons in somatic sensory area I, the phencyclidine effect was in the same

dose range variable and inconsistent; but, in almost all instances different from the

changes in neural activity which accompany slow wave sleep.

The experimental findings are interpreted as evidence for a relatively

specific phencyclidine action on the phylogenetically older and more primitive

somesthetic projection system to somatic sensory area II.

ROSCHENTHALER, R., DEVYNCK M.A., FROMAGEOT, P. and SIMON, E.J. Inhibition

of the synthesis of 5s ribosomal RNA in E. coli by levallorphan. Biochirnica et

Biophysics Acta 182: 481 (1969)

synthesis

Levallorphan (1. 54. 10-3 M) inhibits RNA biosynthesis by 70% whereas the

of protein is inhibited by 14%. The residual synthesis of tRNA under such

conditions is greater by at least a factor of 2 than that of high molecular weight

RNA. mRNA synthesis, on the contrary, seems to be only slightly inhibited or not

at all. Levallorphan therefore exhibits effects similar to levorphanol.

As the origin of 5-S RNA has been the subject of recent discussion we

analyzed the extent of its synthesis in the presence of levallorphan. It has been

found that 5-S RNA synthesis is inhibited by the drug at least as profoundly as high

molecular weight RNA, a result which puts the 5-S RNA in the same class as the

ribosomal RNA’s and suggests that the same type of control mechanism regulates

the synthesis of 5-S, 16-S and 23-S RNA’s.

330
ROSENBERG, H.C. and OKAMOTO, M. Electrophysiology of barbiturate withdrawal in

the spinal cord. Federation Proceedings 33: 528 (1974)

Cats were made physically dependent on sodium pentobarbital administered

twice daily via intragastric route using the maximally tolerable dosing technique

(2nd. Int’l. Symp. Drug Addiction). All animals treated this way exhibited signs

of severe dependence, including grand mal type convulsions. At various times

after abrupt withdrawal of the drug, electro-physiological measurements of spinal

cord activity were made. Under volatile anesthesia, the neuraxis was sectioned

at C-l and artificial respiration was begun. The lumbar cord was exposed and

peripheral nerves of one hindleg were prepared for stimulation. Action potentials

were recorded from ipsilateral L-7 and S-1 ventral roots that had been cut near

their exit through the dura mater. Following single, supramaximal stimuli to the

sciatic trunk, there was little alteration in the size of the monosynaptic (2-N)

response, but the polysynaptic response was increased, and the duration of discharge was increased in abstinent animals as compared to controls. Stimulating

specific motor nerves, the rate of recovery of the 2-N synapse was increased.

The relationship between 2-N post-tetanic potentiation (PTP) and frequency of conditioning tetanic stimuli was shifted in the direction of lower frequencies. The size

of the motor neurone pool, as estimated by maximum PTP, was not changed during

abstinence, but the 2-N discharge zone was slightly enlarged.

ROSENBLATT, J.E., JANOWSKY, D.S., DAVIS, J.M. and EL-YOUSEF, M.K. The

augmentation of physostigmine toxicity in the rat by delta-9-tetrahydrocannabinol.

Research Communications in Chemical Pathology and Pharmacology 3(3): 479-482

(1972)

Sprague-Dawley rats were treated with delta-9-THC (2 mg/kg) and physostigmine salicylate (0.4 mg/kg) or with physostigmine salicylate alone. Seventeen

rats received the combined THC-physostigmine treatment; of these animals, 13

died and four survived. Seventeen rats received physostigmine salicylate and propylene-glycol serum complex without THC; of these animals, two died and 15 survived.

This difference was highly significant (p is less than .0002). Both atropine and

methylscopolamine decreased the lethality of the THC-physostigmine combination.

Delta-9-THC appears to augment physostigmine toxicity in the rat.

ROSENCRANS, J.A. and SHEARD, M.H. Effects of an acute stress on forebrain 5-hydroxytryptamine (5-HT) metabolism in C.N.S. lesioned and drug pretreated rats.

European Journal of Pharmacology 6: 197 (1969)

C.N.S. lesioned or drug pretreated male albino rats were subjected to a

l hr horizontal oscillation stress. An analysis of forebrain 5-HT and 5-HIAA

levels indicated that p-CPA pretreatment or M.F.B. lesions facilitated 5-HT turnover in response to stress. Raphe lesions, on the other hand, prevented this

latter facilitation of indolamine turnover. The results obtained were explained on

the basis of an operative negative feedback system in stressed rats. The lack of

a change in raphe lesioned rats, further reinforced the concept that most forebrain

5-HT containing neurons are the result of axons extending from this nucleus.

331
ROSENFELD, G.C. and BURKS. T.F. Single dose tolerance to morphine hypothermia

in rats. Proceedings of the 6th International Congress of Pharmacbiogy,

Helsinki, Finland, July 20-25, 1975.

Temperature responses to morphine were studied in outbred (TIMCO,

Houston) Sprague-Dawley male rats. Initial subcutaneous injections of morphine

(10 mg/kg) produced biphasic changes in rectal temperature: a fall in temperature

of approximately 2° C. followed by a small rise of 0.5-1.0° above preinjection

temperature. Responses to a second 10 mg/kg dose or morphine depended on the

interval of time separating the two injections. When the second morphine injection was given within seven days of the first, the hypothermic component of the

response was attenuated and the hyperthermic component was exaggerated. Maximum

tolerance to the hypothermic effect of morphine occurred 48-72 hours after the

initial dose. A second dose of morphine was fully effective in comparison with the

first when the two were separated by 15 days. Qualitatively similar results were

obtained in rats maintained on high (300 mg/kg per day) doses of morphine: loss

of the hypothermic response and exaggeration of the hypothermic response. In

these rats, a single 10 mg/kg dose of morphine did not elicit a fall in temperature

until after at least seven days of abstinent withdrawal, after which responsiveness

increased. The hypothermic response was fully restored after 30 days of abstinence.

Our results indicate that a single small dose of morphine can induce early tolerance

which is comparable to that produced by repeated large doses of morphine. The

changes in responsiveness caused by the single dose of morphine can persist for

several days after which recovery occurs.

ROSENMAN, S.J. and SMITH, C.B. 14C-catecholamine synthesis in mouse brain during

morphine withdrawal. Nature 240: 153-155 (1972)

SANDERS-BUSH, E. Recent studies on the mechanism of action of chlorinated amphetamines. Ser

tonin and Behavior. Edited by J. Barchus and E. Usdin. New York: Academic Press, 19

SANDERS-BUSH, E., BLUMBERG, J.B. and SULSER, F. Biochemical effects

of chlorinated amphetamine derivatives. Psychopharmacologia 26(Supplement):

34 (1972)

The administration of p-chloroamphetamine (PCA) to rats causes a

number of changes in cerebral biochemistry which are not produced by

amphetamine. Among these are marked alterations in the metabolism and

release of intraventricularly-administered norepinephrine -H3, and a simultaneous

decrease in the cerebral levels of serotonin (5HT) and its major metabolite,

5-hydroxyindole acetic acid. Recently, by direct examination of cerebral

tryptophan hydroxylase, we have found that the administration of PCA and

p-chloromethamphetamine to rats causes a pronounced reduction in

cerebral tryptophan hydroxylase with no change in the activity of

5-hydroxytryptophan decarboxylase. Since these drugs do not inhibit

tryptophan hydroxylase if added in vitro, experiments were designed to

study the mechanism of the decrease in enzyme activity which follows their

in vivo administration. The in vivo formation of a metabolite of PCA

which inhibits tryptophan hydroxylase, does not appear to occur. Our

results suggest that PCA may reduce the amount of active enzyme without

altering its properties. Following the administration of PCA to rats, the

uptake of 5HT-H3 into a crude suspension of synaptosomes and mitochondria

is reduced. Both the enzyme inhibition and the blockade of uptake are

extremely long-lasting. Two weeks following the administration of PCA

(10 mg/kg, i.p.), the concentration of 5HT and the activity of tryptophan

hydroxylase were significantly reduced in all regions of the brain and in

332
Sanders-Bush, E., Blumherg, J.B. and Sulser, F. Biochemical effects... continued

the spinal cord. The most pronounced reduction was found in the striatum

and cerebral cortex. Likewise, the uptake of 5HT-H3

 into crude synaptosomal

preparations of specific brain regions was significantly reduced in all areas,

with the most pronounced decrease in the cerebral cortex. In contrast to

amphetamine, PCA lowers the endogenous level of cyclic AMP in brain;

the possible significance of this change in relation to the other effects of

PCA will be discussed.

SANDERS-BUSH, E., BUSHING, J. A. and SULSER, F. Long-term effects of p-chloroamphetamine of tryptophan hydroxylase activity and on the levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in brain. European Journal of

Pharmacology 20: 385-388 (1972)

The i.p. administration of a single dose of 10 mg/kg of p-chloroamphetamine to rats causes a reduction in the activity of cerebral tryptophan hydroxylase

and a decrease in levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid

in brain for as long as 4 months after injection. Two weeks after injection, the

activity of tryptophan hydroxylase and the level of 5-hydroxytryptamine in brain

are reduced by 59 and 53% respectively. The irreversible tryptophan hydroxylase

inhibitor, p-chlorophenylalanine, also decreases the brain level of 5-hydroxytryptamine; however, this effect has disappeared 2 weeks after injection.

SANDERS-BUSH, E., BUSHING, J. and SULSER, F. P-chloroamphetamine: Inhibition of

cerebral tryptophan hydroxylase. Biochemical Pharmacology 21: 1501-1510 (1972)

Earlier experiments have suggested that the simultaneous decrease in

the levels of 5-hydroxytryptamine (5HT) and 5-hydroxyindole acetic acid (5HIAA)

in brain following the administration of p-chloroamphetamine and E-chloromethamphetamine may be the consequence of an inhibition of the synthesis of cerebral

5HT. In the present investigations, the effects of these drugs have been examined

on the activity of cerebral tryptophan hydroxylase. The addition in vitro of either

p -chloroamphetamine or p-chloromethamphetamine does not reduce the activity of

tryptophan hydroxylase isolated from brainstems of rats. Under similar conditions,

p -chlorophenylalanine causes marked inhibition. However, when tryptophan hydroxylase was assayed in preparations obtained from brains of rats treated 16 hr previously with p-chloroamphetamine, a dose-related reduction in the activity of the

enzyme was observed. Experiments involving various combinations of enzyme preparations from control rats and from rats pretreated with p-chloroamphetamine do

not indicate the presence of an inhibitor in the preparations isolated from rats pretreated with the drug. Moreover, the reduction in enzyme activity was not removed

by dialysis. Kinetic studies showed that the Km values for tryptophan and DMPH4

were the same for the enzyme isolated from control rats and from rats pretreated

with p-chloroamphetamine. The reduction of cerebral 5HT and the decrease in

the activity of tryptophan hydroxylase occur simultaneously; both effects are still

present 6 days following a single dose of 10 mg/kg of p-chloroamphetamine. It is

concluded that the inhibition of cerebral tryptophan hydroxylase by p-chloroamphetamine can satisfactorily explain the prolonged reduction in the levels of 5HT and

5HIAA in brain.

333
SATTIN, A., RALL, T.W. and ZANELLA, J. Regulation of cyclic AMP levels in guinea

pig cerebral cortex by interaction of alpha-adrenergic and adenosine receptor

activity. The Journal of Pharmacology and Experimental Therapeutics (in press)

Direct assay of cyclic AMP in guinea pig cerebral cortex in vitro has

shown that an alpha-adrenergic receptor that was previously found to increase

tissue content of cyclic AMP requires the co-presence of adenosine. This alphaadrenergic receptor complex was characterized with blocking agents and contrasted

with other activities by examining the effect of other biogenic amines on cyclic

AMP content in the presence of adenosine. Phentolamine (but not propranolol)

reduced the potentiated response to norepinephrine (or epinephrine) + adenosine

to the level seen with adenosine alone. Theophylline, an adenosine antagonist,

blocked the entire effect of NE + adenosine. The failure of a high Mg++/Ca++

ratio to block the effect of NE + adenosine argues against indirect mediation of

the alpha-receptor effect via the release of K

+

 or via an unknown neurohumoral

agent. The complex variety of potentiative interactions between biogenic amines

and adenosine is unique to brain. These interactions may be explained by the

proposed existence of both independent and dependent receptors. The dependent

receptors respond only to the co-presence of two or more neurohumoral agents.

An alternative explanation would involve a compartmentally selective impairment

of cyclic AMP degradation.

SCHANBERG, S.M. and COOK, J.D. Effects of acute and chronic methamphetamine on

brain norepinephrine metabolism. Current Concepts in Amphetamine Abuse.

Edited by E. Ellinwood, Jr. and S. Cohen. Washington, D.C.: U.S. Government

Printing Office, 1972.

SCHECHTER, M.D. and WINTER, J.C. Effect of BOL on the LSD induced alteration of

flicker discrimination in the rat. Archives internationales de Pharmacodynamie

et de Therapie 196(1): 64 (1972)

Rats were trained on a multiple schedule of positive reinforcement. A

stimulus light source flickering at 100 cycle/sec provided the discriminative

stimulus (Sd). Under the S

d

 condition, reinforcement was contingent upon an

FR10 schedule.

S

delta condition.

The same light source flickering at 30 cycle/sec constituted the

Brom-lysergic acid diethylamide (BOL), at doses of 1 and 3

mu-mol/kg had no effect on discriminative ability, whereas, 10 mu-mol/kg BOL

significantly decreased it. A dose of 0.2 mu-mol/kg lysergic acid diethylamide

(LSD), which by itself elevated discriminative ability, was shown not to be

effected by co-administration of the three doses of BOL. The results indicate

that BOL lacks LSD-like effects in this test system and the LSD congener is

incapable of antagonizing the LSD-induced alteration of discrimination when coadministered.

334
SCHECHTER, M.D. and WINTER, J.C. Effect of mescaline and lysergic acid diethylamide

on flicker discrimination in the rat. The Journal of Pharmacology and Experimental Therapeutics 177(2): 461 (1971)

Rats were trained on a multiple schedule of positive reinforcement. A

stationary light source flickering at 100 cps provided the discriminative stimulus

(Sd). In the presence of S

d

, reinforcement was contingent upon a fixed ratio 10

schedule. The same light source flickering at either 20 or 30 cps constituted the

S

delta period. Mescaline, at doses of 40 and 60 mu-mole/kg, produced a significant decrease in discriminative ability, whereas lysergic acid diethylamide (0.2,

0.3 and 0.4 mu-mole/kg) caused a significant increase. A dose of mescaline

(20 mu-mol/kg) which by itself had no significant effect on discrimination, significantly reduced the increase caused by lysergic acid diethylamide. Likewise, a subeffective dose of lysergic acid diethylamide (0.1 mu-mol/kg) significantly antagonized the depression of discriminative ability caused by mescaline. These results

indicate that flicker discrimination provides a sensitive measure of drug action

in the rat. The pharmacologic data suggest that lysergic acid diethylamide and

mescaline are mutually antagonistic in this system.

SCHEEL-KRÜGER, J. Behavioural and biochemical comparison of amphetamine derivatives,

cocaine, benztropine and tricyclic anti-depressant drugs. European Journal of

Pharmacology 18: 63-73 (1972)

The present biochemical studies demonstrate that tricyclic antidepressant

drugs, such as desipramine, imipramine and protriptyline, which inhibit the

reuptake process in central noradrenaline neurons, and benztropine, which inhibits

the reuptake process in central dopamine neurons do not increase the accumulation

of O-methylated noradrenaline. normetanephrine, nor-O-methylated dopamine,

3-methoxytyramine in the brain of rats pretreated with a monoamineoxidase inhibitor, nialamide.

The central stimulant drugs, d-amphetamine, l-amphetamine, p-chloroamphetamine and cocaine increased accumulation in the brain of both normetanephrine and 3-methoxytyramine. Furthermore these central stimulants decreased the

brain noradrenaline level; the brain dopamine level remained unchanged. Dextroamphetamine and l-amphetamine were equally active on brain noradrenaline metabolism,

whereas d-amphetamine was most potent on dopamine metabolism.

These results suggest that the effect on normetanephrine and 3-methoxytyramine in this biochemical test is correlated with catecholamine-releasing properties of the central stimulant drugs and not with an influence on the reuptake mechanism in catecholamine neurons. Comparative behavioral studies in the rats

demonstrate similarities between d-amphetamine, l-amphetamine, p-chloroamphetamine and cocaine with respect to development of locomotor and rearing activity

as well as stereotyped behaviour. Dextroamphetamine was 10 times more potent

than l-amphetamine with respect to locomotor activity and 4-6 times more potent

with respect to the development of stereotyped behaviour. Benztropine increased

locomotor and rearing activity but produced no stereotyped behaviour.

335
SCHEEL-KRÜGER, J. Central effects of anticholinergic drugs measured by the apomorphine gnawing test in mice. Acta Pharmacologia et Toxicologia 28: 1-16 (1970)

Apomorphine in doses ranging from 10 up to 60 mg/kg given subcutaneously to mice induced only weak gnawing behaviour and 10 mg/kg was without

effect. The addition of anticholinergic drugs given 15 min. before 10 mg/kg

apomorphine potentiated the gnawing behaviour. 9 tertiary and 3 quaternary drugs

were tested. Among these some quinuclidinylesters, scopolamine and benztropine

were found to be very active compared with atropine. The quaternary compounds

showed much weaker activity than the corresponding tertiary analogues. The

gnawing activity produced by atropine plus apomorphine was only weakly antagonized by the apomorphine antagonistic drug spiramide; physostigmine showed a

better inhibitory effect and combined treatment with spiramide and physostigmine

gave a pronounced antagonistic effect. Since the apomorphine gnawing behavior

is most probably related to an interaction with central dopamine receptors, these

findings suggest there is a central counter balancing dopaminergic-cholinergic

system.

SCHEEL-KRÜGER, J. Comparative studies of various amphetamine analogues demonstrating different interactions with the metabolism of the catecholamines in the

brain. European Journal of Pharmacology 14: 47-59 (1971)

Behavioural studies on the effects of amphetamine, methamphetamine,

phenmetrazine, pipradol, NCA and methylphenidate administered to rats pretreated

with reserpine or alphamethyltyrosine and additional biochemical analyses demonstrated that all six stimulants affected both brain dopamine and brain noradrenaline

metabolism.

The present study permits a distinct separation of these drugs into two

groups since the interaction with the catecholamines was found to be mediated by

two different mechanism of action: behaviourally, excitation, consisting of locomotor and stereotyped activities after amphetamine, methamphetamine and phenmetrazine, was virtually impossible to inhibit with reserpine even in extremely high doses

(50 mg/kg), but was, in contrast, strongly inhibited by alpha-methyltyrosine. Biochemically, the excitation in reserpinized rats was correlated with the metabolic

influence on a reserpine-resistant pool of dopamine.

The very similar behavioural effects produced by pipradrol, NCA, and

methylphenidate were in sharp contrast found to be correlated with the influence on

a reserpine-resistant pool of the catecholarnines and not with the newly synthesized

catecholamines.

Reserpine completely inhibited all behavioural and biochemical effects of

pipradrol, NCA and methylphenidate.

SCHEEL-KRYÜGER, J. On the possible interrelationship in mechanism of action

between morphine, amphetamine and neuroleptic drugs. Frontiers in

Catecholamine Research. Edited by E. Usdin and S.H. Snyder. New York:

Pergamon Press, 1973. Pp. 1027-1029.

336
SCHEEL-KRÜGER. J. Pharmacological studies on a counter -balancing adrenergic -

cholinergic system in the brain. Acta Physiologica Scandinavica 330

(Supplement): 66 (1969)

Previous papers have described the behavioural excitation with

increased locomotion and stereotyped behaviour induced by amphetamine

or apomorphine in rats and mice. Particularly, the stereotyped

behaviour seems produced by activating a doparninergic mechanism in

corpus striatum.

The results of this paper show that a cholinergic system exists,

which shows antagonism against this adrenergically provoked behaviour,

since the stereotypy is potentiated and prolonged by anticholinergica

(atropine, scopolamine) and weakly antagonized by cholinergica

(physostigimine, oxotremorine). Among the characteristic actions

for neuroleptica are the antagonism of amphetamine or apomorphine

induced stereotyped behaviour and development of catalepsy, which actions

are probably produced by blockage of adrenergic (dopaminergic?) mechanisms

in brain. Results of combined drug treatments of nenrolcptica and

anticholinergica or cholinergica show that the inhibitory activity of a

cholinergic system also contributes to the development of these characteristic

actions of neuroleptica.

It is concluded that a counterbalancing adrenergic-cholinergic

system exists in brain, which involves behavioral features as locomotor

activity and stereotyped behavior.

SCHEEL-KRÜGER, J. Some aspects of the mechanism of action of various stimulant amphetamine analogues. Psychiatria, Neurologia, Neurochirurgia 75: 179-192 (1972)

In the present paper the available evidence on the possible mechanisms of

action of amphetamine and various amphetamine derivatives is discussed. The

conclusion is that the central stimulant effects of these drugs are mainly correlated

with catecholamine-releasing properties, while the inhibitory influence of these

drugs on the reuptake mechanisms in dopamine and noradrenaline neurons is considered of secondary importance.

It is discussed that the moderate influence of amphetamine and other betaphenylisopropylamines on monoamine-oxidase is not related to the central potency

of these drugs. This effect seems mainly indirectly related to the effect of these

drugs on the release and the re-uptake mechanisms but is also of importance for

the protection of these drugs against a rapid inactivation and metabolism via oxidative deamination.

Finally evidence is presented, which allows a separation of various amphetamine derivatives into two groups due to the interaction with two different intraneuronal pools of the brain dopamine (and noradrenaline?).

SCHEEL-KRÜGER, J. Studies of various amphetamines, apomorphine and clonidine

on body temperature and brain 5-hydroxytryptamine metabolism in rats.

Psychopharmacologia 36: 189-202 (1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

337
SCHEEL-KRÜGER, J. Studies on the accumulation of O-methylated dopamine and noradrenaline in the rat brain following various neuroleptics, thymoleptics and aceperone.

Archives internationales de Pharmacodynamie et de Therapie 195: 372-377 (1972)

The influence of some neuroleptic drugs (chlorpromazine, chlorprothixene.

pimozide, spiramide), thymoleptic drugs (desipramine, imipramine) and the noradrenaline blocking drug aceperone on the accumulation of brain normetanephrine

and 3-methoxytyramine was studied in rats pretreated with a monoamine oxidase

inhibitor, pargyline. The results demonstrate that the neuroleptic drugs in common

produced a highly significant increase of O-methylated dopamine, 3-methoxytyramine, while the other drugs did not produce alteration on this metabolite. Chlorpromazine and chlorprothixene in a 10 mg/kg dose produced furthermore the largest

increase of O-methylated noradrenaline, normetanephrine (2.0 and 1.8 times the

control value, respectively). Spiramide (5 mg/kg) and pimozide in various doses

(1; 5 and 10 mg/kg) in common produced a small but signigicant increase of normetanephrine (1.4 times the control), whereas aceperone (10 mg/kg) and imipramine

(50 mg/kg) produced an even smaller (1.3 times the control) but still significant

increase of normetanephrine. None of the used drugs produced large changes on

the brain dopamine and noradrenaline levels.

SCHEEL-KRÜGER, J., BRAESTRUP, C., EPLOV, L. and NIELSEN, M. The

effect of amphetamine and reserpine on 3H-noradrenaline and its metabolites

synthesized from intraventricular injected 3H-dopamine. Acta Pharmacologica

et Toxicologica 35(Supplement I): 50 (1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

SCHEEL-KRÜGER, J., EPLOV, L. and NIELSEN, M. The effect of protriptyline on the

metabolism of labelled dopamine and noradrenaline in the rat brain. Psychopharmacologia 26(Supplement): 45 (1972)

For abstract, see Section II. Drug Chemistry and Metabolism.

SCHEEL-KRÜGER, J. and HASSELAGER. E. Studies of various amphetamines, apomorphine and clonidine on body temperature and brain 5-hydroxytryptamine metabolism

in rats. Psychopharmacologia 36: 189-202 (1974)

Amphetamine and various amphetamine derivatives, phenmetrazine,

pipradrol. methylphenidate and NCA can increase the concentration of 5-HIAA in

the rat brain without changing that of 5-HT. Metamphetamine produced a decrease

in 5-HT and no effect on 5-HIAA whereas p-hydroxyamphetamine produced no

effects on 5-HT and 5-HIAA. The experiments performed at different environmental

temperatures (12-14°C, 21-22°C and 21-28°C) with simultaneous measurements of

the body temperature indicate that no simple correlation exists between the drug

induced hyperthermia and the effect on 5-HIAA. The amphetamine and phenmetrazine effect on 5-HIAA seems to be related to hyperthermia whereas the pipradrol

and methylphenidate effect on 5-HIAA appears independent of hyperthermia.

Apomorphine (2 x 2.5 mg/kg) which activates central dopamine receptors produced

a significant increase in 5-HIAA whereas clonidine (0. 5 mg/kg) which activates

central noradrenaline receptors produced a significant decrease in 5-HIAA.

In conclusion, the effect of various amphetamines on 5-HT metabolism seems

very complex in mechanism of action and might be related to hyperthermia, to a direct

effect on 5-HT neurons and to the ratio between central dopamine/noradrenaline

receptor activation of these drugs.

338
SCHBEL-KRÜGER, J. and JONAS, W. Pharmacological studies on tetrabenazine induced

excited behaviour of rats pretreated with amphetamine or nialamide. Archives

internationales de Pharmacodynamie et de Therapie 206(1): 47-65

(November, 1973)

Tetrabenazine (50 mg/kg) injected 1 after various doses of

amphetamine (0.25-10 mg/kg) produced a 5-10 times potentiation of the

amphetamine-induced gross behavioural effects in rats: locomotion,

rearing and stereotyped activities. However, the amphetamine-tetrabenazine excitation was shortlasting. 6-36 min dependent on the amphetamine

dose. Tetrabenazine (50 mg/kg) injected after cessation of the amphetamine

excitation (i. e. 4 h after 5 mg/kg amphetamine) was also able to reinduce

a shortlasting and typical amphetamine-like stimulation lasting 12-18 min.

Neuroleptic drugs with dopamine receptor blocking properties haloperidol,

perphenazine and spiramide produced in very small doses complete

inhibition of all behavioural effects in the amphetamine-tetrabenazine

reversal test, whereas noradrenaline receptor blocking drugs aceperone

and phenoxybenzamine in very high doses only produced partial inhibition of the

locomotor and rearing activities. Scopolamine increased the tetrabenazine

reversal effect. A single, relatively low, dose of alpha-methyltyrosine

(100 mg/kg) produced no inhibition of the amphetamine-tetrabenazine excitation,

whereas high repeated doses of alpha-methyltyrosine (2 x 350 mg/kg) or

reserpine (7.5 mg/kg) produced complete inhibition of the amphetaminetetrabenazine excitation. The present studies indicate that the strong

potentiation effect of tetrabenazine in amphetamine pretreated rats is

dependent on a tetrabenazine-induced release of the catecholamines from

a reserpine sensitive storage pool to an extragranular pool available for

amphetamine release. The excitation produced by nialamide-tetrabenazine

was found very longlasting but not as strong and intense in appearance as

after amphetamine. The nialamide-tetrabenazine excitation was potentiated

by scopolamine, completely antagonized by the dopamine antagonist

spiramide and partially antagonized by the noradrenaline antagonists,

aceperone and phenoxybenzamine.

SCHEEL-KRÜGER, J. and RANDRUP, A. Evidence for a cholinergic mechanism in

brain involved in the tetrabenazine reversal by thymoleptic drugs. Journal of

Pharmacy and Pharmacology 21: 403-406 (1969)

SCHEEL-KRÜGER, J. and RANDRUP, A. Pharmacological evidence for a cholinergic

mechanism in brain involved in a special stereotyped behaviour of reserpinized

rats. British Journal of Pharmacology 34(1): 217 (1968)

SCHEEL-KRÜGER, J. and RANDRUP, A. Production of a stereotyped behaviour in rats

by dopamine in the absence of noradrenaline.

25 (4): 61 (1967)

Acta Pharmacologia et Toxicologia

Randrup, Munkvad and Usdin (1963) and Randrup and Munkvad (1967)

have described the stereotyped behaviour induced in many species of animals by

amphetamine. The same form of a stereotype behaviour can be produced in rats

after injection of 1-DOPA, the physiological precursor of dopamine and noradrenaline (Randrup and Munkvad, 1966).

In this paper the various forms of experiments are presented, which have

been done to obtain a differentiation between the behavioural effects induced by

dopamine and noradrenaline.

339
Scheel-Kruger, J. and Randrup, A. Production of a stereotyped. . . continued

Biochemical analyses have been made of these brain amines and their

3-o-methylated metabolites, 3-methoxytyramine and normetanephrine (ScheelKrüger and Randrup, 1967).

Analyses were made at various times after 1-DOPA, of the brain amines

from rats pretreated with either a monoamine inhibitor (MAOI) pargyline or of

rats first depleted of catecholamines by reserpine and then treated with nialamide

(a MAOI) + 1-Dopa.

The best differentiation between the behavioural effects of noradrenaline

and dopamine was however obtained, when diethyldithiocarbamate DDC was added

to the treatment. DDC blocks the biosynthesis of noradrenaline from injected

DOPA but not that of dopamine (Goldstein, 1966).

These analyses together with other results show that a continuous stereotype behaviour induced after injection of 1-DOPA to rats is dependent on a high

level of dopamine.

Furthermore it is shown that this behaviour is independent of the levels

and turnover of noradrenaline.

SCBEEL-KRÜGER, J. and RANDRUP, A. Stereotyped hyperactive behaviour produced by

dopamine in the absence of noradrenaline. Life Sciences 6: 1389 (1967)

Two phases of behavioural excitation result from injection of DOPA (physiological precursor of dopamine and noradrenaline) into rats pretreated with a

monoamine-oxidase (MAO) inhibitor. The first phase, starting 20 to 35 min. after

the injection, is characterized by rage: hissing and spitting, some rapid movements,

fighting if animals were put together. During this period the head is kept elevated

in a characteristic fashion, and there is no sniffing.

1 to 2 hrs. after the injection there is a gradual transition into the second

phase, where the behaviour is completely different, characterized by continuous

stereotype sniffing, licking or biting of the cage wire netting. This behaviour is

similar to that elicited by medium doses of amphetamine or apomorphine.

Since it is generally agreed that the behavioural excitation produced by

DOPA is due to the formation of the catecholamines dopamine and noradrenaline

in the brain, we thought that determination of these brain amines might help to

explain the behavioural observations. In the following we present the results

obtained by this approach.

SCBELLING, J-L. and LASAGNA, L. A study of cross-tolerance to circulatory effects

of organic nitrates. Clinical Pharmacology and Therapeutics 8: 256-260 (1967)

Ten hospitalized volunteer subjects were given pentaerythrol tetranitrate

‘(PETN) daily in divided doses over a period of four weeks. Before and during

PETN treatment, the subjects were challenged with 0.3 mg sublingual nitroglycerin (NTG). The changes in blood pressure and heart rate after NTG were significantly decreased while subjects were receiving PETN. Reports of NTG- and

PETN-related headache also decreased during PETN administration. Since longacting nitrates may carry within them the seeds of their own therapeutic failure

via the development of tolerance, it is suggested that animal studies on such agents

routinely include repeated pharmacological testing designed to detect and measure

the development of tolerance to cardiovascular and other effects.

340
SCHLANT, R.C. and NUTTER, D.O. Effect of lysergic acid diethylamide (LSD) upon

ventricular function and myocardial contractility. Clinical Research 18: 72

(1970)

The effects of intravenous lysergic acid diethylamide (LSD) upon ventricular function and myocardial contractility have been studied in a total of 8 open

chest dogs anesthetized with chloralose (total 114 mg/kg i.v.) and morphine

(0.7 mg/kg i. m.). Dose response curves were obtained following the intravenous

injection of cumulative doses of LSD ranging from 0.1 to 160 mu-g/kg. Insignificant

changes were noted at cumulative doses less than 40 mu-g/kg; however, cumulative doses of 40, 80 and 160 mu-g/kg resulted in progressive, marked depression

of left ventricular (LV) function and myocardial contractility. A cumulative dose

of 80 mu-g/kg in 3 dogs resulted in the following average changes from control

values: LV systolic pressure -14.4%, LV end-diastolic pressure +17.1%, LV

max dp/dt -25.4% (Telco micromanometer); LV end-diastolic internal diameter

+7.7% (sonomicrometer); peak LV isometric tension -28.4%, max rate of tension

development -32.7% (Brodie-Walton guage); LV stroke output -24.4% and peak

aortic flow rate -16.2% (electromagnetic flow meter). Heart rate decreased an

average of 31 beats/mm and transient A-V dissociation occurred in 1 dog.

Average aortic diastolic pressure decreased by 16.1%. The administration of

intravenous LSD in moderate dosage in the anesthetized dog produces marked

depression of LV function and contractility together with moderate bradycardia.

SCHUBERT, J., FYRO, B., NYBACK, H. and SEDVALL, G. Effects of cocaine and

amphetamine on the metabolism of tryptophan and 5-hydroxytryptamine in mouse

brain in vivo. Journal of Pharmacy and Pharmacology 22(11): 860-862 (November,

1970)

SCHUBERT, J., NYBACK, H. and SEDVALL, G. Accumulation and disappearance of

3H-tryptophan in mouse brain; effect of LSD-25. European Journal of Pharmacology

10: 215-224 (1970)

For abstract, see Section 1. Methodology of Drug Research.

SCHUBERT, J., NYBACK, H. and SEDVALL, G. Effects of antidepressant drugs on

accumulation and disappearance of monoamines formed in vivo from labelled

precursors in mouse brain. Journal of Pharmacy and Pharmacology 22: 136-139

(1970)

SCHUBERT, J., NYBACK, H. and SEDVALL, G. Regional differences in synthesis and

turnover of 5-hydroxy-tryptamine formed in vivo from 3H-tryptophan in rat brain.

College of International Neuropsychopharmacology. Prag, Czechoslovakia, 1970.

P. 391.

For abstract, see Section I. Methodology of Drug Research.

SCHULZ, R., CARTWRIGHT, C. and GOLDSTEIN, A. Reversibility of morphine tolerance

and dependence in guinea pig brain and myenteric plexus. Nature 251(5473): 329-

331 (1974)

341
SCHULZ, R. and GOLDSTEIN, A. The effect of catecholamines, acetylcholine and serotonin on the morphine tolerant longitudinal muscle strip of the guinea pig ileum.

Federation Proceedings 32: 688 (1973)

Electrically stimulated morphine tolerant muscle strips display reduced

sensitivity to catecholamines. The required epinephrine concentration for a 50%

twitch inhibition is about 5 times higher (1.1 x 10-7 M) than in controls. The doseresponse curve observed for isoproterenol showed a similar shift to the right,

producing a maximal depression of only 3% (3 x 10-6 Ml. The greatest loss

of sensitivity was seen for dopamine. The ED50 in controls required a concentration of 5.8 x 10-6 M, but in the morphine tolerant state the maximal depression was only about 25% at 1.2 x 10-4M. The response of the unstimulated strip

to acetylcholine was not different in controls or tolerant preparations (ED50

4 x 10-10M). On the other hand, the tolerant strip exhibits a 10 times higher

sensitivity to serotonin (ED50 5 x 10-8 M). Naloxone (225 nM) did not block or

reverse the effects of the test compounds, The supersensitivity to serotonin

could be caused by a feedback mechanism in the excitatory pathway of the myenteric plexus, and it could account for the morphine tolerance. In this system, a

catecholamine may act as an inhibitory modulator of neurotransmission.

SCHULZ, R. and GOLDSTEIN, A. Inactivity of narcotic glucuronides as analgesics and

on guinea pig ileum. The Journal of Pharmacology and Experimental Therapeutics

183(2): 404 (1972)

The effects of morphine, levorphanol, morphine -3-glucuronide and

levorphanol-3-glucuronide in the electrically stimulated longitudinal muscle strip

of the guinea-pig ileum as well as the analgesic action of intracerebrally injected

levorphanol and levorphanol-3-glucuronide in mice have been studied. Morphine-3-

glucuronide and levorphanol-3-glucuronide did not influence the tension of the

electrically stimulated muscle strip. After hydrolysis, twitch inhibition was the

same as with morphine and levorphanol standards. Intracerebral injections of

113 pmol (48.9 ng) of doubly labeled 3H-levorphanol-3-14C-glucuronide produced

analgesia in mice. Detailed investigations of the mouse brain have shown 3H

radioactivity (levorphanol) not to be bound to glucuronic acid. It was demonstrated

that intracerebral injection of comparable small amounts of levorphanol could

produce analgesia. These results support the conclusion that analgesia seen after

intracerebral injection of levorphanol-3-glucuronide is acused by the free base

resulting from hydrolysis in vivo.

SCHULZ, R. and GOLDSTEIN, A. Morphine tolerance and supersensitivity to 5-hydroxytryptamine in the myenteric plexus of the guinea pig. Nature 224(5412): 168-170

(July, 1973)

SCHULZ, R. and GOLDSTEIN, A. Morphine tolerance in the longitudinal muscle strip

of the guinea pig ileum. Abstracts of Volunteer Papers, Fifth International

Congress on Pharmacology, San Francisco, California, 1972.

SCHULZ, R. and GOLDSTEIN, A. Morphine tolerant longitudinal muscle strip from

guinea pig ileum. British Journal of Pharmacology 48: 655 (1973)

SCHUSTER, C.R. and VILLARREAL, J.E. The experimental analysis of opioid dependence. Psychopharmacology: A Review of Progress, 1957-1967. Edited by

D. Efron, J. Cole, J. Levine and J.R. Wittenborn. Washington, D.C.: U.S.

Government Printing Office, 1968. Pp. 811-828.

342
SCHWARTZ, A.S. and MARCHOK, P.L. Depression of morphine-seeking behaviour by

dopamine inhibition. Nature 248(5445): 257 (March, 1974)

SCHWARTZ, A.S. and MARCHOK, P.L. Depression of morphine-seeking behavior in

1974.

the rat by haloperidol. Committee on the Problems of Drug Dependence.

Washington, D.C.: National Academy of Sciences, National Research Council,

SCHWARTZ, J., FELDSTEIN, S., FINK, M., SHAPIRO, D.M. and ITIL, T.M.

Evidence for a characteristic EEG frequency response to thiopental. Electroencephalography and Clinical Neurophysiology 31: 149-153 (1971)

SCHWEITZER, J.W. and FRIEDHOFF, A.J. Enzymatic (brain) formation of

mescaline from 4-hydroxy-3, 5-dimethoxyphenethyl-amine. Transactions of

American Society of Neurochemistry 3: 1, 119 (1972)

SCRAFANI, J.T., WILLIAMS, N. and CLOUET, D.H. The subcellular distribution of

narcotic analgesics in rat brain. Committee on Problems of Drug Dependence.

Washington, D.C.: National Academy of Sciences, National Research Council,

1970, P. 7030.

SEEGAL, R.F. and ISAAC, W. Sensory influences upon amphetamine tolerance. Physiology and Behavior 7: 877-879 (1971)

The effects of illumination, noise, and d-amphetamine upon locomotor

activity were studied in the rat. While both noise and illumination altered

activity level, only illumination was related to the drug effects. The effectiveness

of the drug was found to decrease, primarily in the dark, over repeated trials.

SEEVERS, M.H., DAVIS, V.E. and WALSH, M.J. Morphine and ethanol physical

dependence: A critique of a hypothesis. Science 170: 1113 (1970)

SEEVERS, M.H. and DENEAU, G.A. A critique of the “dual action” hypothesis of morphine

physical dependence. Research Publications of the Association for Research in

Mental Diseases 46: 199 (1968)

Newer observations suggest that the hypothesis of dual action can no

longer be considered as the sole explanation of morphine addiction. For example,

prolonged morphine administration does not result in physical dependence when

covered by an antagonist. It is suggested that the development of physical dependence requires reasonably prolonged occupation by morphine-like narcotic

analgesics of those receptor sites which induce depression.

343
SEGAL, D.S. and KUCZENSKI, R. Tyrosine hydroxylase activity: Regional and subcellular distribution in brain. Brain Research 68: 261-266 (1974)

The ratio of soluble to membrane-bound tyrosine hydroxylase activity was

determined in the cell bodies and nerve endings of the nigro-striatal pathway (substantia nigra and caudate-putamen, respectively) and of the dorsal NE pathway

(locus coeruleus and hippocampus-cortex, respectively) as well as in the hypothalamus which contains both CA cell bodies and nerve endings. Regional dissection

was accomplished by a new procedure which allows for the rapid and consistent

dissection of discrete brain areas.

The cell body and nerve ending regions obtained by this procedure were

found to be distinguishable with respect to subcellular distribution of tyrosine

hydroxylase activity independent of the absolute amount of tyrosine hydroxylase.

Locus coeruleus and substantia nigra showed a significantly greater proportion of

soluble to membrane-bound tyrosine hydroxylase activity than did the caudateputamen and hippocampus-cortex, where nerve endings predominate. The ratio

for the hypothalamus is consistent with the presence of both CA cell bodies and

nerve endings in this region. The necessity to distinguish between relatively

discrete cell body and nerve ending regions as well as between NE and DA pathways is discussed as a prerequisite for the adequate characterization of the

effects of experimental manipulations.

SEGAL, D.S., KUCZENSKI, R. and MANDELL, A.J. Theoretical implications of druginduced adaptive regulation for a biogenic amine hypothesis of affective disorder.

Biological Psychiatry 9(2): 147-159 (1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

SEGAL, D.S., McALLISTER, C. and GEYER, M.A. Ventricular infusion of norepinephrine and amphetamine: Direct versus indirect action. Pharmacology Biochemistry and Behavior 2: 79-86 (1974)

The behavioral hyperactivity produced by intraventricular infusions of

norepinephrine in rats is potentiated by pretreatment with 6-hydroxydopamine.

Pretreatment with the catecholamine uptake blocker desmethylimipramine does

not alter the effect of norepinephrine, which indicates that the potentiation

observed after 6-hydroxdopamine is due to an enhancement of receptor sensitivity

rather than to a loss of an uptake inactivation mechanism. Intraventricular infusions of d-amphetamine result in behavioral effects which are comparable to those

observed following systemically administered amphetamine: (1) increasing doses

produce a graded increase in locomotor activity; (2) high doses elicit a pattern of

stereotypy; and (3) d-amphetamine is more potent than l-amphetamine in producing

these behavioral effects. The behavioral effects of amphetamine, in contrast to

those induced by norepinephrine, appear to be dependent upon the functional levels

of brain catecholamines as indicated by the suppression of amphetamine effects

following pretreatment with alpha-methyl-p-tyrosine or reserpine. These results

provide evidence for a direct mechanism of action for infused norepinephrine and

indicate the potential usefulness of norepinephrine-induced activity as an index

of alterations in receptor sensitivity.

344
SETHY, V.H. and WINTER, J.C. Effect of chronic treatment with mescaline upon tissue

levels of the drug. Experimentia 29: 571 (1972)

SETHY, V.H. and WINTER, J.C. Effects of yohimbine and mescaline on punished behavior

in the rat. Psychopharmacologia 23: 160-166 (1972)

This investigation tested the hypothesis that conditioned aversive stimuli

and drugs such as yohimbine and mescaline produce a common state in animals.

Rats were trained to press a bar on a multiple schedule of reinforcement in which

one component was variable interval 30 sec (food) and the other component was

fixed ratio 10 (concurrent food and electric shock). Yohimbine did not have a

selective depressant effect on response rate during the punished component. Indeed,

punished rates were elevated or near normaI when responding in the nonpunished

component was decreased to less than 50% of control values. In contrast, mescaline concurrently depressed rates on both components of the schedule. If yohimbine produces an anxiety-like state in animals which is akin to the state engendered

by punishment procedures, the effects of punishment and yohimbine should be

additive in terms of their depressant effects on lever-press responses. No such

additivity was observed in this investigation. The present data do not support

the assumption that punishment procedures and the administration of yohimbine

produce a common state in the rat. No definitive conclusion could be drawn with

respect to the actions of mescaline.

SHAGASS, C. Effects of LSD on somatosensory and visual evoked responses and on the

EEG in man. Recent Advances in Biological Psychiatry 9: 209 (1967)

SHAGASS, C. Effects of psychotropic drugs on human evoked potentials. Evoked Potential

Findings. Edited by T.M. Itil. Modern Problems in Pharmacopsychiatry, Vol. 8.

New York: S. Karger, 1974.

During the past decade, the technique of extracting potentials evoked by

sensory stimuli from the scalp EEG by averaging has become almost commonplace.

A brief review of the effects of psychotropic agents on sensory evoked activities

will be presented here. Other event-related potentials are often considered within

the context of evoked potentials: examples are the motor potentials and contingent

negative variation (CNV). Only the CNV has received much attention with respect

to drug effects; the CNV will be dealt with elsewhere in this volume.

SHAGASS, C. Invited discussion of Drs. M. Fink and T. Itil’s paper: Evoked response

and behavioral effects of LSD and ditran. Pharmacology: A Review of Progress

1957-1967. Edited by D.H. Efron. Washington, D.C.: PHS Publication No. 1836,

1969.

345
SHAGASS, C., OVERTON, D.A. and STRAUMANIS, J.J., JR. Evoked response findings

in psychiatric illness related to drug abuse. Biological Psychiatry 3: 259-272

(1971)

Possible neurophysiological correlates of psychotic reactions associated

with drug abuse were explored by means of a cerebral evoked response test.

Median nerve shocks of varying intensity were applied as single conditioning

stimuli, or trains, preceding a test shock of fixed intensity. Test response

amplitudes were generally lower in 10 drug-abuse patients with a history of

psychotic reactions than in 20 nonpatients or in 9 drug-abuse patients without

psychotic reactions. Additional data were obtained for 9 male schizophrenics

and 5 male nonpsychotic patients without a drug abuse history. Comparing male

subjects only, test response amplitudes of groups composed of 8 psychotic drug

abusers, 9 schizophrenics, and 5 nonpsychotic patients without drug abuse history

were not different from one another, but they differed significantly from those

of 15 nonpatients and 6 nonpsychotic drug abusers. Not only were test response

amplitudes lower in the former three male groups than in the latter two, but they

showed less variation as a function of conditioning stimulus intensity. This relative lack of variation, taken together with lower amplitudes, was interpreted as

evidence of a generalized restriction of the level of cortical responsiveness to

external stimuli. Such restriction appears to be associated with severe states

of emotional disturbance, whether or not they were precipitated by drugs.

SHAGASS, C. and STRAUMANIS, J.J. Evoked potentials and psychopathology.

Neurobiological Aspects of Psychopathology. Edited by J. Zubin and

C.Shagass. New York: Grune and Stratton, Inc., 1969. Pp. 22-51.

SHANI, A. and MECHOULAM, R. A new type of cannabinoid. Synthesis of Cannabielsoic

Acid A by a novel photo-oxidative cyclisation. Chemical Communications, 1970.

London, England: The Chemical Society, 1970. P. 273.

For abstract, see Section II. Drug Chemistry and Metabolism.

SHANI, A. and MECHOULAM, R. Photochemical reactions of cannabidiol. Cyclization

to delta-1-THC and other transformations. Tetrahedron Letters 27: 601 (1971)

For abstract, see Section II. Drug Chemistry and Metabolism.

SHARPE, L.G., GARNETT, J.E. and CICERO, T.J. Analgesia and hyperreactivity produced by intracranial microinjections of morphine into the preiaqueductal gray

matter of the rat. Behavioral Biology 11(3): 303-313 (1974)

Produced by intracranial microinjection of morphine, 137 such injections

of morphine sulfate in doses of 1.0-50 mcgs were made into various midbrain

sites of 46 rats implanted with chronic indwelling cannulae. Three to 6 mcgs of

morphine injected in a 0. 5 mcl volume produced a marked increase in hot plate

reaction time when injected into a circumscribed region of the periaqueductal gray

matter ventral to the cerebral aqueduct encompassing the dorsal raphe nucleus

and bordering tissue. Higher doses of morphine eliminated the pain response to

limb pinching, but in addition caused rats to become hyperreactive. The results

of these studies are seen to be in agreement with those studies that showed

identical sites of action for electrical analgesia in the rat. It is suggested that

morphine and electrical stimulation have similar mechanisms of action in producing analgesia when these active midbrain sites are involved.

346
SHEARD, M.H. Aggressive behavior: Modification by amphetamine, p-chlorophenylalanine and lithium in rats. Agressologie 14(5): 323-326 (1973)

Male rats were habituated to home cages and then exposed to intruder

male rats treated with either saline, d-amphetamine, p-chlorophenylalanine,

or raphe lesions. There was a significant increase in the aggression of the home

cage rat towards intruder rats given the drugs or with lesions. Lithium treatment

of home cage rats abolished the aggression.

SHEARD, M.H. The effect of p-chloroamphetamine on single raphe neurons.

Advances in Biochemical Psychopharmacology Vol. 10. Edited by E. Costa,

G.L. Gessa and M. Sandler. New York: Raven Press, 1974. Pp. 179-184.

An observation of interest during these acute experiments was the

fact that with the intravenous injection of PCA there was often an increase

in temperature. Previous studies have suggested a relationship between

the activity of 5-HT neurons and temperature control. For example, there

are increases in 5-HIAA due to hyperthermia (Reid, Volicer, Smookler,

Beaven, and Brodie, 1968; Weiss and Aghajanian, 1971). Treatment

with PCPA results in a drop in temperature of approximately half a

degree. On the other hand, treatment with PCA results in a marked rise

in temperature of 1 to 2° C.

In view of the marked motor activity seen in the PCA-treated rats,

which is probably related to catecholamine metabolic effects (e.g.,

increased turnover rate of striatal dopamine; Costa, Naimzada, and

Revuelta, 1971b). it appears at first sight that this temperature increase

may also be related to catecholamine release and motor activity.

However, following pretreatment with AMPT (100 mg/kg, i.p.), which

blocks the synthesis of NE, there is an even greater rise in temperature

following treatment with PCA, whereas pretreatment with PCPA blocks

the rise of temperature.

These findings raise interesting questions with regard to the

relationship between 5-HT neuron activity, the control of temperature, and

depression.

SHEARD, M.H. The effect of p-chlorophenylalanine on behavior in rats:, Relation

to brain serotonin and 5-hydroxyindoleacetic acid. Brain Research 15:

524-528 (1969)

Investigations into the role of serotonin (5-HT) in brain have been

considerably advanced by the introduction of p-chlorophenylalanine (PCPA),

a drug which inhibits 5-HT synthesis through inhibition of tryptophan hydroxylase

in vitro. The most striking behavioral consequences of this chemical

depletion of brain serotonin are: a severe impairment in sleep; the development

of muricide tendencies in domestic rats; reduction of aggressive behavior in mice;

and the development of excessive sexual activity in cats. The experiment

reported here was performed in order to clarify further the relationship

between these behavioral changes and the brain concentrations of 5-HT and

5-dydroxyindoleacetic acid (5-HIAA).

347
SHEARD, M.H. and AGHAJANIAN, G.K. Neuronally activated metabolism of brain serotonin: Effect of lithium. Life Sciences 9(1): 285 (1970)

SHEARD, M.H., ZOLOVICK, A. and AGHAJANLAN, G.K. Raphe neurons: Effect of tricyclic

antidepressant drugs. Brain Research 43: 690-694 (1972)

These results indicate that the tricyclic antidepressants IMI, AMI and

CMI, like the MAO inhibitors, have a significant depressant effect on the

firing rate of 5-HT containing neurons in the brain. The findings confirm the

recent report that imipramine depresses unit activity of the midbrain raphe

of rats. This effect of the tertiary amines on the physiology of 5-HT neurons

fits well with their effect on uptake of 5-HT in biochemical studies. These

studies also showed that the tertiary amines were much more potent than

secondary amines in their effect on 5-HT uptake. It is interesting in this

regard also that clinicians prefer to use the tertiary amines over the

secondary amines for treating depression. These findings also lend weight

to the idea that the mechanism explaining the phenomenon of depressed firing

rate of 5-HT neurons seen with both MAO inhibitors and tertiary amine

antidepressants may be due to a negative feedback. The feedback is

postulated to result from the accumulation of 5-HT at the synapse secondary

either to MAO inhibition on the one hand or to a block in the reuptake of

5-HT with the tricyclic compounds on the other. In contrast, the tricyclic

compound chlorpromazine, which does not block reuptake of 5-HT, does

not modify the firing rate of raphe units. It is suggested that this method

of monitoring raphe unit firing rates may be useful in the assessment of

potential antidepressant drugs.

SHERMAN, A. and MITCHELL, C.L. Blood citric acid cycle and individual response to

morphine analgesia in rats. Experientia 29:176 (1973)

The effect of morphine on glycolytic intermediaries has been studied by

numerous investigators. The significant effects on glycolytic intermediaries

suggest the possibility of a correlation between glycolytic activity and analgesia.

The purpose of this study was to determine whether existing blood levels of citric

acid cycle intermediaries were related to the effectiveness of morphine as an

analgesic.

Two studies were performed, one to determine whether a relationship

between blood levels and individual, response to morphine existed, and the second

to determine whether this relationship was due to differential uptake of morphine

or to biochemical factors.

SHERMAN, A.D. and MITCHELL, C.L. Effect of morphine on regional levels of gammahydroxybutyrate in mouse brain. Neuropharmacology 13: 239-243 (1974)

Four experiments were performed on 340 male CFI mice to determine the

effects of morphine and other agents on brain gamma-hydroxybutyrate (GHB) levels.

Gas chromatographic analysis demonstrated that morphine produced a significant

elevation of GHB levels, the increase occurred primarily in “subcortical” areas,

these effects were blocked by pretreatment with naloxone, nonanalgesics failed to

produce the same effect, the effect failed to occur in morphine-tolerant animals,

the dose-response curve of the effect of morphine on GHB was nonlinear, and

brain levels following morphine roughly follow the time course of analgesia.

348
SHERMAN, A.D. and MITCHELL, C.L. Effects of morphine and pain on brain intermediary metabolism. Neuropharmacology 11: 871-878 (1972)

Three studies were performed to determine (1) whether morphine produced different biochemical effects in the presence and absence of pain and (2)

whether these differential effects could be related to analgesia.

In Experiments I and II, 3-day-old chickens were given either saline or

morphine and were exposed to pain or not. After testing, animals were frozen

in liquid nitrogen and brains analyzed for acids of the Krebs cycle plus pyruvate

and lactate by gas chromatography. In Experiment III, the effect of malonic

acid (a competitive inhibitor of metabolism of several acids) on analgesia was

determined in chickens.

The results of Experiments I and II agreed closely, and an interaction

between drug (morphine vs saline) and test (pain vs no pain) was shown by analysis

of variance. Morphine without pain depressed whole-brain levels of many acids,

as did pain, but the combination of morphine and pain, instead of producing a further decrease, produced an increase in many levels. Prevention of this increase

by malonate significantly reduced the effectiveness of morphine.

The data suggests that, in evaluation of morphine, the behavioral state

of the organism must be considered since it may change the metabolic state on

which the drug acts.

SHERMAN, A. and MITCHELL, C.L. Influence of naloxone and tolerance on citric acid

cycle response to morphine and pain. Neuropharmacology 12: 363-366 (1973)

Sherman and Mitchell (1972) have described a drug-test interaction

between morphine and pain which consisted of three phases: (1) a reduction in levels

of Krebs cycle intermediaries by morphine, (2) a reduction due to pain, and (3) a

return toward control levels with the combination of morphine and pain.

Three studies were performed to determine (1) whether the drug-test

interaction was also observed in mouse brain or liver, (2) the effect of tolerance

on the development of this phenomenon, and (3) the effect of naloxone on this phenomenon.

Male CFI mice were given either saline or morphine and either exposed to

analgesic testing or not, then frozen in liquid nitrogen. Brains and livers were

analysed for acids of the citric acid cycle by gas chromatography. In experiment

II, a tolerant population was used. In experiment III, the effect of naloxone was

observed.

In experiment I, the three-part interaction was observed in brain, but not

in liver. Experiment II showed that tolerance prevented the occurrence. Experiment III showed that naloxone counteracted the effect of morphine on pain. However,

naloxone itself also blocked the alteration in Krebs cycle intermediaries produced

by pain. This latter finding argues against these changes in Krebs cycle intermediaries being related to either pain or analgesia but they may be related to some

other action of morphine.

349
SHIH, T., KHACHATURIAN, Z. and BARRY, H. Evidence for cholinergically mediated

effect of methylphenidate hydrochloride in the central nervous system. The

Pharmacologist 16(2): 242 (1974)

Intravenous injection of methylphenidate HCL (MPH) significantly

attenuates single unit activity (UA) in the collateral sensory pathways of the

mesencephalic reticular formation in immobilized rats. In further studies, this

effect of MPH was mimicked by the cholinergic stimulants nicotine (0.125 and

0.25 mg/kg i.v.) and oxotremorine (OXO: 0.5 and 1 mg/kg i.v.). The effect of

MPH was abolished by the nicotinic blocker mecamylamine HCL, 4 mgs/kg i.v.,

but was not affected by the muscarinic blocker atropine sulfate, 4 mgs/kg i.v.

The attenuation UA was only slightly reduced when catecholamines and serotonin

were depleted by pretreatment with reserpine (5 mgs/kg i.p.) at 3 hours before

MPH or OXO. These results suggest that inhibitory effects of MPH in the collateral sensory pathways of the MRF might be mediated by the cholinergic system.

SHISH, T.M. and OSKOUI, M. The effects of delta-1-tetrahydrocannabinol (delta-1-THC

or delta-9-THC) and ethanol on monosynaptic and polysynaptic transmission in

the central nervous system. Federation Proceedings 32: 756 (1973)

The effects of delta-1-THC on monosynaptic (MS) and polysynaptic (PS)

potentials (P), post-tetanic potentiation (PTP), heart rate (HR), and blood pressure (BP) were studied in anesthetized spinal cats. Administration of delta-1-

THC (2.5 and 5.0 mg/kg i.v.) effectively resulted in bradycardia, hypotension

and depression of MSP in all experiments. No marked change occurred in the

areas under the PSP; however, some changes did occur in their configuration.

MSP was depressed maximally by 30-73% of the control, occurring 30 to 105

minutes after a high dose of delta-1-THC (5.0 mg/kg) and recovering completely

after 3 to 4 hours. The dose of 2.5 mg/kg produced a similar but lesser

response. No direct relationship between the change in blood pressure and the

observed changes in MS responses could be established. The percentage increased

in MSP following tetanus was greater after delta-1-THC; however, the absolute

PTP value was less than the control PTP. Ethanol, the solvent, has very little

effect on all measured parameters. It is concluded that delta-1-THC depresses

spinal MS activity, and that this alteration occurs independently of changes in

blood pressure.

SHUSTER, L. Some biochemical effects of morphine on cultured brain cells. Intra-Science

Chemical Reports 8: 149-160 (1974)

SHUSTER, L. Tolerance and physical dependence. Biochemical Pharmacology of

Narcotic Drugs. Edited by D.H. Clouet. New York: Plenum Press, 1971.

SIMON, E.J. The effects of narcotics on cells in tissue culture. Axenic Mammalian Cell

Reactions. Edited by G. Tritsch. New York: Marcel Dekker, Inc., 1969.

350
SIMON, E.J. Effects of narcotics on the giant axon of the squid. Journal of Neurochemistry. 17: 881-887 (1970)

Levorphanol (10-3 M) reversibly blocked conduction in the giant axon of

the squid and axons from the walking legs of spider crab and lobster. Similar

concentrations of levallorphan and dextrorphan blocked conduction in the squid

giant axon. Under the same experimental condition morphine caused an approximately 40 per cent decrease in spike height. Levorphanol did not affect the

resting potential or resistance of the squid axon. Spermidine, spermine and

dinitrophenol had little or no direct effect on the action potential nor did they alter

the potency of levorphanol. Concentrations of levorphanol as low as 5 x 10-5 M

blocked repetitive or spontaneous activity in the squid axon induced by decreasing

the divalent cations in the medium. After exposure to tritiated levorphanol, the

axoplasm and envelope of the squid axon accumulated up to 500 per cent of the

concentration of tritium found in the external medium, dependent on time of exposure, and other variables. At pH 6 the levels of penetration were 33-50% of those

found at pH 8, which correlates with our observation that levorphanol is about 33%

as potent in blocking the action potential at pH 6. The penetrability of levorphanol

was not affected by spermidine, dinitrophenol or cottonmouth moccasin venom.

Levorphanol did not alter the penetration of acetylcholine nor did it render

the squid axon sensitive to it. The block of axonal conduction by compounds of

the morphine series is discussed both as to possible mechanisms and significance.

SIMON, E.J. In search of the opiate receptor. American Journal of the Medical Sciences

226(3): 160-168 (1973)

SIMON, E.J. Lipids (and drugs of dependence). Chemical and Biological Aspects of Drug

Dependence. Edited by S.J. Mule and H. Brill. Cleveland, Ohio: Chemical

Rubber Company Press, 1972.

SIMON, E.J. Morphine and related drugs. Methods in Enzymology, Vol. 34, Part B.

Edited by W. B. Jacoby. New York: Academic Press. 1974.

SIMON, E.J. Opiate receptors in animal and human brain. Proceedings of the 9th Congress

of Neuropsychopharmacology, Paris, France, 1974.

SIMON, E.J. Sites of action of narcotic analgesic drugs in single cells. Narcotic

Drugs: Biochemical Pharmacology. Edited by D.H. Clouet. New York:

Plenum Press, 1971. Pp. 310-341.

SIMON, E.J., GARWES. D.J. and RAND, J. Reversible inhibition of RNA phage replication and macromolecular synthesis by levorphanol. Biochemical and Biophysical

Research Communications 40(5): 1134 (1970)

Reproduction of RNA phages MS2 and Qbeta and the synthesis of phage RNA

and protein are markedly inhibited (greater than 99%) by levorphanol. Even at concentrations which are virtually without effect on the host, phage yield is decreased

85%-90%. Levorphanol is most effective when added before or at the time of infection, but no inhibition is observed when it is added 30 minutes or more after infection. Inhibition of phage reproduction is reversed when, even after exposure to levorphanol for an hour, the infected cells are washed free of drug. An effect of levorphanol on an early event in phage replication is postulated.

351
SIMON, E.J., HILLER, J.M., GROTH, J. and EDELMAN, I. Further properties of

stereospecific opiate binding sites in rat brain: On the nature of the sodium

effect. The Journal of Pharmacology and Experimental Therapeutics (in press)

SIMON, E.J., SCHAPIRA, L. and WURSTER, N. Effect of levorphanol on putrescine

transport in Escherichia coli. Molecular Pharmacology 6(6): 577 (November,

1970)

The disappearance of cellular putrescine observed when Escherichia coli

cultures were treated with levorphanol was shown to be largely the result of an

acceleration of putrescine efflux produced by the drug. The efflux of putrescine

from E. coli exhibited a stringent requirement for metabolic energy. It was found

to be greatly reduced by carbon source starvation, by treatment with metabolic

inhibitors, or by low temperature. The efflux of putrescine stimulated by levorphanol was also virtually abolished by such treatments. Levorphanol also

inhibited the uptake of putrescine by E. coli cells. Evidence is presented which

indicates that the inhibition of uptake and the stimulation of efflux represent

separate effects of levorphanol. Competition between levorphanol and putrescine

for a carrier or binding site was ruled out by kinetic experiments, which showed

that inhibition of putrescine uptake by levorphanol was not competitive. The effect

of levorphanol on the putrescine pool was readily reversible. Replenishment began

without measurable delay upon removal of the drug. Levorphanol also produced

reversible alterations in the permeability of E. coli to most, if not all, amino

acids, spermidine, and K

+

. Possible mechanisms of the effects of levorphanol

on cell membranes are discussed.

SJOQVIST, F. and LASAGNA, L. The hypnotic efficacy of doxylamine. Clinical

Pharmacology and Therapeutics 8(1): 48-54 (1967)

The efficacy of doxylamine succinate as a nighttime hypnotic was compared

with that of placebo and a standard drug, secobarbital sodijm, using a double-blind,

randomized black design and replicate observations. The study was performed in

22 hospitalized patients with chronic disease who were accustomed to taking nightly

hypnotics. Doxylamine, in doses of 25 and 50 mg., was found to be an effective

hypnotic drug, with little difference in the performance of the two doses. Doxylamine performed generally better than secobarbital, 100 mg., but was somewhat

inferior to secobarbital, 200 mg. Although the active treatments were significantly better than placebo, 50 per cent of the patients reported satisfactory sleep

on dummy medication. Side effects were mild with little difference between the

different drugs and placebo except for “hangover,” which occurred more often

after doxylamine and secobarbital.

SLOTKIN, T.A. and ANDERSON, T.R. Chronic morphine administration alters epinephrine uptake in rat adrenal storage vesicles. Neuropharmacology (in press)

Chronic administration of morphine in rats altered the kinetics of epinephrine uptake into adrenal medullary storage vesicles measured in vitro. In

controls, the Michaelis constant for epinephrine was 50.5 ± 2.9 mu-M and maximal

uptake was 16. 5 ± 0. 9 nmol/100 mu-g of endogenous catecholamines: after chronic

morphine, the Michaelis constant was 92.2 ± 7.5 mu-M and maximal uptake was

21.1 ± 1.6 nmol/100 mu-g of endogenous catecholamines. These data suggest

that morphine alters the storage vesicle membrane transport system as well as

affecting intravesicular binding of amines.

352
SLOTKIN, T.A. and ANDERSON, T.R. Sympatho-adrenal development in preinatallyaddicted rats. International Journal of Addictive Diseases (in press)

Chronic morphine administration in adult rats results in neurogenic

secretion of adrenal catecholamines and compensatory increases in basal

catecholamine levels, in activities of catecholamine biosynthetic enzymes and in

the number of storage vesicles in the tissue. Perinatally addicted developing

rats demonstrated changes completely different from those seen in adults;

catecholamine levels and dopamine beta-hydroxylase activity were reduced compared to controls and no induction of tyrosine hydroxylase was observed. The

time course of adrenomedullary maturation was delayed through the first 10-20

days of age, with reduced numbers of storage vesicles and larger proportions

of partially filled vesicles. On exposure to morphine, continued until weaning,

perinatally addicted rats did not display any of the changes in catecholamine

synthesis or uptake seen in adult rats. The differences between adults and

developing rats can be partly explained by the absence of functional innervation

of the neonatal adrenal medulla.

SLOTKIN, T.A., ANDERSON, T.R., SEIDLER, F.J. and LAU, C. Inhibition of epinephrine and metaraminol uptake into adrenal medullary vesicles by aralkyl and

alkylamines. Biochemical Pharmacology (in press)

Two amine uptake mechanisms appeared to ‘operate in isolated adrenal

medullary storage vesicles; one site had a high affinity for epinephrine

(Km 30 mu-M) and low capacity (Urna 20 nmols/100 mu-g of endogenous

catecholamines), while the other had a low affinity (Km 2 mM) and a higher

capacity (Umar 130 nmols). The low affinity site was non-specific and did not

display competitive inhibition by agents which affected the high affinity, stimulated transport system. The high affinity system was inhibited in a purely

competitive fashion by a variety of indoleamines and phenethylamines, but the

two classes of compounds displayed different structure-activity relationships.

Substitution on the alpha-carbon decreased the abilities of indoleamines to inhibit stimulated epinephrine uptake, but enhanced activity of phenethylamines.

Ring hydroxylation reduced, and methoxylation eliminated, the inhibitory activity

of tryptamine, but the same substituents markedly enhanced the activity of phenethylamines. Studies of compounds with restricted side-chain conformation indicated that a condensed structure favored activity in indoleamines while an extended

chain enhanced inhibition by phenethylamines.

SMITH, A.A. Adrenergic regulation of the lenticular response to opioids in mice. The

Addictive States, Vol. 46. Baltimore, Maryland: The Williams and Wilkins

Company, 1968.

The transient lenticular opacities produced in mice by parenteral

injections of opioids are of central nervous system origin. Neither cervical

ganglionectomy nor adrenalectomy blocks the lenticular action of levorphanol.

Tolerance develops quickly to the lenticular action of a single dose of

this opioid. Short term tolerance to a second levorphanol dose may appear within

30 minutes of the first levorphanol dose and may last up to 8 hours. Long term

tolerance develops more gradually and may persist 3 weeks. The two phenomena

seem to be independent of each other.

Long term tolerance is blocked by the prior administration of actinomycin

or puromycin. These antibiotics do not affect development of short term tolerance.

Development of long term tolerance is also blocked by anesthetic doses of chloroform or ethanol.

353
Smith, A.A. continued

It was shown that lenticular tolerance develops in mice treated with

reserpine and, for that reason, it was concluded that the sites of opioid and

adrenergic actions are different. Because levallorphan prevented the development of tolerance to levorphanol, the sites for initiating lenticular opacities and

for producing tolerance are thought to be similar. In the tolerant mouse, catecholamines fail to potentiate fully the lenticular activity of levorphanol. It is

suggested, therefore, that tolerance may not develop to the opioid directly but

in relation to the adrenergic portion of the response.

SMITH, A.A. Anamnestic response to an opioid. Experientia 27: 542 (1971)

SMITH, A. Narcotic antagonists. Narcotic Drugs: Biochemical Pharmacology. Edited

by D.H. Clouet. New York: Plenum Press, 1971.

SMITH, A.A. Potentiation of opioid-induced cataracts by catecholamines injected into the

mouse brain. Psychopharmacologia 16: 313-317 (1970)

The cataractogenic effect of parenteral levorphanol was increased by the

injection of catecholamines into the mouse brain. Although L-epinephrine potentiated this effect most strongly, the potency of DL-isoproterenol unexpectedly

equaled that of L-norepinephrine. Phenoxybenzamine, however, blocked the effect

of L-norepinephrine, whereas pronethalol failed to inhibit DL-isoproterenol. That

DL-isoproterenol may act indirectly is supported by the finding that treatment of

the mouse with reserpine blocked the potentiation induced by DL-isoproterenol but

did not inhibit the action of the pressor catecholamines.

SMITH, A.A. and HUI, F.W. Inhibition of neurotrophic activity in salamanders treated

with opioids. Experimental Neurology 39(1): 36 (1973)

Regeneration of the amputated hind limb of the salamander was prevented

by the injection of methadone or levorphanol. Blastema failed to develop despite

formation of a thick epidermal cap at the wound site. Injection of the narcotic

antagonist, levallorphan, blocked blastemal development for 4 wk but normal growth

then began. Phalanges appeared 4 wk later than in controls. Naloxone, a potent

narcotic antagonist without agonist activity, neither altered blastemal development

nor prevented normal regeneration and differentiation. Treatment with the opioids

methadone or levorphanol produced some atrophy of the lingual epithelium and taste

buds of the salamanders. Neither of the antagonists caused these changes.

SMITH, A.A., HUI, F. and CROFFORD, M. Inhibition of growth by methadone and other

cholinolytic drugs. Annals of the New York Academy of Sciences 228: 338-343

(March, 1974)

Hemicholinium-3 or triethylcholine administered daily to salamanders

blocked regeneration of their amputated hind limb and caused atrophy of their taste

buds. These drugs act primarily by blocking synthesis of acetylcholine (ACh).

Injection of the salamander with methadone (2 mg/kg) or with levorphanol (10 mg/kg)

also prevented regeneration of the amputated hind limb. Blastema failed to develop

despite formation of a thick epidermal cap at the wound site. The antagonist,

levallorphan (10 mg/kg), which also possesses agonistic activity, initially blocked

blastemal development for four weeks, but then normal growth began. Phalanges

354
Smith, A. A., Hui, F. and Crofford, M. continued

appeared four weeks later than control. Naloxone, the pure antagonist, neither

altered blastemal development nor prevented normal regeneration and differentiation. Treatment with the opioids methadone or levorphanol produced some atrophy

of the lingual epithelium and of the taste buds of the salamander. Atrophy of taste

buds suggests a peripheral action for opioids. Newborn mice treated daily with

methadone (2 mg/kg-4 mg/kg) for up to six weeks grew far more slowly than did

saline-treated littermates. Concomitant naloxone treatment prevented growth

inhibition. The adverse effects of cholinolytic drugs on growth of salamanders

suggests that the action of methadone in retarding growth of mice may be related

to the ability of this opioid to inhibit the release of acetylcholine. Preliminary

results suggests that growth retardation induced by methadone is targeted in part

for nervous tissue, as suggested by the reduced uptake of injected radioactive

leucine by the brain, as compare to the liver.

SMITH, A. A., KARMIN, M. and GAVITT, J. Tolerance to the lenticular effects of opiates.

The Journal of Pharmacology and Experimental Therapeutics 156(1): 85 (1967)

SMITH, C.B. Neurotransmitters and the narcotic analgesics. Chemical and

Biological Aspects of Drug Dependence. Edited by S.J. Mule and H. Brill.

Cleveland, Ohio: Chemical Rubber Company Press, 1972. Pp. 495-504.

Opiates, when injected in large doses, induce transient lenticular opacities in mice. In this study it was found that a single previous dose of levorphanol

established long-term resistance or tolerance to the lenticular effects of a second

dose. However, high concentrations of epinephrine instilled in the eyes of tolerant

mice were able to restore the normal lenticular response to parenteral levorphanol.

The epinephrine concentrations required for an ED50 response correlated with the

size of the first dose of levorphanol. Morphine or methadone, when substituted

for the first dose of levorphanol, produced a cross-tolerance to the second dose

of levorphanol as measured in terms of an epinephrine concentration. When larger

doses of levorphanol were given, short-term tolerance also was observed. This

effect developed within 30 min and persisted For up to 8 hr. Lenticular tolerance

was found to develop in mice previously treated with reserpine, suggesting that

this phenomenon probably does not require adrenergic mediation. Levallorphan

was able to prevent the development of long-term tolerance when given in a large

dose relative to the dose of levorphanol. The antibiotics actinomycin or puromyciri

also blocked long-term tolerance development, although neither of these inhibitors

of protein synthesis prevented the appearance of short-term tolerance. Evidently,

long-term lenticular tolerance to opiates is a complex phenomenon involving a

decreased sensitivity to instilled epinephrine that may be related to the formation

of an inhibitory protein.

Among the drugs which produce dependence, the narcotic analgesics

have specific effects upon the content and turnover of various neurotransmitters in the brain. Acute administration of these drugs prevents the

release of acetylcholine and causes an accumulation of this substance in the

brains of various species. Tolerance to these effects develops when the

narcotic analgesics are administered over prolonged periods of time. These

effects of the narcotic analgesics are specifically blocked by narcotic

antagonists. Acute administration of the narcotic analgesics also

causes decreases in brain catecholamine content and increases the synthesis

and turnover of both dopamine and norepinephrine in the brain. Tolerance

develops to morphine-induced changes in brain catecholamine turnover when

355
Smith, C.B. Neurotransmitters. . . continued

narcotic analgesics are administered chronically. Specific narcotic

antagonists block the effects of the narcotic analgesics upon catecholamine

turnover in the brain. The acute administration of the narcotic analgesics

does not have pronounced effects upon brain serotonin content. Changes in the

rates of turnover of acetylcholine, dopamine, norepinephrine, and serotonin

have been related to the dependent state produced by chronic administration

of the narcotic analgesics.

SMITH, C.B. and SHELDON, M.I. Effects of narcotic analgesic drugs on brain noradrenergic mechanisms. Agonist and Antagonist Actions of Narcotic Analgesic Drugs.

Edited by H.W. Kosterlitz, H.O. Collier and J.E. Villarreal. Baltimore,

Maryland: Baltimore University Park Press, 1973.

SMITH, C.B., SHELDON, M.I., BEDNARCZYK, J.H. and VILLARREAL, J.E. Morphineinduced increases in the incorporation of 14C-tyrosine into 14C-dopamine and 14Cnorepinephrine in the mouse brain: Antagonism by noloxone and tolerance. The

Journal of Pharmacology and Experimental Therapeutics 180(3): 547-557 (1972)

For abstract, see Section II. Drug Chemistry and Metabolism.

SNYDER, S.H. Putative neurotransmitters in the brain: Selective neuronal uptake, subcellular localization, and interactions with centrally acting drugs. Biological

Psychiatry 2: 357-389 (1970)

For abstract, see Section II. Drug Chemistry and Metabolism.

SNYDER, S.H., TAYLOR, K.M., COYLE, J.T. and MEYERHOFF, J.L. The role of

brain dopamine in behavioral regulation and the actions of psychotropic drugs.

American Journal of Psychiatry 127(2): 199-207 (August, 1970)

By comparing biochemical and behavioral actions of d- and l- isomers

of amphetamine, the authors show that locomotor hyperactivity, an animal model

for the central stimulant effects of amphetamine, is mediated by brain norepinephrine. By contrast, stereotyped, compulsive gnawing behavior in rats, which

resembles symptoms of amphetamine psychosis, appears to be regulated by brain

dopamine. Since haloperidol, a potent blocker of dopamine receptors, is uniquely

efficacious in treating Gilles de la Tourette’s disease, the authors suggest that

hyperactivity of dopamine systems in the brain may be a factor, in the pathophysiology of this condition.

SOFIA, R.D., DIXIT, B.N. and BARRY, H., III. The effect of delta-l-tetrahydrocannabinol in serotonin metabolism in the rat brain. Life Sciences 10(1): 425-436

(1971)

Cerebellum were most affected and apparently accounted for the overall

increase seen in the whole brain levels of 5-HT. Since delta-1-THC did not

affect MAO activity, the increase in 5-HT was evidently not due to inhibition of

its degradation. However, synthesis rate of 5-HT was significantly reduced

(50 percent) by delta-1-THC. Furthermore, pretreatment with delta-l-THC

retarded the rate of reserpine-induced depletion of brain 5-HT. Alteration of

the vesicular membrane is suggested as a possible mechanism for the effects of

delta-1-THC on 5-HT metabolism.

356
SOFIA, R.D., ERTEL, R.J., DIXIT, B.N. and BARRY, H. The effect of delta-l-tetrahydrocannabinol on the uptake of serotonin by rat brain homogenates. European

Journal of Pharmacology 16: 257-259 (1971)

The uptake of (14)C-serotonin by rat brain homogenates (synaptosomes)

was inhibited by delta-1-tetrahydrocannabinol in concentrations of 1 x 10(-7)M

and greater. The antidepressant agent desipramine had the same effect but showed

greater potency, with a concentration as low as 1 x 10(-8)M being needed to inhibit

(14)C-serotonin uptake.

SOKOL, G.H. and MAICKEL, R.P. Toxic interactions of d-amphetamine and tricyclic

antidepressants in mice. Research Communications in Chemical Pathology and

Pharmacology 3(3): 513 (May, 1972)

The interaction of various tricyclic drugs with d-amphetamine toxicity

has been studied under standard conditions in non-aggregated mice. Pre- or

post-treatment with promazine protects the animals in all cases. The tertiary

amines, imipramine and amitriptyline,

action, while the secondary amines,

have either no effect or exert a protective

desmethylimipramine and nortriptyline,

either potentiate or reduce the toxicity of d-amphetamine, depending on the dosage

schedule with respect to time.

SORENSEN, J.P., JR. and HARVEY, J.A. Decreased brain acetylcholine after septal

lesions in rats: Correlation with thirst. Physiology and Behavior 6: 723-725

(1971)

Bilateral lesions in the septal area of the forebrain produced

both a significant decrease in brain content of acetylcholine and a significant

increase in daily water consumption. Only lesioned rats showing hyperdipsia

demonstrated a decrease in brain acetylcholine. These data support

previous suggestions that thirst is mediated by a cholinergic mechanism

in brain.

SPARBER, S.B. Neorochemical

Federation Proceedings

changes associated with schedule-controlled behavior.

(in press)

SPAULDING. T.C., FORD, R.D., DEWEY, W.L., McMILLAN, D.E. and HARRIS, L.S.

Some pharmacological effects of phenitrone and its interaction with delta-9-THC.

European Journal of Pharmacology 19: 310-317 (1972)

For abstract, see Section II. Drug Chemistry and Metabolism.

SPAULDING, T.C., MINIUM, L., KOTAKE, A.N. and TAKEMORI, A.E. The effect of

diazepam on the metabolism of methadone by the liver of methadone-dependent

rats. Drug Metabolism and Disposition 2(5): 458-463 (1974)

For abstract, see Section II. Drug Chemistry and Metabolism.

STEELE, W.J. and JOHANNESON, T. Effects of morphine infusion in maternal rats at

near term on ribosome size distribution in foetal and maternal rat brain. Acta

Pharmacologia et Toxicologia (in press)

357
STEELE, W.J. and JOHANNESON, T. Effects of prenatally administered morphine on

brain development and resultant tolerance to the analgesic effect of morphine in

offspring of morphine treated rats. Acta Pharmacologia et Toxicologia (in press)

STEINERT, H.R., HOLTZMAN, S.G. and JEWETT, R.E. Some agonistic actions of the

morphine antagonist levallorphan on behavior and brain monoamines in the rat.

Psychopharmacologia 31: 35-48 (1973)

The effects of levallorphan, a narcotic-antagonist analgesic, were studied

on locomotor activity, operant behavior (continuous avoidance schedule), and brain

monoamine content in the rat. Levallorphan produced an increase in locomotor

activity and in the rate of avoidance responding. Brain norepinephrine was significantly decreased 1 h after 256 mg/kg of levallorphan. Brain dopamine (DA) levels

were lowered by 64 and 256 mg/kg of levallorphan. There was no effect on brain

serotonin levels. The stimulant effects of levallorphan on operant behavior were

blocked by simultaneous administration of naloxone. A clear antagonism of the

effects of levallorphan on locomotor activity by naloxone could be demonstrated for

low doses of levallorphan but not for doses above 16 mg/kg. Naloxone also failed

to prevent the depletion of brain catecholamines produced by levallorphan. Naloxone

alone had no consistent effect on either of the behaviors under observation or on

brain monoamine content. These findings indicate that levallorphan is a stimulant

of behavior in the rat, and that the stimulant action is mediated by at least two

mechanisms: one which is blocked by naloxone, and one which is not. Furthermore, it is suggested that the rat should be considered as a possible animal

model in which to study the agonistic properties of certain narcotic-antagonist

analgesics on behavior.

STERNBACH, D.D., ABOOD, L.G. and HOSS, W. A benzilate ester of pyrrolizidine and

its stereochemical relationship to other psychotomimetic glycolates. Life Sciences

14: 1847-1856 (19’74)

For abstract, see Section I. Methodology of Drug Research.

STOELTING, R.K., MARTZ, R.C., GARTNER, J., CREASSER, C., BROWN, D.J. and

FARNEY, R.B. Effects of delta-9-tetrahydrocannabinol on halothane MAC in

dogs. Anesthesiology 38(61: 521-524 (June, 1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

STOLMAN, S. and ASTON, R. Relationship of barbital disposition to auto-induced hypersusceptibility in the rat. Biochemical Pharmacology 19: 595-601 (1970)

Two daily doses of barbital induce, in the female rat, a hypersusceptibility to the drug which is present after 18 days, and absent after 38 days of

abstinence. Spectrophotometric and radiometric assays of barbital tissue levels,

at various times from 10 to 360 min after drug administration, reveal no differences

in blood, brain or urinary barbiturate levels among control, hypersusceptible or

posthypersusceptible animals. The data support the suggestion that induced hypersusceptibility does not result from changes in the disposition of barbiturate in vivo.

It appears likely that this phenomenon results from central nervous system alterations in the localization of, or sensitivity to, the drug.

358
STOLMAN, S. and ASTON, R. The role of anoxia and hypercarbia in induced hypersusceptibility to barbital. Archives internationales de Pharmacodynamie et de Therapie

180(1): 40 (July, 1969)

The phenomenon of hypersusceptibility to a barbiturate, occurring several

weeks following two daily doses of the drug, has been previously reported from this

laboratory. This response has been shown to be unrelated to alterations in the in

vivo disposition of barbiturates. Such auto-induced hypersusceptibility might, however, be due to non-specific central nervous system damage resulting from cerebral

hypoxia or hypercarbia coincident with the effects of the initial administration of

barbiturate. The present study was designed to investigate the possibility that

hypoxic or hypercarbic brain damage might be responsible for the later manifestation of an exaggerated response to these drugs.

SULSER, F. On the mode of action of antidepressants. Psychopharmacologic Treatment

in Psychiatry. New York: Marcel Dekker. Inc., 1973.

TAKEMORI, A.E. Biochemistry of drug dependence. Annual Review of Biochemistry 43:

15-33 (1974)

TAKEMORI, A.E. and TULUNAY, F.C. Further studies on the receptor alteration induced

by morphine. The Pharmacologist 15: 242 (1973)

In an earlier study, it was shown that pretreatment of mice with M resulted in a significant increase of the apparent pA2

 of morphine-naloxone which

suggested an alteration of the analgesic receptor. The magnitude of this increase

indicated a two-fold increase in the apparent affinity constant (KB) of naloxone

(N) for the receptor. Mice were made highly tolerant to the analgesic effect of

M by implantation of M pellets for 3 days. The apparent pA2 increased significantly from 6.9 in control mice to 7.8 in tolerant mice. This indicates that

the apparent KB of N for the receptor was increased by over 7 fold and that a

qualitative rather than a quantitative change took place on the receptor. Cycloheximide (CHX. 25mg/kg) 12 hr before M pretreatment did not alter the ED50

of M or the increased efficacy of N. However, daily injections of CHX (20 mg/

kg) for 7 days (4 days prior to M implantation and 3 days during the implant)

inhibited the development of tolerance by 84% and the increased efficacy of N by

64%. The increased affinity of N due to M treatment appears related to the development of tolerance, The possibility that N may act at an allosteric site to

produce an apparent competitive antagonism is suggested.

TAYLOR, K.M. and SNYDER, S.H. Amphetamine: Differentiation by d and 1 isomers of

behavior involving brain norepinephrine or dopamine. Science 168: 1487-1489

(June 19, 1970)

d-Amphetamine is markedly more potent an inhibitor of catecholamine

uptake by norepinephrine neurons in the brain than is l-amphetamine, whereas

the two isomers are equally active in inhibiting catecholamine uptake by the

dopamine neurons of the corpus striatum. In behavioral studies, d-amphetamine

is ten times as potent as l-amphetamine in enhancing locomotor activity, while

it is only twice as potent in eliciting a compulsive gnawing syndrome. This

suggests that the locomotor stimulation induced by amphetamine involves central

norepinephrine, while dopamine neurons play an important role in the induced

compulsive gnawing behavior. Assessment of differential actions of d- and lamphetamine may be an efficient method to differentiate behaviors involving

norepinephrine or dopamine in the brain.

359
TAYLOR, W.A. and SULSER, F. Effects of amphetamine and its metabolites on cerebral

noradrenergic mechanisms. The Journal of Pharmacology and Experimental Therapeutics 185(3): 620-632 (1973)

TAYLOR, W.A. and SULSER, F. Effects of intraventricularly administered l- d- and dl-phydroxyamphetamine (POH) on behavior and cerebral catecholamines. Presented

at the Fifth International Congress on Pharmacology, San Francisco, California,

1972.

TESCHEMACHER, H., OPHEIM, K. and GOLDSTEIN, A. Nonspecific photochemical attachment of opiates to brain tissue. Proceedings of the Sixth International Congress of

Pharmacology, Helsinki, Finland, July 20-25, 1975.

TILSON, H.A., RECH, R.H. and SPARBER, S.B. Release of 14C-norepinephrine into the

lateral cerebroventricle of rats exposed to a conditioned aversive stimulus.

Pharmacology Biochemistry and Behavior (in press)

Rats chronically implanted with push-pull cannulas were injected with a

pulse of -norepinephrine (NE) injected into the lateral cerebroventricle under

a variety of pretreatment and behavioral conditions. Subjects pretreated intraventricularly with 6-hydroxydopamine (Group A) or ascorbic acid vehicle (Group

B) were subsequently perfused under four conditions: (I) presentation of a novel,

visual stimulus in a one-way avoidance chamber; (II) presentation of the light (CS)

followed by shock; (III) training to a high level of avoidance behavior, after which

the CS was presented in the absence of opportunity for an avoidance response and

in the absence of shock; and (IV) after forced extinction, followed by CS without

opportunity to avoid and without presentation of shock. Samples of perfusate were

analyzed for total in a scintillation counter and for proportion of NE and

normetanephrine (NM) by TLC from rats

During tests I and IV the perfusion

subjected to the four test conditions.

“wash-out” did not differ from control

values for either Group A or B. During test II, total radioactivity as well as the

proportions of NE and NM increased in the perfusate for both Grous A and B.

Presenting the CS without shock (III) resulted in an increase in and NE and

NM for Group B (vehicle), but not for Group A (6-OHDA). To test for non-specific

release unrelated to a brain catecholaminergic function, another group of rats was

subjected to identical treatments with the exception that -urea replaced

NE as a pulse-label. In these subjects test II (shock) induced an increase in

in the perfusate, while tests I, III and IV yielded wash-out curves essentially

identical to controls.

TINKLENBERG, J.R. Study group (ad hoc): Cannabis study group on marihuana and alcohol.

Psychopharmacology Bulletin 8(1): 9-10 (1972)

Moderate doses of marihuana and alcohol used in the study induced significant cognitive changes from placebo conditions and baseline predrug performances

only in time production tasks. There were, however, consistent trends suggesting

marihuana was somewhat more disruptive of tasks which required appropriate temporal sequencing and that marihuana induced greater variability in cognitive performance. Marihuana consistently increased amplitudes of AEP and CNV in electrocortical measures. Moderate doses of marihuana and alcohol induce minor alterations

along simple cognitive dimensions. There are concomitant electrocortical changes

which more appreciably differentiate the 2 drugs.

360
TOLOSA, E.S. and SPARBER, S.B. Apomorphine in Huntington’s Chorea: Clinical observations and theoretical considerations. Life Sciences 15: 1371 (1974)

TRUITT, E.B., JR. and ANDERSON, S.M. Biogenic amine alterations produced in the brain

by tetrahydrocannabinols and their metabolites. Annals of the New York Academy

of Sciences 191: 68-73 (1971)

For abstract, see Section II. Drug Chemistry and Metabolism.

TRUITT, E.B., JR. and ANDERSON, S.M. The role of biogenic amines in the central

actions of tetrahydrocannabinols and their metabolites. Acta Pharmaceutica

Suecica 8: 696-697 (1971)

Five patients, four definitively diagnosed as suffering from Huntington’s

disease and the fifth with abnormal involuntary movements (AIM) and dementia but

no apparent family history of the disease, were administered apomorphine. Although the short duration of action and stressful side-effects produced by apomorphine limited its use regarding a complete dose- and time-response evaluation,

slight to marked diminution of AIM was seen in all patients. Optimal doses

ranged from 1-2 mg across patients, producing a significant reduction in AIM for

the entire hour of observations. Theoretical interpretations of these effects regarding dopaminergic receptor stimulation and/or blockade by apomorphine are

discussed.

For abstract, see Section II. Drug Chemistry and Metabolism.

TSENG, L.F., WEI, E. and LOH, H.H. Brain areas associated with bulbacapnine catalepsy. European Journal of Pharmacology 22: 363-366 (1973)

Bulbocapnine is the prototype of chemical agents used in the experimental

study of catalepsy (DeJong, 1945). Based on the structural similarity of bulbocapnine to apomorphine, a postulated dopaminergic receptor agonist (Ernst and Smelik,

1966; Roos, 1969; Anden et al., 1967). Ernst (1969) suggested that bulbocapnine may

act by blocking dopaminergic receptors in the striatum. Administered systemically, bulbocapnine will antagonize d-amphetamine-stimulated stereotyped behavior

(Tseng and Walaszek, 1972). Apomorphine in turn, will antagonize bulbocapnine- ,

induced catalepsy (Divry and Evrard, 1934). Stille and Lauener (1971) observed a

correlation between the cataleptic effect of bulbocapnine and the increase of

striatal homovanillic acid. These studies indicate a reciprocal interaction between bulbocapnine and brain dopaminergic mechanisms. In this investigation,

we attempted to localize, by intracerebral micro-injections of bulbocapnine into

the rat brain, the neuroanatomical sites related to bulbocapnine catalepsy. The

results indicate that bulbocapnine acts in the striatum to produce catalepsy.

TULUNAY, F.C., SPARBER, S.B. and TAKEMORI, A.E. The role of dopaminergic stimulation and blockade on the nociceptive and antinociceptive responses of mice.

European Journal of Pharmacology (in press)

Agents which stimulate dopaminergic receptors directly or indirectly

such as apomorphine and L-dopa, increased the reactivity of mice to a nociceptive

stimulus. The increased reactivity was pharmacologically quantitated by estimating the hyperalgesic ED50 to be 4.4 and 115 mg/kg for apomorphine and L-dopa,

respectively. This hyperalgesia was blocked by the dopamine receptor blocking

agents, haloperidol and pimozide, but not by the narcotic antagonist, naloxone.

Apomorphine antagonizes morphine analgesia however the induced hyperalgesia

only accounts for part of the antagonistic activity of apomorphine. The majority

of the antagonistic activity of apomorphine appears to be by means other than

action on dopaminergic receptors.

361
TULUNAY, F.C. and TAKEMORI, A.E. Dopaminergic system and analgesia. The Pharmacologist 16: 248 (1974)

We showed earlier that pretreatment of mice with narcotic agonists

caused a marked increase in the antagonistic effect of narcotic antagonists and

suggested that the increased efficacy of antagonists might be a sensitive indicator

of the initiation of tolerance. In the present study we investigated the effect of

the dopaminergic system on morphine (M) analgesia and the naloxone (NLX)

efficacy using the tail-flick assay in mice. Dopaminergic receptor agonist apomorphine (APO) and L-DOPA produced hyperalgesia (hyperalgesic ED50’s were

4.4 (3.1-6.1) and 115.0 (72.8-181.7) mg/kg respectively), and this hyperalgesia

was inhibited by dopaminergic receptor blocking agents, haloperidol (HAL) and

pimozide (PMZ) but not by NLX. Both APO and L-DOPA caused an increase in

M ED50 while HAL decreased it and PMZ was without effect. However NLX

shifted the M ED50 in all treated animals proportionately similar to that seen in

control mice. In animals pretreated with a single dose of M; L-DOPA, APO and

PMZ increased and HAL, decreased the M ED50. The increased efficacy of NLX

seen after M pretreatment was again proportionately the same in all treated groups.

Our results suggest that the dopaminergic system may play a modulating role in

the action of M but not in the efficacy of NLX.

TULUNAY, F.C. and TAKEMORI, A.E. The effect of morphine on the incorporation of

3H-leucine into retinal proteins and subsequent axonal transport in the optic

system of rats. Life Sciences (in press)

TULUNAY, F.C. and TAKEMORI, A.E. Further studies on the alteration of analgesic

receptor-antagonist interaction induced by morphine. The Journal of Pharmacology and Experimental Therapeutics 190(3): 401-407 (1974)

For abstract, see Section I. Methodology of Drug Research.

TULUNAY, F.C. and TAKEMORI, A.E. The increased efficacy of narcotic antagonists

induced by various narcotic analgesics. The Journal of Pharmacology and

Experimental Therapeutics 190(3): 395-400 (1974)

For abstract, see Section I. Methodology of Drug Research.

TURKANIS, S.A., CELY, W., OLSEN, D.M. and KARLER, R. The anticonvulsant properties of cannabidiol. Research Communications in Chemical Pathology and

and Pharmacology 8(2): 231 (June, 1974)

A series of laboratory tests were conducted in mice to evaluate the anticonvulsant properties of cannabidiol (CBD). The drug abolished hindlimb extension

induced by maximal electroshock (MES) and raises the MES (extensor) and 6-Hzelectroshock thresholds, but does not affect the 60-Hz-electroshock or minimal

seizures caused by pentylenetetrazol (PTZ). As an anticonvulsant, CBD appears

to be more closely related to diphenylhydantoin (DPH) than to its chemical congener,

delta-9-tetrahydrocannabinol (delta-9-THC).

UNGAR, G. and GALVAN, L. Conditions of transfer of morphine tolerance to brain extracts.

Proceedings of the Society for Experimental Biology and Medicine 130: 287-291

(1968)

362
VACHON, L., FITZGERALD, M.X., SOLLIDAY, N.H. GOULD, I.A. and GAENSLER, E.A.

Single-dose effect of marihuana smoke. New England Journal of Medicine 288: 985-989

(1973)

Normal volunteers with previous marihuana smoking experience inhaled the

total smoke from 3.23 mg per kilogram of marihuana, using a bag-in-box technic.

Randomly, nine received marihuana containing a high (2.6 per cent), and eight a low

(1.0 per cent) concentration of delta-9-tetrahydrocannabinol.

Physiologic variables were monitored before and for 20 minutes after

smoking. In the high-dose group the heart rate increased 28 per cent. Concomitantly, airway resistance, measured in a body plethysmograph, fell 38 per

cent; the functional residual capacity remained unchanged (± 50 ml) throughout,

and specific airway conductance increased 44 per cent. Flow volume loops

showed no increase in heart rate but significant, if lesser changes, in airways

dynamics. Carbon dioxide sensitivity, measured by rebreathing remained unchanged in both groups.

Marihuana smoke, unlike cigarette smoke, causes bronchodilation

rather than bronchoconstriction and, unlike opiates, does not cause central respiratory depression.

Proceedings from the National Conference on Marihuana (in press)

VA CHON, L., MIKUS, P., MORRISEY, W., FITZGERALD, M. and GAENSLER, E.

The effects of a single administration of marihuana smoke on bronchial

mechanics were studied in a group of asthmatic subjects. The diagnosis of asthma

was made on the basis of history and evidence of reversible airway obstruction;

the subjects were free of symptoms at the time of testing. They received a standard volume of a mixture of air and smoke from natural marihuana containing

one of two different concentrations (1.9% and 0.9%) of delta-9-THC. Both concentrations showed significant and prolonged reversal of the bronchoconstriction

as well as significant but shorter duration tachycardia.

VAN VUNAKIS, H., WASSERMAN, E. and LEVINE, L. Specificities of antibodies to morphine. The Journal of Pharmacology and Experimental Therapeutics 180(2): 514-

521 (1972)

3-Carboxymethylmorphine was coupled to polylysine with the use of

carbodiimide. The conjugates, complexed to succinylated hemocyanin, were

used to immunize rabbits and guinea pigs.. Antibody activity, found in the 7 S

gamma-globulin fraction of the rabbit serum, increased during the course of

immunization. Codeine was most effectively bound to anticarboxymethylmorphine.

In order of decreasing effectiveness, dihydrocodeine. morphine, heroin, hydromorphone and nalorphine also cross-react with anti-carboxymethylmorphine.

A radioimmunoassay for measurement of these compounds at the picomole level

has been developed. Twenty-two of 35 extracts of autopsy sera from cases of

sudden death suspected of drug abuse were positive when tested for reaction with

the morphine antiserum by this radioimmunoassay.

363
VESTERGAARD, P., RUBIN, V., BEAUBRUNN, M.H., CRUICKSHANK, E. and PICOU, D.

Steroid excretion in chronic cannabis users and matched controls. Acta Pharmaceutica Suecica 8: 671-706 (1971)

A collaborative study is currently under way on Jamaica of the effect of

long term use of cannabis. This study has been organized jointly by the Research

Institute for the Study of Man in New York (Drs. Rubin and Comitas) and the University of the West Indies (Drs. Beaubrunn and Cruickshank).

AS a subproject of this investigation we have compared steroid excretion

patterns in groups of chronic users and matched controls. Apart from creatinine

analyses done with Autoanalyzer techniques the methods used have all been developed

at the Research Center, Rockland State Hospital. A total of 15 urinary steroids

have been determined and two group assays for steroids have been performed on

24 h urines collected on a metabolic ward from a total of 20 subjects from both

groups.

There were no significant differences between the two groups in any

steroid measurement indicating that prolonged exposure to cannabis in this group

of chronic users did not affect adrenal function as evaluated through steroid excretion data.

A collateral study of thyroid function done by another group at the

Research Center showed no significant changes in 3 thyroid indices on comparison

between non-users and chronic users of cannabis.

VOLICER, L., PURI, S.K. and COCHIN, J. Effect of morphine on phosphodiesterase

(PDE) activity in rat striatum. Proceedings of Second International Conference

on Cyclic AMP, July 8-11, 1974

Morphine sulfate (MS) affects the dopaminergic system in the striatum.

Since dopamine-sensitive adenylate cyclase was found in the striatum, we investigated the effect of MS on the cyclic AMP system. PDE activity in the total homogenate of striatum was measured by the method of Brooker et al. (Biochem, 7, 4177,

1968) using cyclic AMP as a substrate. In vitro MS inhibited PDE activity in a substrate concentration of 3.33x-10-3 but not in concentrations of 3.33x10-5

 or

3.33x10-7 M. This effect was dose dependent in the range of 0.1 to 1000 mu-M

concentrations of MS. Administration of MS in vivo (7. 5-30 mg/kg i.p., 1 hr

before sacrifice) inhibited the PDE activity only with the high substrate concentration. PDE activity was compared in homogenates from control and MS-treated

(15 mg/kg) rats; the kinetic analysis was consistent with a competitive inhibition

of PDE activity by MS. Km of cyclic AMP for control rats was 4.4x10-4M and for

MS-treated rats was 6.1x10-4M. Rats given MS in increasing doses for 14 days

developed tolerance to the inhibitory effect of MS on PDE activity. These results

indicate that MS selectively inhibits a high Km PDE in the rat striatum.

VOLLMER, R.R., CAVERO, I., ERTEL, R.J., SOLOMON, T.A. and BUCKLEY, J.P.

Role of the central autonomic nervous system in the hypotension and bradycardia

induced by (-)-delta-9-trans-tetrahydrocannabinol. Journal of Pharmacy and

Pharmacology 26(3): 186-192 (March, 1974)

(-)-Delta-9-trans-tetrahydrocannabinol (delta-9-THC), when given

intravenously (2 mg kg-1) to cats, produced marked decreases in blood

pressure and heart rate which developed gradually and were of prolonged

duration. Cervical spinal transection (C1-C2) abolished these effects

whereas surgical removal of neurogenic tone to the myocardium selectively

eliminated the bradycardia. Bilateral vagotomy alone did not modify the

action of delta-9-THC upon heart rate or blood pressure. Recordings of

spontaneous sympathetic outflow in the inferior cardiac nerve indicated a

rapid reduction in neural discharge rate after delta-9-THC administration.

These observations support the hypothesis that delta-9-THC produces a cardiodecellerator and hypotensive effect by acting as some level within the

sympathetic nervous system. Experiments conducted to investigate

364
Vollmer, R.R., Cavero, I., Ertel, R. J., Solomon, T.A. and Buckley, J.P. continued

transmission in the superior cervical and stellate ganglia demonstrated that

delta-9-THC did not alter ganglionic function. Also, responses to

intravenous isoprenaline and noradrenaline were unchanged which suggested

that delta-9-THC did not interact with alpha- or beta-adrenoceptors.

The possible action of delta-9-THC on central sympathetic structures was

investigated by perfusion of delta-9-THC into the lateral cerebral ventricle.

Delta-9-THC so administered produced a significant reduction in heart

rate without a substantial lowering of blood pressure. Tritiated or

14C-delta-9-THC perfused into the lateral ventricle demonstrated that the

amount of radioactive compound passing into the peripheral circulation

was insignificant and could not account for the decrease in heart rate.

The current data are in agreement with the proposal that delta-9-THC produces

cardiovascular alterations by an action on the central nervous system

which results in a decrease in sympathetic tone.

VOLAVKA, J., CROWN, P., DORNBUSH, R., FELDSTEIN, S. and FINK, M. EEG,

heart rate and mood change (“high”) after cannabis. Psychopharmacologia 32:

11-25 (1973)

Fourteen experienced marijuana users smoked marijuana, hashish,

delta9 -THC, and placebo. EEG, ECG and ratings of subjective feelings of

“high” and pleasantness were recorded. EEGs were processed. by period

analysis.

In EEG, marijuana and delta9-THC increased the amount of alpha

activity, and the three Cannabis preparations decreased the amount of beta

activity. The average frequency of alpha activity was decreased by

0.15-0.20 c/sec after marijuana, hashish and delta9

-THC. The. peak EEG

effect occurred during the first 10 min after smolcing; most of the changes

‘disappeared after 40 min. Heart rate was increased by all the three drugs,

and the effect persisted for the entire observation period (50 min).

Feelings of “high” were elicited by each Cannabis preparation.

This was not true of the pleasantness of the experience: only marijuana and

hashish were perceived as more pleasant than placebo. Intensity of “high” increased with the amount of alpha activity, and decreased with the average alpha

frequency. Pleasantness was unrelated to the EEG.

The “high” showed a linear increase with heart rate, whereas pleasantness of the experience was an inverted U-function of heart rate.

VOLAVKA, J., LEVINE, R., FELDSTEIN, S. and FINK, M. Short-term effect of

heroin in man. Archives of General Psychiatry 30:677 (May, 1974)

Nineteen detoxified male heroin postaddicts received 25 mg of heroin

intravenously, on two occasions, and a placebo intravenously on two other

occasions. Two tasks were administered: an auditory detection task to measure

performance, and a mood monitoring task to measure the subjective reports of

“high.” Each task was administered once after heroin and once after the

placebo. Electroencephalogram, breathing rate, heart rate, and pupil size were

measured before and after each injection. Heroin injections resulted in an increase of heart rate. The time course of these changes and of the heroin “high”

was defined.

While an increase in number of omission errors was associated with

a decrease in EEG frequency, the rate of increase was differentially affected by

heroin and placebo. Admintstration of heroin was followed by a prolongation

of reaction time. Intensity of the subjective “high” was negatively related to

the EEG frequency, breathing rate, and pupil size. This test battery is useful

for measurement of effects of opiates and their antagonists.

365
VOLAVKA, J., LEVINE, R., KOMLOSI, M. and FINK, M. EEG and task performance after heroin in post-addicts. Electroencephalography and Clinical Neurophysiology 37: 195 (1974)

To define the relation between EEG, opiate dose and. task performance,

17 detoxified heroin post-addicts received 25 mg of heroin or placebo i.v. EEGs

were recorded for 10 min before and for 30 min after each injection. A continuous auditory detection task (ADT) was administered in the post-injection period.

Two different tones were delivered in pairs. The subject was asked to press a

key each time a special combination of tones occurred. The interval within each

pair was fixed at 1 sec. and the intervals between the pairs varied between 7 and

25 sec. The frequencies and amplitudes of 5-sec segments of EEG immediately

preceding the presentation of the first tone of any stimulus pair were measured

by period analysis using an IBM 1800 system.

Heroin elicited a decrease of the average EEG frequency, and an increase in the delta and theta percent times. The number of omission errors for

the ADT increased as the EEG frequency decreased. There was interaction between drug condition and EEG frequency: the same degree of slowing was

associated with fewer omission errors after heroin than after placebo. Heroin

increased the reaction time which also increased as the EEG frequencies became

slower.

These results support earlier observations of relation between EEG

frequency and reaction time. They also demonstrate that the relation between

EEG and performance can be altered by a drug.

VOLAVKA, J., ZAKS, A., ROUBICEK, J. and FINK, M. Electrographic effects of

diacetylmorphine (heroin) and naloxone in man. Neuropharmacology 9:587-593

(1970)

Sixty-three addicts were given heroin intravenously at a rate of

20-40 mg/2 cc/ 2 min, and 8-32 min later received 1-2 mg naloxone. The EEG

was recorded in the pre-heroin. post-heroin and post-naloxone periods.

The early response to heroin (first 4 min after the start of the injection)

was an increase in alpha amplitudes, decrease of alpha frequency and an occasional

increase in alpha spindling.

The late response (5-32 min after the start of the injection) was a

decrease in alpha abundance, an increase in theta and sometimes delta activities, and paroxysmal EEG activity. Two clinical seizures were seen.

The tracings returned to the pre-heroin pattern after the administraof naloxone.

These observations of heroin and naloxone are consistent with established theories of association of EEG and behavior in man after psychoactive

drugs.

VOSS, E.W., JR., BABB, J.E., METZEL, P. and WINKELHAKE, J.L. In vitro

effect of d-lysergic acid diethylamide on immunoglobulin synthesis. Biochemical and Biophysical Research Communications 50(3): 950 (1973)

Rabbit anti-fluorescyl antibody producing lymphoid cells incubated in

vitro with LSD do not secrete the 7S form of immunoglobulin. The low molecular

weight extracellular labeled material shows no measurable anti-fluorescyl antibody activity. Results indicate that during a short incubation period LSD interferes with tryptophan incorporation into antibody protein.

366
VOSS, E.W., JR., METZEL, P. and WINKELHAKE, J.L. Incorporation of a lysergic

acid diethylamide intermediate into antibody protein in vitro. Molecular

Pharmacology 9(3): 421-425 (May, 1973)

Antibody-producing lymphoid cells incubated in vitro in the presence of

lysergic acid diethylamide (or a derivative) de novo was indicated by precipitation of labeled peptides with trichloracetic acid and by the retention of label

after dialysis against denaturing agents and high concentrations of a dissociating

ligand. Incorporation of lysergic acid diethylamide by immune lymphoid

cells was inhibited by puromycin and enhanced by homologous antigen.

VOSS, E.W., JR., and WINRELHAKE, J.L. Mechanisms of lysergic acid diethylamide

interference with rabbit antibody biosynthesis. Proceedings of the National

Academy of Sciences 71(4): 1061-1064 (April, 1974)

Lymphoid cells from hyperimmune rabbits producing antibodies to a

hapten, incubated in the presence of d-lysergic acid diethyramide, continued to

synthesize protein at a normal rate. Isoelectric focusing analysis of the lowmolecular-weight protein secreted by the cells incubated with lysergic acid

diethylamide indicated two components, with pI’s of 4.9 and 5.2. Immune cells

not exposed to lysergic acid diethylamide secreted only 7S IgG molecules with

an average pI of approximately 7.0.

WARD, A. and TAKEMORI, A.E. Alteration of receptor sensitivity to morphine in the

guinea pig ileum. Federation Proceedings 33: 502 (1974)

The ED50 of M and pA2 of morphine-nalozone (M-N) were determined

in the coaxially stimulated ileum from GP implanted s.c. with four 75 mg M

pellets (MP) for 1, 2 and 3 days. Over the 3 day period, the ileum developed

tolerance to the depressant effect of morphine as seen by the shift in ED50 from

2.21 x 10-7 to 2.01 x 10-6 M. Concomitantly the apparent pA2 of M-N decreased

progressively from 8.50 to 7.63. The ED50 and pA2

 returned to, control levels

within 48 hr after removal of the MP. In ileums from GP treated with 6-hydroxydopamine (6-OHDA)(20 or 50 mg/kg) 6 days previously, the ED50 of M and pA2

 of

M-N did not differ from control values. In ileums of GP implanted with MP for

3 days h addition to 50 mg/kg 6-OHDA injection, the developnent of tolerance

and the progressive decrease in pA2 were both partially inhibited. In ileums of

6-OHDA treated-GP the ED50 of norepinephrine (NE) was decreased compared

to control. In ileums of MP-GP the ED50 of NE was increased about 4 fold

whereas in ileums from 6-OHDA -treated MP-GP the increase in ED50 was

slightly over 3 fold. In ileums of MP-GP the dopamine dose-response curve.

only reached 50% of max. response. The data indicate that the development‘of

tolerance in the GP ileum to the effects of M is accompanied by a qualitative

change in the M receptors. The integrity of the catecholaminergic nerves does

not appear to be required for the acute action of M but may be partially involved

in the development of tolerance.

367
WASSERMAN, A. and KHAZAN, N. Effects of chronic treatment with imipramine,

desipramine and trimipramine on REM sleep in the rat. The Pharmacologist

13: 255 (1971)

The various tricyclic antidepressants exhibit several dissimilarities in

both pharmacologic and therapeutic profiles. In an acute study, trimipramine,

unlike imipramine and desipramine, demonstrated no suppression of REM sleep

in the rat (Khazan, N. and Brown, P., Life Sci. 9:279, 1970). The present study

was undertaken to determine whether this characteristic would persist during

chronic treatment. Groups of five rats implanted with cortical and muscle electrodes as well as i.p. cannulae were used. Administration of imipramine and

desipramine at doses of both 5 and 10 mg/kg/6hr for 3-5 days resulted in a highly

significant reduction (p less than 0.01) in REM time. REM sleep suppression

was still evident for one to two days after drug withdrawal and was subsequently

followed by a marked REM rebound. Trimipramine given chronically at equivalent doses, on the other hand, exerted essentially no REM suppressant effect

(p greater than 0.05). At a higher dose level of 20 mg/kg, moreover, only

relatively slight reduction (p less than 0.05) in REM time was apparent. These

results suggest that chronic treatment with trimipramine, in contrast with

imipramine and desipramine, exerts only minimal, if any, REM sleep suppression.

WATERS, D.H. and OKAMOTO, M. Increased central excitability in nondependent mice

during chronic barbital dosing. Drug Addiction: Experimental Pharmacology, Vol. 1.

Edited by J. M. Singh, L. H. Miller and H. Lal. Mount Kisco, New York:

Futura Publishing Company, Inc., 1972.

WAY, E. L. Brain neurohormones in morphine tolerance and dependence. Pharmacology and

the Future of Man. Proceedings of the 5th International Congress on Pharmacology,

Vol. 1. San Francisco: Karger, Basel. 1973. Pp. 77-94.

WAY, E.L. Some biochemical aspects of morphine tolerance and physical dependence.

Opiate Addiction: Origins and Treatment. Edited by S. Fisher and A. Freedman.

Washington, D.C.: V. H. Winston and Sons, Inc., 1974.

WAY, E.L., HO, I.K. and LOH, H.H. Brain 5-hydroxytryptamine and cyclic AMP in

morphine tolerance and dependence. Advances in Biochemical Psychopharmacology, Vol. 10. New York: Raven Press, 1974. Pp. 219-229.

WAY, E.L. and SETTLE, A. Cholinergic-dopaminergic interaction during morphine

abstinence. Presented at the 9th International Congress on Neuropsychopharmacology, Paris, France, July, 1974.

WEI, E. Assessment of precipitated abstinence in morphine-dependent rats.

Psychopharmacologia 26: 35-44 (1973)

For abstract, see Section I. Methodology of Drug Research.

368
WEI, E. Brain lesions attenuating “wet shake” behavior in morphine-abstinent rats.

Life Sciences 12 (Part I): 385-392 (1973)

Naloxone precipitates repetitive shaking movements in morphinedependent rats. This response, termed “wet shakes,” is still present in

dependent animals anesthetized with sodium pentobarbital. Transverse brain

lesions, made bilaterally with an iridectomy knife in anesthetized morphinedependent rats, completely inhibited the wet shake response to naloxone when

the transection was made at the mid-collicular level. Lesions anterior to the

fasciculus retroflexus did not significantly affect the wet shake response.

WEI, E. Morphine analgesia, tolerance and physical dependence in the adrenalectomized

rat, British Journal of Pharmacology 47(4): 693-699 (April, 1973)

For abstract, see Section I. Methodology of Drug Research.

WEI, E. and LOH, H. Morphine physical dependence unaltered by previous dependence.

on morphine. Nature 238: 396-397 (1972)

WEI, E., LOH, H.H. and WAY, E.L. Brain sites of precipitated abstinence in morphine -dependent rats. The Journal of Pharmacology and Experimental

Therapeutics 185(1): 198-115 (1973)

For abstract, see Section II. Drug Chemistry and Metabolism.

WEI, E., LOH, H. H. and WAY, E.L. Neuroanatomical correlates of morphine depenWEI, E., TSENG, L.F., LOH, H. and WAY, E.L. Similarity of morphine abstinence

signs to thermoregulatory behaviour. Nature 247: 398 (1974)

WEI, E. and WAY, E.L. Application of the pellet implantation technique for the assessment of tolerance and physical dependence in the rodent. Methods of Narcotic

Research. Edited by S. Ehrenpreis and A. Neidle. New York: Marcel Dekker.

Inc., 1974.

dence. Science 177: 616-617 (August, 1972)

For abstract, see Section I. Methodology of Drug Research.

The precipitated abstinence syndrome consists of a series of behaviooral

events which appear in morphine-dependent organisms after the administration of

narcotic antagonists. Martin has suggested that some precipitated abstinence

signs arise because an error force is generated when a narcotic antagonist

resensitizes a homeostat previously altered by a narcotic. Recently, in studies

on the neuroanatomical correlates of morphine withdrawal, we found that brain

areas associated with the wet shake behaviour of precipitated abstinence in the

rat seemed to be closely adjacent to central pathways of heat dissipation and

heat gain. As morphine has complex effects on central thermoregulatory

mechanisms, the possibility was considered that the generation of an error

signal in central thermoregulatory systems may account for the appearance of

some precipitated abstinence signs. To test this hypothesis, we investigated

the effects of environmental temperature on the precipitated abstinence syndrome.

369
WHITE, R.P., DREW, G.W. and FINK, M. Neuropharmacological analysis of agonistic

actions of cyclazocine in rabbits. Biological Psychiatry 1:217-330 (1971)

The present study was undertaken to determine the neuropharmacological

effects of cyclazocine; its interaction with opiates and to contrast the profile with

imipramine in rabbits. The observations support the hypothesis that cyclazocine

produces agonistic effects, some resembling imipramine, independent of its

ability to occupy narcotic receptors, and these effects contribute to its efficacy

in the treatment of opiate dependence.

WIKLER, A., NORRELL, H. and MILLER, D. Limbic system and opioid addiction in

the rat. Experimental Neurology 34(3): 543-557 (19’72)

Statistical comparisons of means in groups of morphine-dependent (or

post-dependent) rats with and without bilteral lesions in the cingulum, the dorsomedial thalamic nucleus, the anterior temporal lobe (amygdaloid complex and

ventral hippocampus), or the septum, and in nondependent rats with and without

such lesions, revealed no significant lesion effects on specific signs of the 24-hr

primary morphine-abstinence syndrome in this species: decreased water intake;

increased “no-choice” drinking of a 5-mu-g/ml aqueous solution of a potent opioid

(etonitazene); increased “wet dog” shake frequency; fall in colonic temperature.

Lesions in the cingulum attenuated one sign of the secondary (protracted) morphineabstinence syndrome (increased 24-hr water consumption). None of the lesions

altered the suppressive effects on the primary morphine-abstinence syndrome of

“no-choice” etonitazene-drinking or of intraperitoneal injection of morphine. None

of the lesions prevented “relapse” of postdependent rats, as measured by comparisons of mean volumes of etonitazene (5-mu-g/ml) and water consumed in “choice”

trials 9-72 days after permanent withdrawal of morphine.

WILK, S. Cerebrospinal fluid levels of MHPG in affective disorders. Nature 235(5339):

440-441 (February 25, 1972)

WILLEY, T.J., HUNT, G.M. and PETERS, M.A. Computer analysis of methadone

effects on the electroencephalogram. Electroencephalography and Clinical

Neurophysiology 34(7): 715 (1973)

The acute effects of intravenous administration of methadone on

spontaneous brain activity were investigated in the adult cat. Bipolar electrodes

for recording the EEG were placed by stereotaxic methods in subcortical

and cortical brain structures. In most conditions the EEG was recorded

monopolarly except in the prepyriform cortex where the electrodes

straddled the superficial pyramidal cell body layer. An indwelling

intravenous catheter in the external jugular vein was used for placebo and

drug administration. The primary EEG was also recorded on analogue tape for

computer analysis. One channel was used to obtain the EMG from neck

muscles as an adjunct in defining the awake vs. asleep behavioural state

prior to methadone injection.

370
Willey, T.J., Hunt, G.M. and Peters. M.A. continued

Analogue EEG samples from single or up to four channels were

played back to the digitizing input ports on the PDP-12 computer. Frequency

spectra were computed using the Fast-Fourier Transform and stored on Linc

Tape. The EEG spectra consisted of 1.8 sec epochs. For visualization

purposes these spectra were averaged from 2-12 times and plotted dynamically

across time, using hidden-line suppression techniques to give a quasi-three

dimensional representation of the EEG spectral content. Subtle frequency shifts or

alterations attributed to methadone treatment were apparent from these plots.

Multivariate statistical analysis was applied to the frequency spectra to ferret

out significant features related to the drug-induced changes. The major effects

were observed in the occipital and prepyriform cortex, with less effects

observed in hippocampus, caudate nucleus and reticular formation.

the’ pattern was consistent with behavioural altering.

In general

WILLIAMS, N.W. and CLOUET, D.H. The effect of morphine on the uptake and release

of neurotransmitters by isolated synaptosomes. Proceedings of the Fifth

International Congress on Pharmacology, San Francisco, California, 1972.

P. 253.

WILSON, M.C. and SCHUSTER, C.R. The effects of chlorpromazine on psychomotor

stimulant self-administration in the rhesus monkey. Psychopharmacologia 26:

115-126 (1972)

The effects of acute and chronic chlorpromazine treatment

on psychomotor stimulant self-administration behavior in the Rhesus monkey

were determined Chlorpromazine treatment significantly increased the frequency

of self-administration of cocaine, pipradrol, phenmetrazine, d-amphetamine and

methylphenidate. The basis of the effect was thought to either be due to an antagonism of the reinforcing effect of these compounds or an antagonism of those

portions of the psychomotor stimulants which may function in limiting their selfadministration.

WILSON, M.C. and SCHUSTER, C.R. The effects of stimulants and depressants on

cocaine self-administration behavior in the rhesus monkey. Psychopharmacologia

31: 291-304 (1973)

The effects of acute intramuscular pretreatment with several dosages

of a variety of centrally acting compounds on intravenous cocaine self-administration behavior were ascertained. Pretreatment with morphine and pentobarbital

produced no change in this behavior until dosages (2.0 mg/kg and 15.0 mg/kg

respectively) were administered which grossly depressed grooming, exploratory,

and locomotor activity behaviors. d-Amphetamine (0.5-4.0 mg/kg) and phenmetrazine (2.0-12.0 mg/kg) pretreatment produced a dose-related decrease in cocaine

self-administration. Trifluoperazine in dosages of 0.01-0.1 mg/kg increased

the frequency of this behavior; whereas, higher dosages (0.2, 0.4 mg/kg) grossly

depressed behavior. Imipramine (10-50 mg/kg) produced a dose-related decrease

in cocaine self-administration. Potential mechanisms of these drug-behavior and

drug--drug interactions are discussed.

371
WILSON, M.C. and SCHUSTER, C.R. Pharmacological modification of the self-administration of cocaine and SPA in the rhesus monkey. Committee on the Problems of

Drug Dependence. Washington, D.C.: National Academy of Sciences, National

Research Council, 1968.

In a previous report preliminary evidence was presented which showed

that the frequency of self-administration of the psychomotor stimulants fencamfamin

and SPA is an inverse function of the dose/injection.

In the first experiment in the present study we have replicated the previous

findings with SPA and, as well, have investigated the role of unit dosage of cocaine.

The data from this first experiment suggested that there exists a regulatory mechanism which controls the total amount of psychomotor stimulant drugs which monkeys

will self-administer. In a second experiment we have further investigated the

mechanism underlying this regulation by determining the changes in the frequency

of self-administration of cocaine and SPA produced by the administration of other

pharmacological agents.

WINICELHAKE, J.L., VOSS, E.W., JR. and LOPATIN, D.E. Comparative inhibitory

action of d- and l-tryptophan on the effect of d-lysergic acid diethylamide in

vitro. Molecular Pharmacology 10(1): 68 (1974)

The incorporation in vitro of acid diethylamide into

secreted protein from hyperimmune rabbit lymphoid cells was inhibited by

both D- and L-tryptophan. The inhibition was specific for tryptophan isomers

and analogues. On the basis of these findings a pathway was formulated to

describe the preliminary steps culminating in the covalent incorporation of

lysergic acid diethylamide into synthesized protein.

WINTER, B.A. and GOLDSTEIN, A. An aryl azido analogue of levorphanol for the

photochemical labeling of the opiate receptor(s). Federation Proceedings 31:

528 (1972)

A radioactive analogue of levorphanol, -beta-(p-azidophenyl) ethylnorlevorphanal (I) has been synthesized as a photochemical label for the opiate

receptor site(s). Prior to photolysis, it has potent reversible opiate-like

pharmacological activity in whole mice (analgesia. Straub tail, running activity)

and in isolated intact guinea pig ileum (depresses twitch response to electrical

stimulation). Upon photolysis of I (7.7 x 10-6M) in the presence of BSA as a

test protein for non-specific binding, radioactivity is incorporated into 1 out of

26 protein molecules. Incorporation of radioactivity upon photolysis of

I (7.7 x 10-6M) in the presence of 93,000 x g pellet of whole mouse brain

homogenate also occurs. Incorporation is observed in material insoluble in

H2O and CHCl3:MeOH. This incorporation is significantly but incompletely

blocked by both levorphanol and dextrorphan. The implication is that nonspecific binding can occur with this technique and suitable modifications are

required. To determine if cellular localization occurs, radioautography of

the myenteric plexus of the guinea pig ileum is being employed.

WINTER, B.A. and GOLDSTEIN, A. A photochemical affinity-labelling reagent for the

opiate receptor(s). Molecular Pharmacology 6: 601-611 (1972).

For abstract, see Section II. Drug Chemistry and Metabolism.

372
WINTER, J.C. Behavioral effects of n, n-diethyltryptamine: Absence of antagonism

by xylamidine tosylate. The Journal of Pharmacology and Experimental

Therapeutics 169(1): 7 (1969)

This investigation sought todifferentiate the central and peripheral

sites of action of N, N-diethyltryptamine (DET) as an aid to the interpretation

of its effects on operant behavior. Rats were trained to press a bar for a food

reinforcer which was delivered according to a fixed ratio schedule or a differential reinforcement of low rate schedule of reinforcement. DET, 5-hydroxytryptamine (5-HT) and 5-hydroxytryptophan (5-HTP) produced a depression or

responding on the fixed ratio schedule. Cinanserin HCl antagonized the effects

of all three agents. In contrast, xylamidine tosylate clearly antagonized 5-HT,

was less active against 5-HTP and was without effect on DET. The response rate

on the differential reinforcement of low rate schedule was also depressed by

DET, 5-HT and 5-HTP. However, the DET-induced pause in bar pressing was

followed by a period in which the response rate was greater than control values,

The latter effect was not produced by 5-HT and 5-HTP. Rate enhancement by DET

was antagonized by cinanserin HCl but was not altered by xylamidine tosylate.

These results indicate that DET can be differentiated from 5-HT and 5-HTP on a

behavioral basis by the use of an appropriate schedule of reinforcement and on

a pharmacologic basis by the use of selective antagonists. These results support

the hypothesis that DET acts on 5-HT receptors in the central nervous system to

produce its behavioral effects in the rat.

WINTER, J.C. Comparison of chlordiazepoxide, methysergide and cinaserin as modifiers

of punished behavior and as antagonists of n,n-dimethyltryptamine. Archives

internationales de Pharmacodynamie et de Therapie 197(1): 147 (May, 1972)

Comparison of chlordiazepoxide. methysergide and cinanserin as

modifiers of punished behavior and as antagonists of N, N-dimethyltryptamine.

This investigation sought to test the hypothesis that tryptaminergic mechanisms

are involved in the suppression of responding by punishment. Rats were trained

to press a bar for food on a multiple’schedule in which one component was VI 30

(food) and the other was FR 10 (concurrent food and electric shock). Chlordiazepoxide and methysergide produced dose-related increases in both the punished

and the non-punished components. Cinanserin and alpha-methyltryptamine had

no rate-enhancing effects and the actions of alpha-methyltryptamine were not

modified by pretreatment with the peripheral antagonist of 5-hydroxytryptamine,

xylamidine tosylate. These data suggest that the ability of methysergide to

increase rates of punished responding is not shared by cinanserin, a non-ergot

tryptamine antagonist, and that the rate-depressant effects of alpha-methyltryptamine

are not mediated by 5-hydroxytryptamine receptors in the periphery. The ability

of chlordiazepoxide, methysergide, and cinaserin to antagonize the rate-depressant

effects of N, N-dimethyltryptamine (DMT) was not correlated with the degree of

rate enhancement produced by the administration of the drugs in the absence of DMT.

These results suggest that antagonism of tryptamine is neither a necessary condition

nor a sufficient condition for the enhancement of response rates suppressed by

punishment.

373
WINTER, J. A comparison of the stimulus properties of mescaline and 2, 3, 4-trimethoxyphenylethylamine. The Journal of Pharmacology and Experimental Therapeutics 185(1):101 (1973)

This investigation sought to test the hypothesis that those pharmacologic

properties which distinguish hallucinogens and non-hallucinogens in man are reflected in distinctive stimuli in the rat. Subjects were first trained on a variable

interval schedule of positive reinforcement. Two drug treatments were then

assigned to each animal. One treatment was the S

D

, the stimulus in whose

presence responses were reinforced on the variable interval schedule and the

other treatment was the S-delta, the stimulus in whose presence no responses

were reinforced. After 8 to 12 sessions in which the drug treatments were

alternated on successive days, a punishment contingency was added, i.e., in

the presence of S-delta, responses were punishment by the delivery of electric

shock on a variable interval schedule. Approximately every fourth session was

designated a test session and responses were neither reinforced nor punished

during the first five, minutes of these sessions. In this way the efficacy of the

drug treatments as discriminative stimuli was determined. It was first established, in two separate groups of rats, that mescaline, when paired with saline

and 2,3,4-trimethoxyphenylethylamine (2,3,4-TMPEA). when paired with saline,

can be discriminative stimuli. In a third group, equivalent doses of mescaline

and 2, 3, 4-TMPEA were compared directly. If we assume that 2, 3, 4-TMPEA

is without hallucinogenic activity, the hypothesis predicts that mescaline and

2, 3, 4-TMPEA will be discriminable in the rat. No evidence of discriminated

responding was obtained. The present data fail to support the hypothesis that

these different pharmacologic properties of hallucinogens and non-hallucinogens

in man are reflected in distinctive stimuli in the rat.

WINTER, J.C. Hallucinogens as discriminative stimuli. Federation Proceedings

33(7):1825 (July, 1974)

HalIucinogens have been known to man for thousands of years and

scientific methods have been applied to the study of their effects since the

latter part of the last century. However, attempts to establish the pharmacologic mechanisms underlying the actions of these drugs have been hampered,

in man, by ethical constraints on the type of experiments undertaken and, in

animals, by the absence of an adequate model of hallucination. The work

described here represents a preliminary attempt to test the hypothesis that

those pharmacologic properties which serve to distinguish hallucinogens and

nonhallucinogens in man are reflected in distinctive stimuli in infrahuman

species. Operant behavior which is reinforced only in the presence of a

specified stimulus soon occurs with greater frequency in the presence of

the stimulus than in its absence and the behavior is then said to be under the

control of the stimulus. In addition to well-known sensory stimuli, it has been

known for some time that a drug may serve as a discriminative stimulus. In

this report, a general method is presented for the comparison of the stimulus

properties of pharmacologic agents and the method is illustrated by a study of

mescaline, its structural isomer, 2, 3, 4-trimethoxyphenylethylamine,

and 3, 4-dimethoxyphsnylethylamine (DMPEA).

374
WINTER, J.C. Tolerance to a behavioral effect of lysergic acid diethylamide and crosstolerance to mescaline in the rat: Absence of a metabolic component. The

Journal of Pharmacology and Experimental Therapeutics 178(3): 625-630 (1971)

For abstract, see Section II. Drug Chemistry and Metabolism.

WINTER, J.C. Xylamidine tosylate: Differential antagonism of the hypothermic effects

of n, n-dimethyltryptamine, bufotenine, and 5-methoxytryptamine. Archives

internationales de Pharmacodynamie et de Therapie 198(1): 61 (1972)

The effect of pretreatment with a fixed dose of xylamidine tosylate on

the hypothermia produced in rats by N, N-dimethyltryptamine (DMT), bufotenine,

and 5-methoxytryptamine was determined. Such pretreatment had little effect

on DMT-induced hypothermia but the effects of bufotenine and 5-methoxytryptamine were antagonized. Despite the hallucinogenic properties sometimes

attributed to bufotenine, it may reasonably be assumed that, of the three

compounds, only DMT enters the central nervous system of the rat in significant amounts. Therefore, the present results are in agreement with the

hypothesis that xylamidine acts selectively to block the peripheral component

of the actions of tryptaminergic agents.

WOLPERT, A., WHITE, L., DANA, L., SUGERMAN, A.A., ARENGO, A.D.,

SIMPSON, G. M., BISHOP, M.P. and GALLANT, D. M. Clinical pharmacological trial of loxapine succinate. Journal of Clinical Pharmacology

10(3): 175-181 (May-June, 1970)

In an open study loxapine succinate was given to 44 subjects in four

different Early Clinical Evaluation Units. The results of the studies were

remarkably consistent and all investigators agreed on the activity of this

preparation. This was confirmed by the nurses in all four units and received

support from the BPRS in three of the units.

A dose range of 40 to 200 mg was employed, but a suggested dose

range of 40 to 100 mg was put forward. Side effects consisted of drowsiness,

hypotension (one subject), and extrapyramidal disorders. These latter were

similar to those seen with other compounds and did not necessitate withdrawal

of any subject from the trial. It was concluded by all investigators that 1oxapine

possessed neuroleptic properties.

toxicity.

None of the four trials revealed significant

375
WURSTER, N., ELSBACH, P., RAND, J. and SIMON, E.J. Effects of levorphanol

on phospholipid metabolism and composition in Escherichia coli.

Biochimica et Biophysica Acta 248: 282-292 (1971)

The effects of growth inhibitory concentrations of the morphine analogue

levorphanol on the metabolism and composition of membrane phospholipids were

investigated in Escherichia coli.

Incorporation of radioactive precursors into the total lipid fraction is

reduced.

During incubation with levorphanol there is a gradual rise in the proportion of radioactivity incorporated into cardiolipin, from 5% (untreated) to

55-70% after 60 min. In addition to the more rapid labeling of cardiolipin there

is evidence for reduced breakdown of cardiolipin in the presence of levorphanol.

The incorporation of precursors into phosphatidyl ethanolamine is

markedly reduced. The turnover of phosphatidyl glycerol is accelerated and

phosphatidyl ethanolamine, normally stable, exhibits turnover in the presence

of levorphanol.

After 1 h incubation with levorphanol the relative amounts of individual

phospbolipids, determined as phospholipid phosphorus, are 45% phosphatidyl

ethanolamine, 10% phosphatidyl glycerol and 45% cardiolipin, as compared to 68%

phosphatidyl ethanolamine, 25% phosphatidyl glycerol and 7% cardiolipin in untreated bacteria.

In drug-free medium the phospholipid labeling pattern of cells labeled in

the presence of levorphanol slowly reverts towards normal.

Possible relationships between the observed alterations in phospholipid

metabolism and composition and the effects of levorphanol on transport and on

ribosomal RNA synthesis are discussed.

376
WURSTBR, N., ELSBACH, P., SIMON. E.J., PETTIS, P. and LEBOW, S. The effects

of morphine analogue levorphanol on leukocytes. Journal of Clinical Investigations

50(5): 1091 (May, 1971)

Studies on bacteria have suggested that morphine-like drugs have effects

on the cell membrane. To determine the effect of this class of drugs on a

mammalian cell, we selected the rabbit peritoneal exudate granulocyte. which

undergoes striking membrane changes during phagocytosis. We examined the effect

in vitro of the morphine analogue, levorphanol on phagocytosis and metabolism by

granulocytes incubated with and without polystyrene particles or live Escherichia

coli. Levorphanol (1 or 2 mmoles/liter) decreased: (a) acylation of lysolecithin

or lysophosphatidylethanolamine in the medium (which is stimulated about two-fold

during phagocytosis) both at rest (40%) and during phagocytosis (60%); (b) uptake

of latex particles and Escherichia coli, as judged by electron microscopy; (c)

killing of live Escherichia coli (10-fold); (d) 14CO2 production from glucose-1-

14C during phagocytosis by at least 80%; (e) K+

 content of granulcocytes (35%);

(f) oxidation of linoleate-1-14C by 50%, and its incorporation into triglyceride, by

more than 80%. However, levorphanol stimulated 2 to 3-fold the incorporation of

linoleate-1-14C into several phospholipids. Glucose uptake, lactate production,

and adenosine triphosphate (ATP) content are not affected by the drug. Thus,

levorphanol does not appear to exert its effects through generalized metabolic

suppression.

Removal of levorphanol by twice resuspending the granulocytes completely

reverses all inhibition.

In line with observations on bacteria, it appears that the complex effects

of levorphanol on granulocytes may be due at least in part to an effect of the cell

membrane.

YAGEN, B. and MECHOULAM, R. Stereospecific cyclizations and isomerizations of

cannabichromene and related cannabinoids. Tetrahedron Letters 60: 5353 (1969)

YAGIELA, J.A., McCARTHY, K.D. and GIBB, J.W. The effect of hypothermic doses of

1-delta-9-tetrahydrocannabinol on biogenic amine metabolism in selected parts of

the rat brain. Life Sciences 14: 2367-2378 (1974)

Hypothalamic and brainstem biogenic amine metabolism was investigated

in rats following the administration of hypothermic doses of l-delta-9-tetrahydrocannabinol (THC). The dose-dependent fall in body temperature induced by THC

was both rapid in onset and prolonged in duration. The disruption in thermoregulation, however, was unaccompanied by any observed alteration in the concentration or turnover rate of 5-hydroxytryptamine (5-HT) in the brain tissues studied.

Norepincphrine (NE) was also unchanged, with the exception of a reduction in the

amounts of brainstem NE 30 min after the administration of 50 mg/kg THC. These

observations indicate that the hypothermic effect of THC is not mediated by changes

in brain 5-HT of NE metabolism.

377
YAMAMURA, H.I. and HORITA, A. Effect of propranolol on the blockade of alpha

adrenergic receptors. The Journal of Pharmacology and Experimental Therapeutics 164(1): 82 (1968)

Previous studies from this laboratory have demonstrated the antagonism

of various alpha blockers by the beta blocking agent, dichloroisoproterenol. eIn the

present studies, the alpha responses of agents possessing both alpha and beta

adrenergic properties (epinephrine and norepinephrine) were antagonized by

phenoxybenzamine and exhibited partial recovery after subsequent administration

of propranolol. However, the alpha responses of agents possessing only an alpha

stimulatory property (methoxamine and oxymetazoline) were not restored upon

subsequent administration of propranolol. It was also shown that, even after the

antagonism of phenoxybenzamine by propranolol, the phenoxybenzamine -induced

blockade reappeared after the effects of propranolol had dissipated. These data

therefore demonstrate that only the agonist possessing both alpha and beta activities can undergo the reversal and recovery. It is postulated that this antagonism

does not involve a displacement mechanism of phenoxybenzamine by propranolol

but is associated with the unmasking of residual alpha receptor sites which were

not blocked by the original dose of phenoxybenzamine.

YAMAMURA, H.I. and HORITA, A.A further study of the effect of propranolol on the

blockade of alpha adrenergic receptors. European Journal of Pharmacology

7: 258-263 (1969)

The results reported herein have shown that the pressor responses of

adrenergic agonists possessing only an alpha stimulatory property (oxymetazoline)

were not restored to significant values after phenoxybenzamine and propranolol blockade. However, when the alpha agonistic property of oxymetazoline was

combined with the beta stimulatory property of isoproterenol, significant recovery

of the pressor response was noted after alpha and beta blockade. The results indicated that the pressor activity of the oxymetazoline plus isoproterenol mixture

seemed to mimic the actions of a known alpha and beta agonist: epinephrine. The

data also showed that time affected the antagonism of phenoxybenzamine by

propranolol and of significance was the consistent finding that the phenoxybenzamineinduced alpha blockade reappeared after the effects of propranolol had worn off.

These data provide further proof that only the agonists possessing both alpha and

beta stimulatory activities can undergo the reversal after alpha receptor blockade.

It is therefore postulated that the antagonism between alpha and beta blocking agents

is associated with the activation of residual alpha receptors not blocked by

phenoxybenzamine rather than the hypothesis of competitive displacement of

phenoxybenzamine by propranolol.

YAMAMURA, H.I. and SNYDER, S.H. High affinity transport of choline into synaptosomes

of rat brain. Journal of Neurochemistry 21: 1355-1374 (1973)

The accumulation of (

3H)choline into synaptosome-enriched homogenates of rat corpus striatum, cerebral cortex and cerebellum was studied

at (

3H)choline concentrations varying from 0. 5 to 100 mu-M. The accumulation

of (

3H)choline in these brain regions was saturable. Kinetic analysis of the

accumulation of the radiolabel was performed by double-reciprocal plots and by

least squares iterative fitting of a substrate-velocity curve to the data.

With both of these techniques, the data were best satisfied by two transport

components, a high affinity uptake system with Km values of 1.4 mu-M

(corpus striatum), and 3.1 mu-M (cerebral cortex) and a low affinity uptake

system with respective Km

values of 93 and 33 mu-M for these two brain

regions. In the cerebellum choline was accumulated only by the low affinity

378
Yamamura, H.I. and Snyder, S.H. continued

system. When striatal homogenates were fractionated further into synaptosomes

and mitochondria and incubated with varying concentrations of (

3H)choline, the

high affinity component of choline uptake was localized to the synaptosomal

fraction. The high affinity uplake system required sodium, was sensitive to various

metabolic inhibitors and was associated with considerable formation of (

3H)acetylcholine.

The low affinity uptake system was much less dependent on sodium, and was not

associated with a marked degree of (

3H)acetylcholine formation. Hemicholinium-3

and acetylcholine were potent inhibitors of the high affinity uptake system. A

variety of evidence suggests that the high affinity transport represents a

selective accumulation of choline by cholinergic neurons, while the low affinity

uptake system has some less specific function.

YANAGITA, T. Development of tolerance and physical dependence to barbiturates in rhesus

monkeys. Committee on Problems of Drug Dependence,

Academy of Sciences, National Research Council. 1968. P. 5618.

Washington, D.C.: National

YARBROUGH, G.G., BUXRAUM, D.M. and SANDERS-BUSH, E. Increased serotonin

turnover in acutely morphine treated mice. Biochemical Pharmacology 21(Part3):

2667-2670 (1972)

YARYURA-TOBIAS, J.A., DIAMOND, B. and MERLIS, S. The action of L-dopa on

schizophrenic patients (a preliminary report) Current Therapeutic Research

12(8): 528-531 (August, 1970)

YARYURA-TOBIAS, J.A., WHITE, L., WOLPERT, A., DANA, L. and MERLIS, S.

Clinical study of the possible antidepressant action of NC-0687. Current

Therapeutic Research 11(9): 574-576 (September, 1969)

NC-0687 is a new chemical structure which is defined as 4-phenyl-4(4-Nmethyl-delta3

 piperidine)-3 oxatricyclo (4.2.1.02,5) Nonane. It main action as

observed in several animal species is that of a strong antidepressant agent. ‘By

comparison, it appears to have activity one and a half times that of imipramine.

However, twice as much NC-0687 is required to prevent the depression caused by

tetrabenazine. This drug has a marked anticholinergic effect and a mild anorexic

action. It also causes a potentiation of the pressor response to injected norepinephrine. In the dog, hepatoxicity with enlargement of the liver has been reported.

A study of human dose range and toxicity indicated several marked side effects at

the 30 mg daily level. In order of frequency, the side effects were: myalgia,

blurred vision, dry mouth, dizziness, nausea, drowsiness, headache, euphoria,

urinary difficulty, breathing difficulty and testicular soreness. At dosage below

30 mg daily, apparently no untoward side effects were encountered. An open

study to determine possible antidepressant action of NC-0687 was undertaken.

YARYURA-TOBIAS, J.A., WOLPERT, A., DANA, L. and MERLIS, S. Action of L-dopa

in drug induced extrapyramidalism. Diseases of the Nervous System 31: 60 (1970)

YARYURA-TOBIAS, J.A., WOLPERT, A., WHITE, L., AGOLA, P. and MERLIS, S.

A clinical evaluation of clopenthixol. Current Therapeutic Research 12(5):

271-279 (May, 1970)

379
YEH, S.Y. and MITCHELL, C.L. Potentiation and reduction on the analgesia of morphine

in the rat by pargyline. The Journal of Pharmacology and Experimental Therapeutics

179: 642-651 (1971)

gated.

The effect of pargyline on the analgesia of morphine in rats has been investiThe analgesia in the animals receiving morphine one or four hours after an

acute injection of pargyline was increased significantly one and two hours after morphine as compared to those receiving saline followed by morphine. In contrast, 24

hours after an acute injection of pargyline, there was a tendency for a decrease in the

analgesic effect of morphine. The concentration of free morphine in the brain tissue

of rats treated acutely with pargyline four hours prior to the injection of morphine was

significantly higher than that of the saline control animals at one and two hours after

morphine. In contrast to the results obtained after acute administration of pargyline,

chronic administration significantly decreased the analgesic effect of morphine onehalf hour after its injection. Experiments in vitro demonstrated that pagyline in a

concentration as low as 1.0 X 10-4M inhibits morphine glucuonide formation by about

50% in liver microsomes from normal rats. The liver microsomal glucuronyl transferase activity of rats treated with pargyline daily for seven or eight days was increased about 40% of that of the saline control rats. Induction of glucuronyl transferase activity may explain the fact that adverse reactions seldom occur with morphine in patients treated chronically with monoamine oxidase inhibitors.

YOKEL, R.A. and PICKENS, R. Intravenous self-administration of dextro and levo isomer

of amphetamine and methamphetamine by rats. The Pharmacologist 13(2): 281

(1971)

The dextro isomers of amphetamine and methamphenamine have been shown

to be intravenously self-administered by rats. In the present experiments, the levo

isomers of amphetamine and methamphetamine were found to maintain self-administration originally established using the dextro-isomers of both compounds. Drug

naive animals were also found to initiate responding for the levo-isomers of both

compounds. With all 4 isomers, uniform intervals separated each drug infusion,

with the length of the interval inversely related to drug dose, suggesting autotitration of drug effect. Stereotypic head and body movements were seen at all

infusion doses. Intake of levo-amphetamine (4.3 mg/kg/hr) was about 3 times that

of dextro-amphetamine (1.3 mg/kg/hr) using infusion doses of .25-1 mg/kg. Intake

of levo-methamphetamine (10.8 mg/kg/hr) was about 5 times that of dextromethamphetamine (2.2 mg/kg/hr) using infusion doses of 1-2. 5 mg/kg. Slightly

more drug per hour was taken at the higher infusion doses. The dextro and levo intake comparisons agree in magnitude with other reported measures of the central

activity of amphetamine, and methamphetamine. indicating that the autotitration

phenomena with these drugs is mediated centrally rather than peripherally.

ZAKS, A.M., BRUNER, A., FINK, M. and FREEDMAN, A. M. Intravenous diacetylmorphine (heroin) in studies of opiate dependence. Diseases of the Nervous

System 30(Supplement): 89-92 (1969)

380
ZAKS, A., FINK, M. and FREEDMAN, A.M. Duration of methadone induced crosstolerance to heroin. British Journal of the Addictions 66: 205-208 (1971)

ZAKS, A., FINK, M. and FREEDMAN, A.M. Levo-methadyl in maintenance treatment of

opiate dependence. Journal of the American Medical Association 220(6): 811

(May, 1972)

In a comparison of methadone hydrochloride and levomethadyl acetate

(l-alpha-acetylmethadol), 20 male, opiate-dependent subjects were assigned at

random to either regimen. Methadone-treated subjects received methadone

hydrochloride, 100 mg daily. Levomethadyl patients received doses on Monday,

Wednesday, and Friday only. Four received low doses (30 to 50 mg), and six

received high doses (80 mg). Both regimens were well tolerated. At six months,

eight of ten methadone-treated patients and eight of nine levomethadyl-treated

patients were undergoing treatment. In patient acceptance, withdrawal symptoms,

response to heroin challenges, and number of positive results for urine tests

measured for morphine, the two groups were equivalent. Levomethadyl acetate,

80 mg administered three times per week, is equivalent to daily administration of

100 mg of methadone hydrochloride. Large-scale clinical trials of levomethadyl

acetate are suggested.

ZAKS, A., JONES, T., FINK, M. and FREEDMAN, A.M. Naloxone treatment of opiate

dependence. Journal of the American Medical Association 215(13): 2108 (March, 1971)

The duration of action of naloxone hydrochloride, a narcotic antagonist,

was extended by increasing doses in nine male volunteers. Blockade against intravenously administered heroin challenges was measured. A daily dose of 2.4

gm of naloxone hydrochloride elicited blockade to 25 mg of heroin and 3.0 gm

extended blockade to 59 mg of heroin both for 24 hours. No toxic symptoms occurred in nine weeks of naloxone administration. In order to use antagonists in the

prophylaxis of opiate dependence, a long-acting, parenterally administered Formulation must be developed.

ZIMMERMANN, E., BRANCH, B., TAYLOR, A., YOUNG, J. and PANG, C. Dexamethasone

inhibition of morphine-induced release of ACTH in male rats. Proceedings of the

58th Annual Meeting of the Federation of American Societies for Experimental

Biology, Atlantic City, New Jersey, April, 1974.

Morphine (M) stimulation of pituitary-adrenal function in the rat is blocked

by prior administration of dexamethasone (Dex) (PSEDM 143: 1224, 1973). To determine the dose requirements for this blockade adult male Sprague-Dawley rats were

given saline (S) or Dex subcutaneously followed 2 h later by M (30 mg/kg, i.p.). One

h after M injection, plasma levels of corticosterone (B) were elevated (p less than

0. 03) in S-pretreated controls and depressed in rats pretreated with 20 (p less than 0.05)

or 100 (p less than 0.01). but not with 5 (p greater than 0.05). mu-g/kg Dex.

Temporal studies revealed elevated (p less than 0.01) B levels 30 and 60 min, but

not 12 0 min, after injection of M while B levels in Dex (100 mu-g/kg) pretreated rats

were depressed (p less than 0.01) at each of these times. When given either 0, 1,

2, 6 h, but not 12 or 21 h, before M, Dex (103 mu-g/kg) completely blocked the B

response to M. When given 30 min after M. 100 mu-g/kg Dex caused partial (p less

than 0.05) and 40 mu-g/kg Dex caused complete (p less than 0.01) suppression of

the B response to M. Unlike 400 mu-g/kg Dex, equimolar doses of cortisone,

cortisol and desoxycorticosterone failed to suppress the B response to M. These

findings indicate that Dex causes temporary dose-dependent inhibition of M-induced

release of ACTH in the rat, presumably involving neural effects of these two

centrally-active agents.

381
ZIMMERMANN, E., BRANCH, B., TAYLOR, A.N., YOUNG, J. and PANG, C.N.

Long-lasting effects of prepuberal administration of morphine in adult rats.

Narcotics and the Hypothalamus. Edited by E. Zimmermann and R. George.

New York: Raven Press, 1974.

To study effects of prepuberal administration of morphine on body growth

and pituitary-adrenal function, newborn Sprague-Dawley male and female rats were

given subcutaneous saline or morphine (to 8 mg/kg twice daily) from 1 to 21 days of

age. Compared with controls, body weights of morphine-treated animals were reduced (p less than 0.01) by day 7 and remained significantly depressed for 105 days

in females, and for at least 120 days in males. Puberty (vaginal or preputial

opening) occurred simultaneously in morphine- and saline-treated rats of each sex.

On day 56, all groups showed normal diurnal patterns of non-stress levels of

plasma corticosterone. Compared with non-stressed controls on day 72, morphinetreated male and female rats showed intact corticosterone responses to ether stress.

However, female but not male rats showed reduced (p less than 0.05) corticosterone

responses to morphine (20 or 40 mg/kg). Similarly, on day 80, morphine-treated .

females showed reduced (p less than 0.05) analgesic response to morphine (10 mg/kg),

tested using the hot -plate technique, while the males showed an equivocal response.

Finally, on day 92, morphine-treated females but not female controls or males

showed increased (p less than 0.05) plasma corticosterone levels 30 min after injection of naloxone (5 mg/kg). The persistence of growth deficit, tolerance to

morphine, and sensitivity to naloxone suggests that exposure of the immature female

rat to morphine results in prolonged, possibly permanent, morphine-specific alteration of neuroendocrine and nociceptive brain mechanisms.

ZIMMERMANN, E. and CRITCHLOW, V. Inhibition of morphine-induced pituitary-adrenal

activation by dexamethasone in the female rat. Proceedings of the Society for

Experimental Biology and Medicine 140(4): 1224 (September, 1973)

It is well established that morphine sulfate (MS) markedly stimulates

pituitary-adrenal function in the unanesthetized rat. Recently, Kokka et. al. reported complete inhibition of this response to MS by prior administration of a

large dose (600 mu-g/kg) of the synthetic corticosteroid, dexamethasone (Dex).

The present study was performed to examine the sensitivity of MS-induced pituitaryadrenal activation to the inhibitory action of relatively low doses of Dex in the

female rat.

ZIMMERMANN, E., GISPEN, W.H., MARKS, B.H. and DeWIED, D., editors. Drug

Effects on Neuroendocrine Regulations. Progress in Brain Research, Vol. 39.

New York: Elsevier Press. 1973.

382
ZIMMERMANN, E., YOUNG, J., BRANCH, B., TAYLOR, A.N. and PANG, C.N.

Long-lasting effects of prepuberal administration of morphine in female rats.

Narcotics and the Hypothalamus. Edited by E. Zimmermann and R. George.

Kroc Foundation Symposium No. 2, 1974.

To study effects of prepuberal administration of morphine on body growth

and pituitary-adrenal function newborn Sprague-Dawley female rats were given

subcutaneous saline (S) or morphine (M) (to 8 mg/kg, b.i.d.) from 1-21 days of age.

Compared with controls body weights of M-treated animals were reduced (p less

than 0.01) by Day 7 and remained significantly depressed for approximately 120

days. Puberty (vaginal opening) occurred simultaneously in M- and S-treated rats

on Days 36 + 2. On Day 56, both groups showed comparable diurnal patterns of

non-stress levels of plasma corticosterone (B). Compared with controls on Day

72, M-treated rats showed intact B responses to ether stress but reduced (p less

than 0.05) B responses to M (20 or 40 mg/kg). Similarly, on Day 80, M-treated

rats showed reduced (p less than 0.05) analgetic response to M (10 mg/kg) using

the hot-plate test. Finally, on Day 92, M-treated rats, but not controls, showed

increased (p less than 0.05) plasma B levels 30 min after injection of naloxone

(5 mg/kg). Persistence of growth deficit, tolerance to M, and sensitivity to naloxone

suggests that exposure of the immature female rat to morphine results in prolonged,

M-specific alteration of neuroendocrine and noniceptive brain mechanisms.

ZIMMERMANN, E., YOUNG, J., BRANCH, B., TAYLOR, A.N., PANG, C.N. and

SAWYER, C.H. Long lasting effects of prepuberal administration of morphine

in female rats. Journal of Steroid Bipchemistry 5: 387 (1974)

To study effects of prepuberal administration of morphine on body growth

and’ pituitary-adrenal function, newborn Sprague-Dawley female rats were given

subcutaneous saline (S) or morphine (M) (to 8 mg/kg. b.i.d.) from 1-21 days of age.

Compared with controls, body weights of M-treated animals were reduced (p less

than 0.01) by day 7 and remained significantly depressed for approximately 123 days.

Puberty (vaginal opening) occurred simultaneously in M- and S-treated rats on days

35 + 2. On day 56, both groups showed comparable diurnal patterns of non-stress

levels of plasma corticosterone (B). Compared with control on day 72, M-treated

rats showed intact B responses to ether stress, but reduced (p less than 0.05) B

responses to M (23 or 40 mg/kg). Similarly, on day 80, M-treated rats showed

reduced (p less than 0.05) analgetic response to M (10 mg/kg) using the hot-plate

test. Finally, on day 92, M-treated rats, but not controls, showed increased

(p less than 0.05) plasma B levels 30 min after injection of naloxone (5 mg/kg).

Persistence of growth deficit, tolerance to M, and sensitivity to naloxone suggest

that exposure of the, immature female rat to morphine results in prolonged Mspecific alteration of neuroendocrine and nociceptive brain mechanisms.

383
ZUCKER-FRANKLIN, D., ELSBACH, P. and SIMON, E.J. The effect of the morphine

analog levorphanol on phagocytosing leukocytes. Laboratory Investigation 25(5):

415 (1971)

It has been reported recently that the morphine-like drug levorphanol

inhibits several biochemical reactions of polymorphonuclear leukocytes both at

rest and during phagocytosis. The drug also reduces the bactericidal capacity

of the cells. Electron microscope studies were carried out to determine whether

the metabolic effects produced by this compound were reflected by alterations in

the morphologic aspects of the phagocytic process. Accordingly, human and

rabbit granulocytes were incubated with latex particles or Escherichia coli in the

presence and absence of levorphanol. Levorphanol inhibited the uptake of latex

particles by leukocytes by 80 to 90 percent. Phagocytosis of E. coli was less

consistently inhibited, the reduction ranging from 20 to 80 per cent. When E.

coli were the particles ingested by the cells, it was also evident that degranulation

had been reduced by the drug. The effect of levorphanol was readily reversed by

removal of the compound from the medium. Although the exact site(s) of action

of levorphanol remain(s) to be established, the compound may be a useful agent in

the analysis of various aspects of leukocyte function.

384
Indexes

AUTHOR/EDITOR INDEX

Aaronson, B.S. 627

Abbott, S.R. 5

Abel, E.L. 79, 185, 385, 523

Aber, R.C. 110, 113

Abood, L.G. 45, 51, 67, 293, 358,

460, 691

Abrams, C.A.L. 523

Abrams, L.A. 5, 661, 665

Abrams, L.S. 79

Abrams, R. 30, 115, 627, 691, 701

Abu-Shumays, A. 5

Aceto, M.D. 320

Adams, M.D. 185

Adams, P.M. 385, 523

Adams, T.C., Jr. 79, 80

Adams, W.J. 186, 385, 420

Adler, F.L. 5, 6, 14, 18, 50, 80, 91,

102, 298

Adler, M.W. 6, 49, 80, 186, 253,

297, 386, 524, 546

Afifi, A-H. 84, 198

Aghajanian, G.K. 7, 80, 160, 186,

187, 197, 206, 247, 261, 348, 720

Agola, P. 183, 379

Agurell, S. 146, 153, 303, 314, 315

Akai, K. 159, 330

Albers, J.W. 411

Alexander, P.B. 675

Algeri, S. 93, 212

Alker, P.C. 551

Alpert, M. 187

Altshuler, H.L. 7, 188, 189, 258

Amarose, A.P. 189, 524

Amini, F. 595

Amsel, Z. 665

An, R. 438

Andernen, D.K. 299, 547

Anderson, L.J. 130

Anderson, R.E. 549

Anderson, S.M. 174, 361, 505

Anderson, T. 189, 386

Anderson, T.R. 189, 190, 352, 353

Ando, K. 77, 520

Andresko, M. 624

Angel, C.R. 32, 117

Angrist, B.M. 64, 80, 187

Anthony, D, 589, 654

Aqleh, K. 525

Arengo, A.D. 375

Arnfred, T. 190, 386

Arregui, A. 81

Asnis, S.F. 22, 50

Aston, R. 190, 191, 358, 359, 386,

524, 560

Athenholt, T. 140

Atkinson, R.C. 403

Aurori, K.C. 81, 177, 178

Axelrod, J. 139, 140

Ayhan, I.H. 191, 327, 386, 387

Babb, J.E. 366, 562

Babbini, M. 192, 228, 387, 404, 405,

570, 691

Babst, D.V. 595, 600, 627, 665, 669

Back, K.W. 630, 668

Bacon, V.A. 27, 89

Baden, M. 671

Baden, M.B. 552

Baden, M.E. 627

Baden, M.M. 7, 36, 159, 320, 327,

330, 529, 553, 555, 622, 628, 666

Baeder, D.H. 121, 263, 581

Bagley, S.K. 443, 444, 646, 708

Bailey, D.N. 8, 40, 81, 82, 192, 524

Baker, W.W. 192-196, 295, 387, 565,

595, 596, 692

Bakker, C.B. 632, 633

Baldwin, B.A. 596

Ball, J.C. 9, 566, 628, 635, 666,

667, 670

Ball, M.J. 628, 667

Ball, S. 10

Ballantine, P., II. 460

Balster, R.L. 22, 387, 416, 436

Balter, M.B. 388, 466, 480, 629,

651, 652, 653, 667, 680

Banerjee, S.P. 167, 196, 692

Barker, N.W. 615, 646, 677

Barratt, E.S. 221, 385, 399, 523

Barry, H., III. 9, 197, 350, 356, 357

388, 455, 457, 469, 470, 499

Barstow, C.A. 236, 237

Barth, R. 27

Bartolini, A. 82, 388

Bartolucci, G. 389

Basmadjian, G.P. 82

Bass, G.A. 617

Bass, U.F., III. 599, 616

Bates, W.M. 619

Baugh, E.L. 235, 414

Beach, D.J. 32, 117

384i
532

Beaubrunn, M.H. 364

Beaver, W.T. 692

Beck, E.C. 389, 458, 498, 501

Becker, F. 197

Beckman, G.C. 695

Beckner, J.S. 104, 145, 302, 467,

Bednarczyk, J.H. 165, 356, 590

Beecher, H.K. 692

Beeler, G.W. 287, 585

Beighlie, D.J. 234, 533

Bell, R.D. 214, 529

Bellville, J.W. 525

Bendotti, L. 186, 386, 524

Benedict, F. 193, 194

Benn, G.J. 599, 600

Bennett, J.L. 197

Bennett, J.P. 81, 168. 693

Benson, H. 693

Bentler, P.M. 9, 21, 629, 641, 667,

674

Ben-Zvi, Z. 9, 83, 107, 146, 147,

153, 197, 303, 304, 305, 315

Beranek, J.T. 84

Berberian, R.M. 667, 668, 685

Berens, J. 692

Bergen, J.J. 601

Bergen, J.R. 83

Berger, B.B. 625

Bergson, A. 254

Berkowitz, D. 50, 141

Berliner, A.K. 619

Berlow, L. 566, 629

Berman, P. 561

Berry, D.E. 250

Bertani, L.M. 75

Bertel, B. 553

Bertozzi, P.E. 719

Best, J.F. 213

Beyer, J.R. 198

Bhargava, H.N. 84, 198, 389, 566

Bianchine, J.R. 198

Bicher, J.L. 84, 198

Bier, D.M. 707

Bigelow, G. 389

Billings, D.K. 694

Bishop, M.P. 375

Blackford, L.S-C. 10, 668

Blackwell, L.A. 471, 550

Blake, D.A. 48, 76, 586, 594

Blechner, J.N. 554

Bloch, R. 149, 151, 306

Block; J.H. 130

Bloom, F.E. 187

Bloom, R. 566, 668, 676, 707

Blum, K. 34, 72, 251, 389, 427, 428,

525, 575, 704

Blum, R.H. 629, 668

Blumberg, A.G. 596, 602

Blumberg, H. 566

Blumberg. J.B. 199, 332, 556

Bodner, S. 87

Bogan, P. 586, 619

Bohdanecky, Z. 390

Boisse, N.R. 199

Bolt, A.G. 27, 85, 110, 113, 199,

525

Bond, D.D. 525, 567, 596, 629

Bond, M.L. 237, 573

Bonnet, K.A. 10, 200, 390

Boquet, P.L. 232

Borberg, S. 390

Borgatta, E.A. 10

Borgen, L.A. 10, 200, 201, 228,

315, 390, 391, 404, 525, 552

Boshans, R.L. 96, 214

Bosin, T.R. 85

Botto, R.W. 423

Boudin, H.M. 391, 596, 597

Bourque, L.B. 630, 668

Bowen, D.V. 15, 92

Bowers, M.B., Jr. 85, 201, 218,

294, 526, 597

Boyd, E.H. 202, 203

Boyd, E.S. 202, 203

Boyink, N.O. 567, 668

Braceland, F.J. 525, 526, 567, 596,

597, 629, 630

Bradley, P. 242, 423

Bradt, C. 551

Brady, J.V. 11, 391, 436, 579

Braestrup, C. 11, 86, 161, 203,

338, 567

Branch, B. 381, 382, 383, 564

Branchey, L. 87

Brase, D.A. 204, 391, 568

Brattin, W.J. 11

Braude, M.C. 59, 87, 204, 526

Braun, M. 239

Braun, P. 147. 304, 305

Braunstein. M.C. 53, 143, 299, 466,

547

Braverman, S. 49, 297, 546

Breese, G.R. 204, 205, 224, 267,

391, 392, 400, 439

Brehm, M.L. 630, 668

Brennan, T. 536

Bres, J. 29, 115, 250, 540

Breskin, S. 279, 446, 615, 647

Bridge, T.P. 205, 526, 630, 635,

670

Brill, L. 529, 597

Brill, N.Q. 392, 438, 526, 527, 543,

568, 630, 631, 638, 645, 669, 672,

677

384ii
Brisfer, C.C. 205, 405, 531

Bristow, R.L. 124, 266

Brochmann-Hanssen, E. 12, 13, 87, 88

Brodetsky, A.M. 234, 533

Bronaugh, R.L. 88

Brookes, L.G. 27, 88, 89, 110, 111,

527, 703

Brophy, F. 665

Brotman, R. 65, 568, 598, 623, 631,

632, 643, 661, 669, 712

Brown, B.S. 531, 599, 600, 606, 616

Brown, B.W. 613

Brown, D.A. 707

Brown, D.J. 90, 170, 205, 358, 420

Brown, H. 14

Brown, J.W. 669

Brown, L.E. 202, 203

Brown, P. 290

Browne, I.W. 536

Browne-Mayers, A.N. 568, 600

Bruner, A. 78, 380, 574, 594, 609

Brunswick, A.F. 632, 669

Brust, J.C.M. 527, 555, 622

Bruun, B. 555, 622

Bucci, L. 600

Buchenauer, D, 528

Buckley, J.P. 209, 210, 211, 279, 364

Buckpitt, A.R. 85

Buelke, J. 58

Bunney, B.S. 7, 187, 206

Burch, N.R. 7, 188, 189, 258

Burks, T.F. 13, 52, 207, 208, 260,

277, 285, 298, 322, 332, 461, 545

Burns, M. 476

Burstein, S. 9, 13, 83, 90, 138, 197,

208

Bush, M.T. 13, 91

Bushing, J.A. 209, 333, 392

Butler, J.R. 158, 486, 621

Buxbaum, D.M. 91, 182, 208, 209,

379, 392

Byrd,, L.D. 392, 393, 694

Callahan, B. 620

Callahan, D. 620

Callegari, B. 248

Campbell, B.A. 393, 421, 422, 460,

461, 465

Campbell, C. 141, 298

Campbell, N.D. 704

Campo, R.A. 394

Canton, C. 69

Carder, B. 394, 428, 556, 695

Carino, M.A. 209, 271

Carley, J.L. 390

Carlin, A.S. 632, 633

384iii

Carlini, E.A. 394, 408

Carlson, K.R. 711

Carney, J. 395

Carr, E. A., Jr. 148, 305

Carskadon, M. 231, 408

Carter, M.E. 91, 209, 392

Cartwright, C. 341

Casella, G. 152

Cashaw, J.L. 14, 101, 227

Casswell, S. 395

Castles, T.R. 124, 266

Cate, J.C. 528

Cathcart, C.F. 53, 465

Catlin, D. H. 6, 14, 32, 80, 91, 117

Cauthen, S.E. 91, 92, 133, 157

Cavanaugh, J.H. 107

Cavero, I. 209, 210, 211, 364

Cavness, C. 239

Cehrs, F.D. 47

Cely, W. 132, 282, 283, 362, 545

Challenor, Y.B. 553, 555, 622

Chambers, C.D. 9, 274, 529, 535,

566, 568, 595, 597, 600, 601, 602,

625, 627, 628, 633, 634, 635, 636,

646, 665, 666, 667, 669, 670, 671,

677, 678, 689, 695

Champlin, F.B. 695

Chao, F-C. 50

Chaoman, L.F. 489

Chapel, J.L. 211, 529, 602, 636,

637, 671, 696

Chappel, J. 614

Charap, A.D. 396, 430, 432, 522

Chatterjie, N. 15, 92

Chau, T.T. 212, 529

Chen, C.H. 12, 87

Chen, H. 92

Cheney, D.L. 92, 93; 212, 213, 396,

569

Chenoweth, M.B. 93

Cherubin, C.E. 529, 671

Chesluk, D. 672

Chester, P. 642, 674

Chiang, H.C. 12, 87

Chipkin, R.E. 213

Chippendale, T. J. 696

Chiu, P. 34, 119

Cho, T. M. 50, 264, 438

Chorosh, J. 279, 446, 615, 647

Choulis, N.H. 15, 213, 602, 696

Christensen, C. 213

Christie, R.L. 392, 526, 631, 669

Christy, D. 396

Chubb, N.C. 443, 444, 646

Cicero, T.J. 15, 94, 95, 96, 214,

346, 396, 497, 529

Cisin, I.H. 396, 480, 637, 651, 653,

680
Clare, G. 234, 412, 509, 640

Clark, L.D. 396, 397, 637

Clarke, C.C. 253, 611

Clarke, D.D. 15, 92

Cline, M. 665

Cline, W. 671

Clineschmidt, B.V. 95, 214, 271

Cloninger, C.R. 96, 214

Clouet, D. H. 41, 96, 97, 98, 99, 100,

127, 128, 152, 162, 181, 215, 216,

217, 277, 280, 309, 343, 371, 544,

550, 583

Cochin, J. 16, 100, 217, 240, 306, 311,

322, 364, 438, 469, 471, 472, 539,

540, 550, 556, 557, 569, 587

Cohen, A.H. 218

Cohen, C.P. 626, 637, 654, 660

Cohen, M. 16, 596, 602, 603, 637,

638

Cohen, S. 218, 530, 573, 689, 696

Cohn, M. 219, 220, 398, 399, 569,

603

Cohn, M.L. 218, 219, 220, 221, 397,

398, 399, 569, 603

Cohn, R.A. 100, 221, 399

Colasanti, B. 44, 221, 222, 223, 290,

291, 292, 313, 399, 400, 453, 476,

570

Cole, J.O. 638

Collier, W.V. 604

Collins, A.C. 101

Collins, L. 64, 497, 655, 656

Collins, P.I. 223, 570

Comaty, J. 236

Cone, E.J. 137

Connaughton, J.F. 537, 604, 609, 610

Connor, J.D. 194, 195

Connor, T. 546

Conwell, D. 665

Cook, J.D. 224, 334, 400, 489

Coon, K. 400

Cooper, B.R. 204, 205, 224, 267,

391, 392, 400, 439

Cooper, I.S. 468

Copans, S.A. 499, 560, 624

Corby, J.C. 696

Corssen, G. 411

Costa, E. 93, 212

Cotman, C.W. 696

Cott, J.M. 224, 400

Cotter, C.F. 695

Cotter, M.L. 25, 109, 574

Coupal, J.J. 563, 625

Cousens, K. 225, 400, 530

Coussens, W.R. 16, 225, 228, 400,

401, 404, 570

Cowen, J.D. 489

Cox, R.H., Jr. 54, 300, 466, 547

Coyle, J.T. 356, 499

Crawford, G.A. 615, 646, 677

Creasser, C. 170, 358

Creese, I. 101

Critchlow, V. 382

Crofford, M. 225, 354, 530, 559

Crombie, L. 101, 225

Crowder, W.F. 16, 225, 228, 231,

400, 401, 404, 407, 570

Crowley, T.J. 401, 402, 672

Crown, P. 234, 244, 365, 412, 423,

509, 562, 640

Croy, D.J. 252, 428

Cruickshank, E. 364

Crumpton, E. 527, 568, 631, 638,

672

Cuatrecasas, P. 692

Cullen, J. 536

Culver, C.M. 402, 530

Cummins, J.T. 226, 238

Curtis, T. 589, 654

Cushman, P., Jr. 226, 530, 531,

542, 563, 604, 605, 625, 638,

672, 673

Cuskey, W.R. 670

Dabrowska, J. 447

Dachowski, L. 697, 707

Dafny, N. 52, 298, 461

Dahlberg, C.C. 38, 279, 402, 446,

544, 570, 606, 615, 639, 647, 679

Dalzell, B.C. 184

Dalzell, H.C. 158, 184

Dana, L. 375, 379

Darley, C.F. 403

Darrah, H.K. 138, 296, 546

Daves, E.D. 155, 319

Davidow, B. 16, 17

Davidson, S.T. 651

Davies, N.H. 549

Davis, C.M., Jr. 22

Davis, D.H. 675, 684

Davis, F.F. 92, 570, 639

Davis, J.M. 101, 107, 226, 239, 331,

447, 531, 536, 573, 584, 606, 607,

639, 647, 697, 709

Davis, K.H., Jr. 70, 176

Davis, M. 200, 226, 227, 403, 499,

560, 624

Davis, M.M. 531, 606

Davis, P.W. 227

Davis, T.R. 404

Davis, V.E. 14, 101, 180, 227, 343

384iv
Davis, W.M. 10, 16, 59, 66, 192, 200,

201, 205, 225, 228, 229, 230, 231,

287, 288, 307, 308, 313, 315, 387,

390, 391, 400, 401, 404, 405, 406,

407, 452, 474, 497, 498, 525, 531,

532, 550, 552, 570, 571, 606, 623,

691

Dayton, H.E. 17, 101

Deardorff, C.M. 549

DeCato, L., Jr. 18, 102

DeFleur, L.B. 18, 639

DeForest, J.W. 639, 640, 673

de la Pena, A. 711

DeLeon, G. 607, 640, 673, 674

Delivoria-Papadopoulis, M. 537

Demaree, R.G. 407, 607

Dembo, R. 625, 689

DeMello, A.C. 408, 486

Dement, W.C. 231, 408, 711

Denber, H.C. 102, 173, 174, 306, 549

Deneau, G.A. 18, 19, 111, 231, 284,

343, 408, 532, 699

Desmond, D.P. 650

Devynck, M.A. 232, 330

Dewey, W.L. 19, 102, 103, 104, 110,

142, 144, 145, 146, 155, 168, 176,

184, 185, 212, 213, 232, 233, 247,

261, 294, 297, 299, 302, 318, 319,

320, 357, 409, 436, 467, 480, 500,

529, 532, 571, 572, 575, 591, 640

de Wied, D. 183, 382

Dews, P.B. 404, 409, 410, 698

Diab, I.M. 20, 62

Diamond, B. 182, 183, 379, 725

Diamond, F. 187

DiGregorio, G.J. 61, 482

Dilts, S. 672

DiMascio, A. 225, 400, 530

Dinerstein, R.J. 62

Dingell, J.V. 104, 293

Dingledine, R. 233, 532

Ditman, K.S. 218, 233, 530, 533,

689; 696, 699

Dixit, B.N. 356, 357

Dolby, T.W. 234

Dole, V.P. 605

Dole, W.P. 65, 234

Domino, E.F. 82, 93, 105, 106, 138,

234, 295, 313, 388, 410, 411, 447,

455, 468, 473, 476, 488, 533, 546,

699

Donato, D. 144, 175

Doorenbos, N.J. 20, 22, 61, 108, 165,

177

Dornbush, R.L. 234, 244, 365, 412,

423, 509, 510, 562, 627, 640, 691

Dorrance, D.L. 234, 235, 533

Dosher, A. 616

Dossett, R.G. 188, 189

Dougherty, J.A. 412

Dowdall, M.J. 700

Downey, D. 461

Downs, D.A. 413, 519, 572, 594

Drawbaugh, R.B. 255, 414, 429, 572

Dressier, K.P. 259

Drew, G.W. 370, 513, 626

Drew, W.G. 106, 235, 414, 472, 473,

721

Drewes, H.R. 109

Dreyer, D.A. 330

Dronkert, A. 268

Droppleman, L.F. 20

Duarte-Escalante, O. 106, 235, 236,

417, 534, 700

Dubin, J.W. 554

Duffield, A.M. 89

Dunkel, L.D. 624

Dunlap, W.P. 697

Dustman, R.E. 458, 498

DuToit, B.M. 641, 674

Dwarshuis, L. 572, 578, 585, 607,

613, 616, 617, 641, 710

Dykstra, L.A. 21, 415, 572

Dziak, J. 210

Eade, N.R. 198

Eagle, C.T., Jr. 611

Ebbighausen, W.O.R. 21

Ebner, E. 654

Echols, S.T. 236, 415

Edelman, I. 164, 352

Edery, H. 83, 107, 146, 147, 197,

303, 304, 305

Ehrenpreis, S. 236

Eichberg, R.H. 9, 21, 629, 641,

667, 674

Eidelberg, E. 107, 236, 237, 534,

573

Eldridge, J. 77, 594

Elef-Therion, B.E. 558

Elinson, J. 678

Ellinwood, E.H., Jr. 22, 106, 205,

235, 236, 237, 238, 415, 416, 417,

418, 468, 526, 534, 535, 573, 630,

635, 641, 670, 674, 700, 707

Ellinwood, E.J., Jr. 50

Elliott, H.W. 79, 198, 238

Ellis, R.D. 133

Elsbach, P. 376, 377, 384

El-Yousef, M.K. 101, 226, 331, 447,

531, 536, 573, 584, 607, 639, 647,

697, 709

384v
Emich, J.P. 537, 604, 610

Englander, D.M. 9, 667

Englert, L.F. 107, 122, 123, 265

Eplov, L. 152, 161, 314, 338

Erill, S. 488

Erspamer, R. 237, 573

Ertel, R. 210, 357, 364

Ervin, V.G. 88

Estevez, V.S. 107, 122, 123, 265

Estrada, U. 419

Euker, C. 618, 661

Evans, H.L. 419, 700, 703

Evans, M.A. 420

Everhart, B.A. 72

Faith, M.E. 238, 420

Fann, W.E. 107, 239, 536, 584, 606

Farney, R.B. 170, 358

Farquhar, J.K. 72

Farrow, J.T. 108, 178

Fauley, J.J. 120

Faust, R. 658, 686

Fedynskyj, N.M. 54, 143, 547

Feinberg, I. 239

Feinberg, M.P. 217, 240

Feingold, E. 543, 559, 614

Feldman, H.W. 22, 641, 674

Feldman, J. 462

Feldman, J.M. 299, 547

Feldstein, S. 38, 343, 365, 509, 510,

562, 606, 627, 639, 642, 674, 679,

720

Fenimore, D.C. 22, 108, 701

Fentiman, A.F., Jr. 22, 109

Ferguson, L. 621

Ferguson, R.K. 420, 449

Fernandez, J. 536

Ferraro, D.P. 421, 433, 436, 461,

505, 694

Fetterman, P.S. 20, 22, 108, 176,

177

Fibiger, H.C. 393, 421, 422

Fidell, L.S. 573, 588, 642, 654

Field, F.H. 15, 92

Findley, J. 436, 579, 712

Fink, M. 22, 23, 24, 25, 30, 35, 36,

37, 78, 108, 109, 115, 234, 240,

241, 242, 243, 244, 245, 275, 296,

343, 365, 366, 370, 380, 381, 412,

422, 423, 458, 509, 510, 513, 521,

536, 538, 562, 573, 574, 575, 589,

592, 594, 600, 608, 609, 610, 611,

617, 621, 623, 624, 626, 627, 640,

642, 643, 649, 658, 674, 691, 701,

702, 703, 708, 720

Finkle, B.S. 702

Finnegan, L.P. 448, 456, 536, 537,

546, 558, 561, 604, 609, 610

Finney, J. 647

Fiorentino, D. 27, 28, 64, 425, 497,

642, 655, 656, 702

Fischer, I. 536

Fischer, R. 537

Fisher, D.D. 689

Fisher, S. 423, 482, 653, 680

Fishman, J. 25, 26, 50, 109, 140,

245, 574, 575, 579, 586, 610, 613,

665

Fitch, F.W. 71, 72, 121, 122, 178,

179, 543, 593

Fitzgerald, M.X. 363, 592, 722

Fitzwater, J.E. 245

Fleiss, J.L. 544

Fog, R. 245, 246, 247, 316, 327,

424, 486, 538

Foltz. R.L. 22, 109, 133

Foote, R.S. 109

Foote, W.E. 247, 702

Forbes, J.E. 110, 247, 575

Ford, D.H. 247, 248

Ford, J.M. 702

Ford, R.D. 168, 299, 357, 500

Foree, D.D. 425

Forgy, E.W. 233, 533

Forney, R.B. 57, 90, 139, 205, 420,

466, 548

Forrest, F.M. 26, 27, 110, 249, 702

Forrest, I.S. 5, 26, 27, 33, 50, 57,

85, 88, 89, 110, 111, 112, 113,

148, 182, 199, 249, 525, 527, 538,

702, 703

Fort, J. 689

Fox, J. 111

Fracchia, J.F. 27, 28, 65, 425, 656,

657, 658, 703, 720

Frank, I.M. 527, 568, 631

Frankenheim, J.M. 299

Fredin, E.S. 649

Freedman, A.M. 78, 243, 244, 245,

296, 380, 381, 412, 423, 458, 509,

521, 538, 573, 574, 575, 589, 594,

596, 597, 608, 609, 610, 611, 617,

621, 625, 626, 638, 640, 643

Freedman, D.X. 20, 80, 187, 486, 525,

526, 567, 629, 630

Freeman, D.X. 61, 327

Freeman, J.J. 249

Freeman, R.R. 22, 108

Freemark, N. 501

Freilich, N. 703

Frey, L.G. 250, 425

384vi
Fried, J. 71, 72, 178, 179

Friedel, R.O. 250

Friedhoff, A.J. 28, 64, 87, 113, 114,

159, 161, 187, 309, 343, 525, 526,

538, 567, 587, 596, 597, 629, 630

638, 703

Friedler, G. 539, 540

Friedman, M.A. 261

Fritchie, G.E. 123, 127, 445

Fromageot, P. 232, 330

Fryer, L. 389

Fu, C-C. 12, 87

Fuchs, M. 600

Fujimoto, J.M. 15, 92, 157

Fukayama, G. 703

Funk, W.A. 233, 533

Fyro, B. 341

Gaensler, E. 363, 592, 722

Gallager, D.W. 114, 425

Gallant, D.M. 375

Galvan, L. 362

Gaoni, Y. 115, 146, 147, 148, 250,

303, 304, 305

Garfield, E. 5, 661, 665

Garman. R.H. 703

Garnett, J.E. 346, 497

Garrett, E.R. 29, 30, 115, 250, 540

Gartner, J. 170, 358

Garwes, D.J. 351

Gaston, E.T, 611

Gavitt, J. 355

Gaztanaga, P. 30, 115

Geber, W.F. 540

Gebhart, G.F. 251, 426, 427

Geis, G. 669

Geisler, A. 558

Geller, A. 430, 487

Geller, I. 251, 252, 427, 428, 437,

575, 704

Gellert, V.F. 428, 575

Gentner, W.A. 49

Gerald, M.C. 704

Gerber, N. 51, 116, 142

Gerlach, J. 252, 428, 611

Gershman, H. 30

Gershon, S. 64, 80

Gessner, P.K. 31, 116, 162, 252, 253,

254, 429, 541, 575, 576, 611

Gessner, T. 116, 253

Geyer, M.A. 134, 255, 293, 344, 429

Ghezzi, D. 186, 386, 524

Ghiselli, W.B. 419, 704, 721

Gianutsos, G. 255, 429

Gibb, J.W. 377

Gibbon, J. 445, 705

Gibbons, J.L. 470

Gildenberg, P.L. 6, 186, 386, 524

Gillespie, H.K. 268, 269, 439, 469,

504, 543, 646

Gintzler, A.R. 256

Gispen, W.H. 183, 382

Gitlow, S.E. 75

Gjika, H.B. 178

Glaser, D. 669

Gleason, T.C. 645, 675

Glendinning, S.T. 531, 606

Glick, S.D. 396, 429, 430, 431, 432,

487, 522, 706

Gluck, J.P. 421, 433

Gold, G.J. 41, 97, 217, 277, 544,

583

Goldberg, S.R. 256, 433, 434, 439,

451, 576, 577

Goldfarb, T.L. 430, 487, 706

Goldiamond, I. 611

Goldstein, A. 31, 92, 93, 116, 117,

118, 154, 159, 181, 212, 213, 233,

256, 257, 258, 260, 298, 316, 328,

341, 342, 360, 372, 396, 435, 496,

532, 541, 569, 577, 578, 590, 612,

613, 706

Goldstein, B.B., Jr. 596

Goldstein, D. 723

Goldstein, D.B. 116, 541

Goldstein, J.W. 31, 258, 541, 578,

613, 644, 645, 650, 661, 674, 675,

679

Gonzalez, L.P. 258

Goo, G.P. 489

118, 137

Goode, E. 435, 645, 675

Goodwin, D.W. 437, 494, 675, 684

Gordon, N.B. 263, 435, 614

Gordon, R.A. 52, 298, 461, 619, 650

Gorodetzky, C.W. 31, 32, 33, 46, 117,

Gorodezky, M. 572, 578, 585, 607,

613, 617, 641

Gott, C.T. 512, 706

Gottschalk, L.A. 675

Gould, I.A. 363

Gould, M.H. 313, 476

Grabarits, F. 238, 420

Grabowy, R. 238, 707

Graham, J. M., Jr. 436, 541

Gray, A.P. 578, 579, 613

Grayson, H.M. 631

Green, D.E. 27, 33, 43, 50, 57, 111,

112, 125, 131, 148, 182

Green, J.P. 128, 130, 131, 259, 280,

282, 707

384vii
Green, M.L. 158, 486, 621

Green, T.K. 259

Greenberg, D. 167

Greenberg, J. 236

Greene, L.A. 692

Greenwald, E.K. 90, 205

Grell, R. 311, 587

Gresik, E. 248

Grieco, M.H. 530, 542, 605

Griffith, J.D. 107, 239

Griffiths, R. 11, 391, 436, 579

Grisham, M.G. 436

Grace, J.W. 118

Grose, S.A. 716

Gross, S.J. 34, 118, 141, 298

Grote, S.S. 94

Groth, J. 352

Grover, T. 259

Grover-Johnson, N. 320

Groves, P.M. 259, 260

Grubb, M.N. 207, 208, 260, 285, 322,

545, 584

Grunfeld, Y. 107, 146, 147, 303, 304,

305

Grupp, S.E. 675

Guerrero, O. 108

Gupta, S. 542 Hasselager, E. 262, 338, 437, 581

Hayman, M. 218, 530, 696

Hays, J.R. 566, 567, 581, 593, 622,

Haavik, C.O. 260

Haber, B. 252, 428

Haberman, P. 678

Hadley, K.W. 69, 70, 177

Haga, M. 521

Hahn, D.L. 118, 260

Hahn, E.F. 25, 26, 109, 245, 575, 579,

625, 626, 639, 640, 668, 672, 675,

676, 690, 707

610, 613

Heath, E.C. 104

Heaton, A.M. 596, 602

Hecht, A. 492

Hedley-White, J. 138, 296, 546

Heilman, R.D. 579, 613

Hein, G. 620

Haigler, H.J. 187, 261 Heinrich, R. 61, 327

Halaris, A. 486 Heiser, J.F. 675

Haldemann, G. 525 Hellman, L. 26, 109, 575, 610

Halpern, B. 27 Helpern, M. 159, 330

Halpern, L. 632, 633 Helrich, M. 76, 594

Hamilton, A.E. 271, 272, 443 Helveg, E. 428, 611

Hamilton, H.E. 34, 72 Hembree, W. 26

Hamlin, T.A. 227 Henderson, A. 263, 614

Hammond, W.E. 22, 50 Henderson, G.L. 311, 476

Hanaway, J.K. 542 Hendley, E.D. 120, 263

Handrick, G.R. 158 Heneen, W. 551

Hanis, J, 237 Herbert, B., III. 135, 294

Hanlon, T.E. 580, 585, 586, 614, Herd, J.A. 448, 451, 452, 693, 698,

617, 619, 719

Hansteen, R.W. 613

Harakal, J.J. 162

Haraszti, J.H. 163

Harbison, R.D. 542, 548

716

Herd, R. 57, 144

Herin, R.A. 213

Herndon, B.L. 121, 263, 329, 581

Herndon, G.B. 421

Hardman, H.F. 260, 273

Hardman, H.R. 295

Harik, S.I. 119, 552

Harindranath, A. 543, 614

Harper, R.G. 543, 559, 614

Harrigan, S.E. 580

Harris, L. 569

Harris, L.S. 45, 102, 103, 104, 110,

142, 144, 145, 146, 155, 165, 168,

176, 184, 185, 212, 213, 232, 233,

247, 261, 294, 297, 299, 302, 318,

319, 320, 357, 385, 409, 415, 436,

458, 467, 480, 500, 529, 532, 546,

571, 572, 575

Harris, P.D. 90, 205

Harris, R.A. 299

Harris, R.T. 53, 142, 426, 437, 461

Harris, T. 692

Harris, W.C. 481

Harrison, S.D., Jr. 34, 119, 143

Hart, L. 700

Hart, R. 672

Hartmann, R.J. 252, 428, 437, 575

Harvey, J.A. 34, 60, 77, 238, 259,

260, 262, 297, 357, 420, 437, 459,

543, 707, 718

384viii
Herndon, R.M. 727

Hersch, R.G. 622, 654

Herskin, B. 620

Hibbeln, P. 191, 386, 524

Hibi, S. 239

Hickenbottom, J.P. 229, 571

Hickman, C. 37, 275, 708

Bigbee, K.L. 581

Hijazi, Y.A. 604

Hill, H.F. 264, 272, 437, 544

Hill, J.H. 121, 122, 543

Hill, R.M. 537

Hill, S.Y. 437, 494

Hiller, J.M. 65, 164, 264, 320, 352

Hindman, R.D. 438, 472

Hinesley, R.K. 636, 670

Hirschhorn, I.D. 264, 438

Hitomi, M. 517

Hitzemann, R.J. 122, 141, 264, 265, 438

Ho, B.T. 53, 107, 122, 123, 142, 265,

438, 461

Ho, I.K. 35, 123, 124, 127, 180, 264,

265, 266, 368, 438, 446, 505, 510,

543, 581, 582, 583, 592, 593, 614

Ho, J.E. 495

Hoats, D.L. 504

Hochman, J.S. 438, 527, 543, 568,

631; 645, 677

Hoddes, E. 231, 408

Hodgson, J.R. 124, 266

Hoffmeister, F. 434, 439, 576

Holbrook, J.M. 315, 405

Holden, J.M. 35, 703, 708

Holland, S. 607, 640, 674

Holland, W.H. 707

Hollander, C. 35, 439, 582, 645

Hollenberg, M.D. 119

Hollister, A.S. 267, 439

Hollister, L.E. 43, 67, 124, 125, 126,

131, 267, 268, 269, 293, 403, 439,

468, 469, 504, 543, 544, 551, 561,

582, 614, 620, 645, 646, 660

Holmes, M.A. 89, 527

Holmes, W.F. 707

Holtzman, S.G. 36, 270, 271, 358,

440, 441, 442, 500, 582, 583, 591,

707

Hopkins, J.T. 161

Horita, A. 95, 129, 143, 209, 214,

227, 264, 271, 272, 323, 378, 437,

443, 483, 544, 589

Horn, A.S. 126

Horns, W.H. 613

Hosko, M.J. 273

Hoss, W. 67, 358, 691

Houry, S. 273

Howes, J.F. 184, 232, 409, 571

Hsu, L.L. 60, 155

Huang, J. C-Y. 36

Huang, J.T. 127

Huang, P. 273, 544

Hudick, J.P. 72, 273

Hudson, R.D. 105, 234

Hug, C.C., Jr.. 127, 274

Hughes, J. 36, 274, 583

Hughes, L.F. 707

Hughes, P.H. 614, 615, 646, 661,

677

Hui, F.W. 354, 559

Hunt, C.A. 29, 30, 115

Hunt, G.M. 370

Hunt, H.F. 36, 274, 443, 583, 705

Hurst, P.M. 443, 444, 445, 646, 708

Hutchings, D.E. 445

Hutchings, M.L. 714

Hydinger, M. 402

Hynes, M.D. 255, 429

Idanpaan - Heikkila, J.E. 127, 445

Iglauer, C. 446, 459

Ikeda, C. 566

Ikeda, T. 468

Inciardi, J.A. 274, 529, 568, 646,

670, 677, 678

Inturrisi, C.E. 15, 17, 41, 42, 92,

101, 129, 130

Isaac, W. 274, 275, 282, 343, 446,

495, 722, 726

Ishida, K. 520

Itil, T.M. 24, 35, 36, 37, 108, 242,

243, 244, 275, 343, 423, 543, 574,

623, 642, 649, 658, 702, 703, 708

Ito, A. 275, 276

Iwamoto, E.T. 127, 446, 510, 583,

593

Iwatsubo, K. 127, 277, 544, 583

Jackson, C.S. 599

Jacobs, G.R; 277

Jacquet, Y.F. 37, 277, 278, 446

Jaffe, J. 38, 279, 446, 544, 606, 614,

615, 639, 646, 647, 661, 677, 679

James, J. 38, 584, 616

Jandhyala, G.S. 209, 210, 211, 279

Janiger, O. 234, 235, 533, 534

Janowsky, D.S. 101, 107, 226, 239,

331, 447, 536, 573, 584, 606, 607,

647, 697, 708, 709

Janowsky, I.S. 531, 639

384ix
Jansen, D.R. 599, 600, 616

Jaquette, D. L. 208, 322

Jarvik, L.F. 544

Jarvik, M.E. 390, 430, 431, 447, 487,

522, 706, 709, 718

Jatlow, P.I. 8, 38, 39, 40, 41, 81, 82,

128, 192, 524, 528, 544, 545

Jenkins, J. 102, 233, 409

Jesperson, S. 280, 447, 584

Jessor, R. 647, 648

Jessor, S.L. 647, 648

Jester, J.R. 140

Jewett, R.E. 36, 236, 270, 271, 358,

415, 441, 442, 500, 583, 591

Joe, G.W. 41, 616, 678

Joffe, P. 551

Johanneson, T. 357, 358, 560

Johanson, C.E. 447

Johnson, A.O. 177, 178

Johnson, B. 66

Johnson, C.L. 128, 131, 280, 707

Johnson, J.C. 41, 97, 128, 217, 280

Johnson, J.R. 250

Johnson, S. 447

Jolles, C. 149

Jonas, W. 129, 281, 323, 339, 447,

490

Jones, L.A. 79, 80, 109, 118

Jones, L.C. 448

Jones, R. 129, 281, 448, 545, 584

Jones, R.T. 281, 545, 648

Jones, T. 30, 115, 381, 594, 626

Jordan, J.H., Jr. 593

Josephson, E. 678

Joyce, P. 473

Juchau, M.R. 129

Judson, B.A. 117, 213, 257, 569, 613

Kaiko, R.F. 41, 42, 129, 130

Kallman, M.W. 282

Kaluzny, A.D. 621

Kananen, G. 42

Kandeel, E.M. 130

Kandel, D. 42, 43, 66, 648, 649, 658,

679, 686

Kang, S. 128, 130, 131, 282, 707,

717

Kanter, S.L. 43, 67, 125, 131, 268,

269, 551

Kaplan, J. 584, 709

Kaplan, S.L. 448, 456

Karler, R. 132, 282, 283, 362, 545

Karmin, M. 355

Karniol, I.G. 394

Karynack, B. 569

Kasl, S.V. 685

Kassebaum, B.A. 36

Kato, T. 544

Kaufman, C. 402

Kaufman, J.J. 43, 283, 284, 584

Kaufman, M. 159, 330

Kaufmann, J.S. 107, 239

Kavaler, F. 665, 671

Kayan, S. 449, 450, 451

Kaymakcalan, S. 284, 408, 532

Keegan, J.F. 622

Keinath, S. 49, 297, 546

Keith, E.S. 22, 108

Kelleher, R.T. 451, 452, 475, 693,

709, 710, 716

Keller, A. 561

Kelly, R.J. 285

Kendig, J. 233

Kennedy, D.K. 285, 545, 584

Kennedy, J.S. 43, 545

Kensler, C.J. 404

Kerman, E. 43, 283, 284, 584

Kerman, F. 617

Kerr, F.W. 285, 286, 287, 452, 585

Keskiner, A. 623, 649, 658, 708

Kety, S. 702

Khachaturian, Z. 350

Khalsa, J.H. 228, 229, 287, 288, 391,

404, 405, 452, 531, 570

Khanna, K.L. 132, 155, 159, 171

Khazan, N. 44, 221, 222, 223, 259,

288, 289, 290, 291, 292, 303, 309,

313, 330, 368, 399, 400, 452, 453,

474, 475, 476, 487, 570, 585, 587,

616

Kidd, M.R. 91, 92, 133, 157

Kimizuka, H. 45, 293

King, F.W. 402, 530

King, W.T. 391

Kinneberg, K.F. 48, 139

Kinzer, G.W. 22, 133

Kiplinger, G.F. 57, 293, 302, 414,

453, 466, 467, 545, 548

Kiplinger, G.R. 420

Kirchman, A. 44

Kiremitci, N. 37, 275, 708

Kirk, T. 158, 486, 621

Kjellberg, B. 453, 454, 486

Klausner, H.A. 104, 293

Klein, D.F. 16, 596, 602, 603, 637,

638

Kleinsmith, L.J. 234

Kleman, M.T. 466, 651, 662, 686

Klemm, W.R. 45, 455

Kline, F.G. 649

Kline, N.S. 21

384x
Knapp, D.E. 455

Knapp, S. 134, 293, 300, 301

Knobloch, L.C. 162

Knox, M. 607

Knowler, W.C. 455

Kokkevi, A. 412

Kokoski, R.J. 45, 134, 617

Kolb, L.C. 525, 526, 567, 596, 597,

629, 630

Kolton, M. 607, 616, 617, 641, 710

Kolton, M.S. 572, 578, 585, 613

Komlosi, M. 366, 510

Kopac, M.J. 174

Kopell, B.S. 293, 455, 504, 660, 696,

702, 710, 711, 714, 719

Kopin, I.J. 139, 140

Koppelhus, P. 428, 611

Korchin, S.J. 624

Korn, J.H. 645, 650, 675, 679

Kornetsky, C. 217

Kosek, J.C. 113

Kosersky, D.S. 45, 294

Koski, W.S. 43, 284, 584

Kosterlitz, H.W. 36, 46, 274, 294, 583,

585

Kostowski, W. 80, 186, 524

Kotake, A.N. 169, 357

Kozar, M.D. 696

Krall, R.G. 549

Kratky, M. 195, 196, 565, 595, 596,

692

Krause, R. 411

Kraynack, B. 220, 221, 399

Kreek, J.J. 226

Kreek, M.J. 605

Kreinick, C. 237

Krieger, G. 614

Krimmer, E.C. 455

Kron, R.E. 448, 456, 546, 610

Krug, D. 665

Krumholtz, W.V. 546

Krumholz, W.V. 711

Kubena, R.K. 135, 210, 294, 388, 457

Kuczenski, R. 135, 136, 143, 162, 301,

344

Kuhar, M.J. 136, 187, 725

Kuhn, C.M. 137

Kulics, A.T. 711

Kullberg, M.P. 33, 46, 118, 137

Kupfer, D. 90, 138, 294

Kurland, A.A. 45, 134, 580, 585, 586,

614, 617, 619, 650, 713, 719

Laasberg, L.H. 138, 296, 546

Labrecque, G. 138, 295

Laddu, A.R. 295

Lahiri, P.K. 295

Ladner, R.A. 663

Lajtha, A. 37, 72, 273, 277, 278, 446

Lal, H. 255, 295, 318, 414, 429, 457,

480, 483, 487, 572, 654

Lalley, P.M. 195, 295, 565

Lang, D.W. 138, 296, 546

LaPidus, J.B. 120

Larosa, R.T. 254

Larrison, S.B. 92

Lasagna, L. 340, 352

Laties, V.G. 46, 457, 458, 512, 513,

564, 712, 723

Lau, C. 353

Law, N.C. 46, 47

Lawrence, R.H., Jr. 47, 48, 138, 139

Lazar, R. 619

Leafe, T.D. 48, 77, 586, 594

Leander, J.D. 49, 458, 546, 586

Lebman, R.I. 480

Lebow, S. 377

Lebrecque, G. 546

Lee, C-T. 495

Lee, H.K. 296

Legator, M.S. 546

Leger, R.M. 51, 116, 142

Leighty, E.G. 109

Lemberger, L. 139, 140, 420

Lentz, P.L. 49

Lerner, S. 671

Leslie, F.M. 36, 46, 274, 294, 583,

585

Leung, A.T. 13, 88

Leventhal, H. 10

Levi, N. 248

Levin, B. 431

Levin, E. 138

Levine, J. 388, 619, 629, 667

Levine, L. 30, 178, 363

Levine, R. 296, 365, 366, 458,’ 510,

617

Levine, R.M. 54, 299, 466, 547

Levine, R.R. 179

Levison, P.K. 712

Levit, S. 574, 609

Levy, J.A. 261, 297, 436

Levy, M.R. 661

Levy, S. 146, 303, 661

Levy, S.J. 618

Lewis, E. 208

Lewis, E.G. 458, 498, 501

Liao, P-Y. 523

384xi
Lief, V.F. 712

Lin, C. 6, 524

Lin, C.H. 49, 186, 297, 386, 406, 532,

546

Lin, S.C. 140, 297

Linder, C. 50, 140, 586

Lindgren, J.E. 153, 314

Lints, C.E. 262, 297, 459

Lipetri, N. 17

Lipper, S. 100, 569

Lipscomb, W. 50

Liptzin, M.B. 596

Liras, P. 140

Litt, M. 448, 456, 546

Littlejohn, D.P. 33

Liu, C-T. 5, 6, 14, 50, 80, 91, 298

Livenstein, M.A. 631

Llewellyn, M. 395, 459

Lloyd, S.C. 22, 50

Loe, P.R. 713

Loeffler, K.O. 5, 50

Loew, G.B. 140

Loew, G.H. 50, 141

Logan, W.J. 81, 693

Logston, D.G. 229, 571

Loh, H.H. 35, 50, 73, 74, 122, 123,

124, 141, 180, 181, 204, 264, 265,

266, 361, 368, 369, 391, 438, 505,

510, 511, 543, 563, 568, 581, 582,

592, 593, 614

Lokhandwala, M.F. 210

Lomax, P. 141, 298, 527, 568, 631

Longnecker, D.E. 90, 205

Lopatin, D.E. 141, 372, 564

Lorens, S.A. 77, 186, 385, 459

Lorick, E. 279, 446, 615, 647

Loschiavo, C.M. 237, 573

Lott, G.C. 201

Laurie, R.S. 525, 526, 567, 596, 597

629

Lowery, P.J. 257, 298, 578

Lowney, L.I. 31, 154, 257, 258, 298,

316, 578

Lowy, D.G. 622, 654

Lowy, K. 51, 460, 713

Loy, P.R. 22, 108, 701

Lu, S.E. 582

Ludwig, A.M. 618, 619

Luria, J. 279, 446, 615, 647

Lutz, M.P. 313, 476

Lynch, G.S. 460, 696

Lynch, R.D. 233, 533

Lynn, R.K. 51, 116, 142

Lyon, M. 298, 314, 460, 477, 486,

588

Lyons, J. 461

Lyons, J.E. 461

Lytle, L.D. 393, 461

McAllister, C. 344

McAree, C.P. 650, 659, 686, 687,

688

McAuliffe, W.E. 52, 298, 461, 619,

650

McBride, D.C. 663, 679

McCabe, O.L. 580, 585, 586, 614,

617, 619, 650, 713, 719

McCarthy, D.A. 580, 593, 699

McCarthy, K.D. 377

McClung, R. 52, 298, 461

McCoy, C.B. 679

McCoy, D.F. 473

McDonald, L. 389, 525

McGaugh, J. 702

McGinn, T.G. 529

McGlothlin, W. 475, 527, 568, 631

McGlynn, M. 53, 143, 299, 466, 547

McGuire, F.L. 675

McIsaac, W.M. 53, 123, 127, 142,

438. 445, 461, 546

McKay, D. 40, 545

McKearney, J.W. 462, 714

McLaughlin, B.R. 227

McLean, J.R. 593

McLendon, D. 437

McMahon, E.M. 299, 547

McMahon, T. 462

McMaster, S.E. 543

McMillan, D.E. 21, 49, 53, 76, 103,

142, 168, 185, 233, 299, 357, 385,

415, 425, 458, 462, 463, 464, 465,

500, 517, 546, 572, 587

McMonigle, J.J. 143, 271

McMurtrey, K.D. 14

McNair, D.M. 20

McNeil, J.H., Jr. 142, 299

McRae, D.J. 53, 623, 679

Mabry, P.D. 393, 465

Maciewicz, R. 702

MacNew, B.A. 610

Mac Nicol, M.F. 268, 439

MacPherson, L. 702, 714, 715

Maddux, J. 389, 525, 619, 650

Mader, G. 607

Mahoney, R. 196

Maickel, R.P. 34, 53, 54, 85, 119,

143, 299, 300, 357, 466, 499, 547,

559, 704, 715

Major, V. 625

384xii
Malloy, K.P. 279

Maloney, G.J. 300, 466

Malseed, R.T. 196

Mandell, A.J. 55, 60, 134, 143, 155,

162, 293, 300, 301, 344, 495, 496,

650

Manheimer, D.I. 396, 466, 637, 651,

652, 653, 662, 667, 679, 680, 686

Manian, A.A. 54, 69, 143, 175, 259,

547

Manigault, I. 72, 563

Manno, B.R. 56, 57, 144, 301, 302,

466, 467, 547, 548

Manno, J.E. 56, 57, 144, 293, 301,

302, 453, 466, 467, 545, 547, 548

Mansaert, R. 87, 204, 526

Mantilla - Plata, B. 542, 548

March, J.E. 70, 144, 175, 177

Marchok, P.L. 343, 494, 589

Marks, B.H. 183, 382

Marks, D.F. 395

Marks, M.J. 148, 302, 305

Marley, E. 467

Marr, M.J. 467, 715

Marriott, R.G. 433

Marsanico, R.G. 431, 432

Marshall, I. 144, 302

Martin, A.R. 130

Martin, B.R. 103, 104, 144, 145, 146,

302, 467, 532

Martin, J.C. 468

Martinez, J. 90

Martz, R. 139, 170, 358, 420

Marx, M. 414

Masoud; A. 61, 165

Masterson, J. 536

Masur, J. 303

Matefy, R.E. 549, 620

Matheu, H. 536

Matsuoka, S. 468

Matsuzaki, M. 468

May, E.L. 302, 467

Mayo, G.A. 620

Mead, R.N. 716

Mechaneck, R. 606, 639, 679

Mechoulam, R. 9, 83, 84, 90, 101,

107, 115, 146, 147, 148, 153, 163,

182, 197, 198, 208, 225, 250, 273,

303, 304, 305, 314, 315, 346, 377

Medzihradsky, F. 148, 302, 305, 306

Mejta, C. 400

Melges, F.T. 468, 469, 504, 549, 561,

660

Melikian, A.P. 57, 111, 148

Meller, E. 159

Mellet, L.B. 57, 111, 549, 587

Mellinger, G.D. 466, 469, 651, 652,

653, 662, 679, 680, 686

Meltzer, L. 475, 587

Menezes, F. 90, 208

Merenda, P.F. 590, 655

Merlis, S. 27, 28, 58, 64, 65, 69,

70, 175, 182, 183, 379, 425, 497,

543, 546, 558, 642, 643, 655, 656,

657, 658, 695, 702, 703, 715, 716,

720, 725, 726

Meshel, E. 306, 549

Metcalf, J.E. 148, 305

Metzel, P. 366, 367, 562

Meyer, E.R. 15, 94, 95, 214, 396,

529

Meyer, F.J. 48, 76, 586, 594

Meyer, R.E. 438, 469, 472, 653,

680

Meyers, F.H. 549

Meyerhoff, J.L. 149, 356, 499

Meyers, F.H. 685

Miczek, K.A. 469, 470

Middaugh, L.D. 471, 521, 550, 564

Mikus, P. 363, 592, 722

Miller, A.T., Jr. 464

Miller, D. 370, 515, 516

Miller, F.N. 90, 205

Miller, J. 28, 114, 306, 556

Miller, J.M. 438, 469, 471, 472

Miller, J.W. 329

Miller, K.W. 104

Miller, L.L. 58, 106, 235, 306, 414,

472, 473, 550, 653, 721

Miller, P.V. 649

Miller, R.C. 551

Miller, R.J. 149

Minium, L. 169, 357

Mirin, S.M. 653, 680

Misra, A.L. 58, 59, 149, 150, 151,

152, 306

Mitchell, C.L. 150, 183, 186, 251,

307, 312, 328, 348, 349, 380, 385,

420, 426, 427, 449, 450, 451, 459,

716

Mitchell, R.I. 133, 700

Miyasaka, M. 473

Mizoguchi, K. 307, 716

Moffett, A.D. 601, 602, 636, 670, 671

Molander, L. 307, 473

Moldestad, M. 636, 670, 671

Mole, M.L., Jr. 58, 59, 70, 151

Monrad, A. 428, 611

Moon, J.H. 59

Moorcroft, W.H. 461

Moore, F. 43, 125, 126, 131, 269

Moore, S.R. 587, 662

384xiii
Mora, A. 574, 609

Morales, R.R. 662

Moralishvili, E. 544

Mordes, J.P. 702

Moreton, J.E. 59, 307, 308, 309, 474,

475, 550, 587

Moretz, F.H. 425

Morin, A.M. 226

Morrisey, W. 363, 592, 722

Morrison, A.J. 649

Morrow, C.W. 421

Morse, W.H. 451, 452, 465, 467, 475,

587, 693, 710, 716

Moskowitz, H. 475, 476, 496, 497

Moskowitz, M.D. 695

Moss, T. 233, 533

Mowat, J.M. 21

Muchmore, J.S. 203

Mudgill, L. 309, 587

Mueller, R.A. 204, 391

Mulder, A.H. 168

Mule, S.J. 58, 59, 149, 150, 151, 152,

306, 309, 550

Muller, T.P. 189, 524

Munkvad, I. 61, 158, 309, 310, 324,

325, 326, 327, 476, 483, 484, 485,

486, 553, 620, 621, 654, 718

Munoz, L. 570, 639

Munson, A.F. 261, 297

Musacchio, J.M. 256

Mushlin, B. 311, 587

Naditch, M.P. 550, 551

Nair, X. 272

Nakai, Y. 476

Nakamura, J. 311, 312, 431, 476

Nakamura, R.K. 706

Nakashima, E.N. 397

Nandhasri, P.J. 148

Nash, C.B. 245

Nash, I.B. 100, 399

Nash, P. 313, 476

Neher, J. 588

Neidle, A. 97, 217

Nelson, L.M. 418

Nemes, G. 263, 614

Nemoto, H. 12, 87

Neumann, J.H. 155, 319

Newman, L.M. 313, 476

Nichols, W.W. 551

Nicholson, M.T. 313, 552

Nielsen, E.B. 314, 477, 486, 588

Nielsen, M. 86, 152, 153, 161, 203,

252, 314, 338

Nilakantan, B. 314, 316

Nilsson, I.M. 146, 153, 303, 314

Nilsson, J.L.G. 146, 153, 303, 314

Nixon, H.L., II. 686

Noble, E. 269

Noel, J.T. 225, 401

Norrell, H. 515, 516

North, R.B. 552

Norton, B.I. 25, 26, 109, 245, 574,

575, 610

Norton, S. 477

Norrell, H. 370

Nuite, J. 232, 409, 571, 593

Nurco, D.N. 684

Nutter, D.O. 341, 493

Nyback, H. 59, 63, 315, 341

Oates, J.A. 107, 239, 584

O’Brien, C.P. 478

O’Brien, J. 457

Oglesby, M.W. 315, 478

Ohlsson, A. 153, 314

Okamoto, M. 62, 199, 331, 368, 468,

510, 555

Olds, M.E. 411

Olsen, D.M. 362

Olsen, G.D. 51, 116, 142

Olsen, J.F. 717

Olson, J. 394, 478

Oltmans, G.A. 60

O’Neill, C. 720

Opheim, K. 360

Ordes, D. 65, 623

O’Rourke, T. 102, 233, 409

Osiewicz, R. 42

Oskoui, M. 350

Oster - Granite, M.L. 727

Osterholm, K.C. 322, 482

Otis, L.S. 112, 113, 182

Overall, J.E. 620

Overton, D.A. 315, 346, 479, 480

Owen, C.A. 549

Pace, H.B. 313, 315, 525, 552

Pacific School of Religion 661

Packman, P.M. 96, 214

Paez, P.D. 558

Page, T.F., Jr. 109

Pakkenberg, H. 245, 246, 247, 310,

316, 424, 476, 538

Pal, B.K. 31, 154, 258, 316

Palmer, G.C. 316

Pang, C. 381, 382, 383

Pang, C.N. 316, 564

384xiv
Papadopoulos, H. 15, 213, 602, 696

Papeschi, R. 60, 317, 318, 480

Parker, R.B. 588

Parry, H.J. 480, 651, 653, 680

Pars, H.G. 184

Pasternak, G.W. 119, 154, 156, 167,

181, 588, 593

Patrick, G.A. 102, 154, 318, 319, 480,

572

Patton, R.A. 419

Paul, A.G. 82, 132, 155, 159, 171

Paul, S.M. 60, 155

Pearl, J.H. 411

Pearlman, S. 680, 681, 683

Pearson, J. 264, 320, 552, 553, 554,

555, 622

Pedigo, N.W. 320

Peek, L. 158, 486, 621

Pelikan, E. 556

Perchonok, K. 444

Perhach, J.L., Jr. 135, 294

Perris, C. 389

Persing, B.F. 687

Person, P., Jr. 616

Pert, C.B. 156, 167, 588, 717

Pescor, F.T. 515, 516

Peters, B.A. 458

Peters, M.A. 157, 370, 528, 553

Petersen, D.M. 535, 635, 670

Peterson, D.W. 321, 481, 500

Peterson, G.R. 75, 321

Peterson, K.E. 10, 390

Petrucelli, L.M. 330, 724

Pettis, P. 377

Petty, C. 72

Philip; A.F. 680, 681, 683

Phillips, P. E. 189

Phoenix, D.D. 621

Phoenix, M.D. 448, 456

Pickens, R. 380, 412, 481, 502, 503,

521

Picou, D. 364

Pietle, L.H. 259

Pillard, R.C. 322, 423, 482, 553, 653,

654, 680, 681

Piraino, A.J. 61, 482

Pirch, J.H. 100, 221, 322, 399, 482

Plain, W.M.. 157

Plaintidosi, S. 261, 436

Plunkett, C.R. 481, 502

Pokorny, A.D. 620, 717

Pollock, S.H. 157

Polsky, R. 717

Ponsford, R. 101, 225

Porath, G. 83, 197

Portoghese, P.A. 171

Post, R.D. 632, 633

Potter, W.Z. 54, 143, 547

Potvin, A.R. 411

Powell, B.J. 437, 494

Power, M. 536

Powers, E. 30

Pozuelo, J. 286, 585

Prather, J.E. 588, 654

Prince, A.M. 529, 533

Pruitt, D.B. 322

Pryor, G.T. 482

Puri, S.K. 255, 295, 322, 364, 429,

457, 483

Quame, B. 17

Quimby, M.W. 20, 22, 61, 165, 177

Quintos, A. 725

Quirce, C.M. 54, 299, 466, 547

Quack, R.M. 323, 483, 589

Radlow, R. 443, 444, 445, 646

Rado, M. 613

Rall, T.W. 334

Rand, J. 351, 376

Randrup, A. 60, 61, 158, 190, 191,

246, 247, 252, 262, 307, 310, 314,

318, 323, 324, 325, 326, 327, 339,

340, 386, 387, 424, 437, 453, 454,

460, 473, 476, 480, 483, 484, 485,

486, 490, 492, 538, 553, 581, 621,

654, 718

Rapaport, G. 432

Rapoport, H. 149

Ratner, M. 97, 98, 217

Raye, J.R. 554

Raz, A. 208

Razdan, R.K. 158, 184

Reaven, G. 544

Rebec, G.V. 259, 260

Recchia, V. 80, 186, 524

Rech, R.H. 360, 504

Reddy, C. 487, 654

Reeser, C. 537, 558

Regelson, W. 158, 486, 621

Reichman, L.B. 327

Reid, L. 396, 400

Reisby, N. 252

Reiss, B. 197

Renault, P.F. 61, 327, 394, 486

Renner, J. 692

Rennick, P. 411

Repa, B.S. 411

384xv
Resenthal, M.S. 607, 640, 674

Resnick, R.B. 244, 245, 423, 574, 575,

589, 608, 609, 611, 621

Retka, R.L. 616

Rhines, R.K. 247, 248

Riblet, L.A. 328

Ricca, E. 65, 643, 656, 657, 658

Rich, E. 508

Richards, R.K. 269

Richman, A. 681, 682

Richamn, V.V. 682

Richter, J.A. 159, 328

Richter, R.W. 320, 327, 527, 552,

553, 554, 555, 622, 683

Richter, W.J. 13, 88

Ringle, D.A. 121, 263, 329, 581

Rittenhouse, J. 10

Rivrind, L. 665

Robbins, E.S. 680, 681, 683

Robbins, L.C. 680, 681, 683

Robbins, T. 589. 654

Roberts, T.K. 639

Robertson, L.W. 49

Robins, E. 94, 96, 214

Robins, L.N. 62, 675, 683, 684

Robinson, D.S. 579, 613

Robinson, E. 680, 681, 683

Robison, G.A. 63, 161, 316

Robustelli, F. 430, 487, 718

Rochlin, M. 329

Rodda, B.E. 57, 139, 420, 468, 548

Roehrs, T. 292, 309, 320, 453, 474,

487, 587, 616

Roerig, S. 15, 92

Roffman, M. 487, 654

Roffwarg, H. 26, 109, 575, 610

Rogers, J. 200

Roizin, L. 159, 330

Rolf, L.L., Jr. 29, 115, 250, 540

Rolinski, Z. 262, 437, 488, 581, 589

Romano, J. 526, 567, 597, 630

Rompalo, A.M. 54, 300, 466, 547

Roos, L. 263, 614

Roppolo, J.R. 320, 724

Roschenthaler, R. 330

Rose, A. J. 549

Rose, S.D. 27, 112

Rose, S.L. 33

Rosenberg, H.C. 62, 132, 155, 159,

331, 555

Rosenberg, J. 315, 478

Rosenberg, J.S. 667, 685

Rosenberg, N. 65, 658

Rosenblatt, J.E. 331, 573

Rosenblith, J.Z. 718

Rosencrans, J.A. 331, 488

Rosenfeld, G.C. 332

Rosenfeld, J. 13, 90

Rosengarten, H. 159

Rosenman, S.J. 159, 332

Rosenthal, W.S. 529

Rosow, C. 469, 556

Ross, N.W. 624

Ross, S. 445, 708

Rossi, G.V. 195

Rossman, M. 695

Rossman, T. 197

Roth, B.F. 718

Roth, L.J. 20, 62

Roth, R.H. 85, 160

Roth, W.T. 403, 719

Rothberg, R.M. 71, 72, 121, 122,

178, 179, 543, 593

Roubicek, 3, 245, 366, 574, 592, 627,

691

Rowe, H. 139

Rozsa, P.W. 558

Rubin, V. 364

Rubinstein, I. 629

Rutledge, C.O. 401

Rutschmann, R. 705

Sagales, T. 488

Salasnek, S. 595

Salzman, C. 63, 654

Samanin, R. 80, 186, 386, 524

Samuelov, Y. 147, 304

Sanders - Bush, E. 13, 91, 114, 209,

332, 333, 379, 392, 425, 556

Sands, F.L. 45, 134

Santos, C.A., III. 471, 550

Sarner, S.F. 48, 586

Sassenrath, E.N. 489

Sato, S. 521

Sato, T. 525

Sattin, A. 334, 719

Savage, C. 586, 619, 713, 719

Sawyer, C.H. 316, 383, 564

Sbordone, R. J. 556

Scattaregia, F. 220, 399

Schanberg, S.M. 137, 189, 224, 250,

275, 276, 299, 334, 386, 400, 462,

489, 547

Schapero, M. 475

Schapira, L. 352

Schechter, M.D. 334, 335, 489

Scheel - Kruger, J. 61, 86, 129, 152,

160, 161, 203, 280, 281, 314, 327,

335, 336, 337, 338, 339, 340, 447,

486, 488, 489, 490, 584, 589

384xvi
Scheib, J. 537

Schelling, J-L. 340

Schiff, P.L.; Jr. 165

Schibrring, E. 486, 491, 492, 589, 622,

654

Schlant, R.C. 341, 493

Schlichting, U.U. 434, 576

Schlosberg, A.J. 262

Schmidt, D.E. 63, 161, 209, 392

Schmidt, F.E. 659

Schmidt, M.J. 63, 161

Schmitter, B. 680, 681, 683

Schneider, F.H. 707

Schnelle, K. 29, 115, 250, 540

Schock, H. 619

Schoenfeld, R.I. 493

Scholfield, C.N. 707

Schooff, K.G. 622, 654

Schoolar, J.C. 622, 626, 637, 654,

660

Schramm, L.C. 540

Schreiber, R.A. 436, 541

Schubert, J. 59, 63, 315, 341

Schultz, J. 158, 486, 621

Schulz, K. 298

Schulz, R. 341, 342

Schumann, S. 615, 677

Schuster, C.R. 61, 64, 189, 342, 371

372, 387, 394, 419, 434, 486, 493,

494, 503, 517, 519, 524, 556, 576,

577, 593, 721

Schuster, R.E. 34, 118

Schut, J. 537, 604, 609

Schwartz, A.S. 107, 237, 343, 494,

534, 589

Schwartz, J. 343

Schwartz, W.E. 109

Schweiter, J.W. 28, 64, 114, 161,

343

Schwin, R. 437, 494

Scott, J.P. 495, 655

Scrafani, J.T. 162, 343

Sedvall, G. 59, 63, 315, 341

Seegal, R.F. 343, 495

Seelye, E.E. 568, 600

Seevers, M.H. 231, 343, 408, 494,

495, 655

Segal, B. 590, 655

Segal, D.S. 143, 162, 255, 301, 344,

429, 495, 496

Segal, M. 557

Segelman, A.B. 64, 162, 557

Segelman, F.P. 162, 557

Seidler, F.J. 353

Seixas, F. 568. 600

Sekerke, H.J. 101, 226, 447, 531,

584, 607, 639, 647, 697, 709

Seligson, D. 40, 41, 545

Sells, S.B. 64, 66, 616, 622, 625,

685

Semo, N.M. 284, 584

Senay, E. 614

Serra, M.T. 27, 89, 110, 111, 112,

113, 249, 527, 703

Sessa, G. 282

Sethy, V.H. 163, 345, 496

Sette, W.F. 726

Settle, A. 180, 368, 593

Shader, R.I. 63, 654

Shaffer, T.H. 558

Shagass, C. 345, 346, 389, 496, 557

Shah, R. 598, 631

Shani, A. 101, 146, 147, 163, 225,

303, 304, 305, 346

Shanks, B.L. 531, 606

Shapiro, D.M. 24, 25, 36, 37, 243,

275, 343, 642, 653, 680, 708, 720

Sharkawi, M. 496, 590

Sharma, S. 475, 496, 497

Sharoff, R. 574, 609, 611, 643

Sharpe, L.G. 94, 95, 214, 346, 497

Shaskan, E.G. 136, 163, 164

Shea, R. 476

Sheard, M.H. 226, 227, 247, 331,

347, 348, 403, 488, 497, 720

Sheehan, J.C. 184

Sheehan, P. 93, 212, 257, 258, 435

Sheldon, M.I. 165, 356, 590

Shelton, J. 614

Sheppard, C. 27, 28, 64, 65, 425,

497, 546, 558, 642, 643, 655, 656,

657, 658, 695, 702, 703, 720, 725,

726

Sheridan, B.K. 636, 671

Sherman, A.D. 348, 349, 427

Sherman, C. 531, 605, 672

Sherman, W.R. 707

Shick, J.F. 685

Shih, T. 350

Shim, C.S. 327

Shish, T.M. 350

Shock, H. 586

Shopsin, B. 80

Shore, B.L. 707

Shourare, Z. 537, 558

Shuster, C.R. 327

384xvii
Shuster, L. 75, 321, 350, 497, 558,

717

Siegel, L. 721, 723

Sikic, B. 486

Silberg, I.A. 27

Silberstein, S.D. 139

Silverman, I. 65, 568, 623, 632, 685

Simeon, J. 30, 35, 109, 115, 244, 574,

600, 623, 649, 658

Simon, E.J. 65, 164, 197, 232, 234,

264, 320, 330, 350, 351, 352, 376,

377, 384, 423, 700

Simpson, D.D. 66, 623, 685

Simpson, G.M. 375

Single, E. 66, 658, 686

Siva Sankar, D.V. 558

Sjoqvist, F. 352

Skinner, G.C. 112

Skinner, G.L. 113

Skinner, J.L. 57, 148

Slagel, D.E. 235

Slatkin, D.J. 165

Slotkin, T. 189, 190, 352, 353

Small, A. 239

Smith, A.A. 225, 273, 353, 354, 355,

530, 544, 559

Smith, C.B. 144, 159, 165, 183, 302,

332, 355, 356, 590

Smith, D.E. 549, 685

Smith, K.P. 6, 186, 386, 524

Smith, R. 51, 116, 142, 205, 392

Smith, S.G. 66, 225, 228, 229, 230,

231, 401, 404, 406, 407, 497, 498,

570, 571, 606, 623

Smithloff, B.R. 94, 95, 214, 396

Smythe, H. 231, 408

Snodgrass, W.R. 53, 143, 299, 466,

547, 715

Snyder, E.W. 498

Snyder, S.H. 81, 101, 119, 120, 126,

136, 149, 154, 156, 163, 164, 165,

166, 167, 168, 172, 173, 181, 183,

196, 263, 356, 359, 378, 498, 499,

502, 552, 588, 593, 658, 692, 693,

717, 725, 727

Soares, J.R. 34, 118

Soble, A.G. 254, 541, 575, 576, 611

Sofia, R.D. 162, 356, 357, 499, 557

Sokal, M. 543, 614

Sokol, G.H. 357, 499, 559

Solish, G. 543, 559, 614

Solliday, N.H. 363

Solomon, T. 211, 364

Somers, R.H. 466, 651, 662, 686

Song, C.H. 67

Sorensen, J.P., Jr. 357

Soskin, W. 499, 560, 590, 623, 624,

658

Soule, A.B. 499, 560, 624

Southern Regional Education Board

590, 662, 686

Sparber, S.B. 321, 329, 357, 360, 361,

428, 481, 500, 504, 505, 575, 592

Spaulding, T.C. 168, 169, 261, 319,

357, 436, 500, 591

Spector, M. 560

Speedy, G.A. 591, 662, 663

Spero, M. 109

Spiegel, D.K. 624, 686

Spivak, C.T. 100, 569

Squires, C. 179

Srebrenick, S. 50

Standley, K. 499, 560, 624

Stark, J.D. 59

Stark, L. 619

Stawiski, M. 699

Steele, W.J. 357, 358, 560

Steffenhagen, R.A. 650, 658, 659,

686, 687, 688

Steiner, L. 563

Steinert, H.R. 358, 500, 591

Stenger, R.E. 529

Sternbach, D.D. 67, 358

Sterns, H. 21

Stesin, A.J. 68, 502

Stitzer, M. 500, 520

Stoeckel, M. 546

Stoelting, R.K. 170, 358

Stokes, P. 568, 600

Stolman, S. 358, 359, 560, 582

Stone, G.C. 281, 545, 648

Straight, R.C. 458, 501

Straumanis, J.J., Jr. 346

Strauss, R. 529

Strobel, J. 57, 549, 587

Stryker, J.C. 624

Student American Pharmaceutical

Association 663

Student Association for the Study of

Hallucinogens, Inc. 67, 170, 501,

560, 591, 624, 659, 660, 663, 688,

689, 721

Stynes, A.J. 402

Sudilvosky, A. 238, 418

Suffet, F. 65, 568, 623, 661, 669

Suffet, S.L. 598, 631, 632

Sugerman, A.A. 375

Sulkowski, A. 508

Sullivan, D. 619, 650

Sullivan, J.G. 461

384xvii
Sullivan, R. 501, 721

Sulser, F. 114, 199, 249, 316, 332, 333,

359, 360, 425, 502, 556

Sun, C.D. 59

Sunshine, I. 11, 42, 59

Sutherland, V.C. 35, 140, 266, 297

Svennild, I. 460, 486

Swanson, G.D. 525

Swisher, J. 5, 661, 665

Takahashi, S. 77, 520

Takemori, A.E. 67, 68, 69, 127, 169,

171, 175, 357, 359, 361, 362, 367,

502, 591, 592

Takido, M. 132, 155, 159, 171

Talevia, L. 179

Tamatkin, N.R. 140

Tansey, L.W. 438

Tart, C.T. 68, 502, 660, 689

Taylor, A. 381, 382, 383, 564

Taylor, D.W. 211, 529, 637, 671, 696

Taylor, F.H. 220, 221, 399, 569

Taylor, J.F. 68, 171

Taylor, K.M. 172, 173, 263, 356, 359,

499, 502

Taylor, R.E. 199

Taylor, R.M. 721

Taylor, W.A. 360, 502

Taylor, W.J. 601, 602, 625, 671, 689

Teland, V.G. 171

Teller, D.N. 173, 174

Teplitz, R.L. 234, 235, 533, 534

Terada, C. 468

Teschemacher, H. 360

Tessel, R.E. 503, 519

Tessman, D.K. 593

Thatcher, K. 537

Thompson, T. 389, 481, 493, 503, 721

Thompson, W.D. 668

Thor, C.J. 504

Thor, D.H. 503, 504, 704, 721

Thum, D. 660, 689, 690

Tietz, W. 533

Tilson, H.A. 360, 504

Ting, R. 561

Tinklenberg, J.R. 126, 269, 293, 360,

403, 468, 469, 504, 549, 561, 660

Tobey, J. 309, 587

Tolosa, E.S. 361, 505

Tomko, D.L. 713

Tomporowski, R.A. 315

Torres, D.M. 112

Tourtellotte, W.W. 411

Tres, R. 49, 297, 546

384xix

Tresky, R. 6, 186, 386, 524

Trimbach, C. 422

Triplett, J.N., Jr. 287, 585

Troelstrup, R. 275, 446

Trost, J.G. 505

Truitt, E.B., Jr. 87, 133, 174, 361,

505, 526

Truitt, E.G., Jr. 109, 204

Tsau, J. 30, 115

Tseng, L. 204, 361, 369, 391, 505,

511, 568, 592

Tulunay, F.C. 68, 69, 175, 359, 361,

362, 502, 592

Turano, P. 69, 70, 144, 175, 177

Turk, R.F. 103, 104, 142, 176, 233;

299

Turkanis, S.A. 132, 282, 283, 362,

545

Turnbow, M. 528

Turner, C.E. 20, 49, 58, 59, 61, 69,

70, 108, 151, 176, 177

Turner, W.J. 69, 70, 144, 175, 177

Uehling, B.S. 505, 722

Ukena, T.E. 455

Ulett, G. 708

Umbrecht, W.W. 140

Ungar, G. 362

Unger, S. 713

Ungerleider, J.T. 689

University of the State of New York

625, 689

Uyeno, E.T. 70, 505, 506, 507, 561,

562

Vachon, L. 363, 508, 592, 722

Vadlamani, N.L. 58, 149, 151, 306

Vaillant, G.E. 508, 592

Valanju, N.N. 7

Valanju, S.N. 7

Valentine, V.E., III. 391, 597

Valerino, D.M. 177, 178

Valzelli, L. 186, 386, 524

Van Der Kolk, B.A. 63, 654

Van Dyke, R.A. 93

Vanvunakis, H. 30, 108, 178, 363

Varanelli, C. 208

Varconi, H. 147, 304, 305

Venator, E.R. 722

Veney, J.E. 621

Veress, F. 625

Verma, S.K. 7

Vesell, E.S. 81, 177, 178
Vestergaard, P. 21, 364

Villarreal, J.E. 64, 71, 165, 342, 356,

419, 442, 509, 519, 556, 590, 592,

594

Voeller, K. 247, 248

Volavka, J. 234, 244, 245, 365, 366,

412, 423, 509, 510, 562, 574, 592,

627, 640, 691

Volicer, L, 322, 364

Vollmer, R.R. 364

Voss, E. W., Jr. 76, 141, 366, 367,

372, 562, 564, 625

Waddell, F.B. 53, 465

Waddell, W.J. 43, 545

Wainer, B.H. 71, 72, 121, 122, 178,

179, 543, 593

Wajda, I.J. 72, 273, 563

Wajda, S.H. 563

Walker, K.E. 123, 438

Wallace, J.E. 34, 72, 389, 525

Wallace, S.C. 76, 517

Waller, C.W. 108, 177

Wailer, G.R. 47, 48, 138, 139

Walsh, C.T. 179

Walsh, M.J. 14, 180, 343

Walsworth, D. 57, 144

Walter, J.L. 109

Walter, P.V. 602

Walters, J.R. 160

Wang, R.I.H. 15, 92

Wang, S.C. 296

Ward, A. 171, 367

Ward, T.B. 704

Wardell, J.N. 624

Warner, A. 595, 600, 627, 665, 669

Wasserman, A. 368

Wasserman, E. 363

Watanabe, M. 62

Waterfield, A.A. 46, 294, 585

Waters, D.H. 368, 510

Waters, W. 437

Watkins, T.D. 689

Watson, D. 625

Wax, J. 593

Waxer, E. 669

Way, E.L. 73, 74, 84, 123, 124, 127,

140, 141, 180, 181, 198, 204, 223,

265, 266, 297, 368, 369, 389, 391,

438, 446, 505, 510, 511, 543, 563,

566, 568, 570, 581, 582, 583, 592,

593, 614

Wayne, A.W. 501

Webb, R.W. 53, 143, 299, 466, 547,

Weber, E. 546

Webster, G.W. 321, 497, 558

Webster, J.B. 563, 625

Wechsler, H. 660, 689, 690

Wechsler, M.B. 113

Wei, E. 73, 74, 181, 223, 361, 368,

369, 505, 510, 511, 563, 570, 593

Weidner, M.F. 444, 445

Weinstein, H. 50

Weisenthal, L.M. 388

Weisfus, D. 248

Weiss, A.B. 564, 712

Weiss, B. 51, 74, 458, 460, 511, 512,

513, 564, 703, 706, 712, 713, 722,

723, 726

Wellisch, D. 625, 690

Wells, K. 663

Weppner, R.S. 663, 679

Werner, G. 330, 711, 713, 723, 724

Werner, I. 75

West, L.J. 527, 568, 631

Westerman, G. 239

White, A.I. 130

White, E.H. 626, 637, 654, 660

White, L. 183, 375, 379, 711, 725,

726

White, R.P. 245, 370, 513, 626

Whitsel, B.L. 330, 723, 724

Wiesel, T.N. 698

Wiest, W.G. 214, 529

Wikler, A. 370, 414, 473, 514, 515,

516

Wilcox, C.E. 94, 95, 214

Wilcox, H.G. 293

Wilk, S. 75, 370, 724

Willette, R.E. 59

Willey, T.J. 370

Williams, N. 97, 99, 100, 162, 181,

217, 343, 371

Williams, R.J. 100, 399

Williams, T. 702

Williamson, E. 90, 208

Willis, T. 636, 671

Wilson, A.E. 106, 234

Wilson, H.A. 154, 181, 588, 593

Wilson, M. 231, 532

Wilson, M.C. 371, 372, 516, 517

Wilson, R.S. 302, 467, 626

Wilson, T.W. 76, 517

Winburn, G.M. 566, 567, 593, 622,

668, 676, 690, 707

Winger, G. 11, 391, 520

Winkelhake, J.L. 76, 141, 366, 367,

372, 562, 564

Winkelman, A.C. 692

Winter, B.A. 181, 372

384xx
Winter, J.C. 163, 182, 250, 264, 315,

334, 335, 345, 373, 374, 375, 425,

438, 478, 480, 489, 496, 518, 594

Winters, W.D. 311, 476

Wittner, W.K. 293, 455, 710

Wittstruck, T. 90

Wofsey, A.R. 725

Wolpert, A. 183, 375, 379, 725, 726

Wong, S-L. R. 34, 118

Wood,, R.W. 564, 726

Woodhouse, E.J. 124

Woodland, J.H.R. 48, 76, 77, 586,

594

Woods, J.H. 59, 395, 413, 434, 446.

459, 493, 494, 503, 519, 520, 572,

577, 594

Woods, L.A. 150, 385, 450, 451

Work, D.R. 566

Worthington, C.S. 726

Wursch, M.S. 27, 112, 182

Wurster, N. 352, 376, 377

Wurster, R. 436, 579

Wuttke, W. 520

Yagen, B. 148, 182, 305, 377

Yagiela, J.A. 377

Yagnitinsky, B. 101, 147, 148, 225,

304, 305

Yamamoto, I. 35, 124, 266, 543

Yamamura, H.I. 167, 378

Yamaoka, H. 220, 221, 399, 569

Yamanaka, Y. 14, 180

Yanagita, T. 76, 77, 231, 379, 408,

520, 521, 564

Yarbrough, G.G. 91, 182, 379

Yaryura-Tobias, J.A. 182, 183, 379,

711, 726

Yeh, S.Y. 32, 117, 183, 380, 385

Yen, F-S. 544

Yokel, R.A. 380, 481, 521

Yolles, S. 48, 76, 77, 586, 594

Yoshii, V. 234, 533

Young, A.B. 168, 183, 727

Young, G.A. 475, 587

Young, J. 381, 382, 383, 564

Young, L.D. 238, 420

Young, R.L. 565, 596

Yu, G. 497, 558

Yu, J.H. 183

Yunger, L.M. 77, 262, 543

Zalkind, D. 621

Zanati, G. 12, 87

Zanella, J. 334

Zanes, A. 678

Zarcone, V.P. 231, 408, 711

ZemIer, H. 146, 303

Zemp, J.W. 436, 471, 521, 541, 550,

564

Zheutlin, L.S. 650, 687, 688

Zimmerberg, B. 432, 522

Zimmermann, E. 183, 316, 564

Zitko, B.A. 184

Zivanovic, D. 196, 692

Zlatkis, A. 701

Zografi, G. 105, 234

Zolovick, A. 348

Zucker-Franklin, D. 384

Zunin, L.M. 233, 533

Zaks, A.M. 78, 234, 243, 244, 245,

296, 366, 380, 381, 412, 423, 458,

509, 521, 574, 575, 592, 594, 608,

609, 611, 617, 626, 640, 643

384xxi
384xxii
SUBJEC’T/DRUG INDEX

Abuse potential, 8, 11, 16, 18, 71, 77, 274,

394, 408, 524, 535, 606, 630, 635

aceperone, 86, 203, 281, 314, 338, 339,

488, 567

acetaminophen, see analgesics

acetylcholine, 7, 37, 82, 84, 99, 106,

130, 152, 193-196, 198, 209, 215,

216, 233, 234, 236, 267, 273, 295,

309, 310, 320, 321, 342, 351, 355-

357, 379, 388, 389, 392, 411, 496,

508, 546, 563, 565, 566, 577, 587,

717

acetylcholinesterase, 82, 133, 194, 264,

321, 565, 595

acetyldeoxyephedrine, 250, 425

actinomycin, 353, 355

Addict populations, see Epidemiology

Adverse effects, (biological, psychobehavioral, social) 523-564

aerosols, 696

alcohol, with other drugs, 14, 40, 66,

105, 117, 226, 253, 257, 261, 293,

302, 313, 360, 388, 395, 402, 435,

439, 444, 455, 467, 475, 476, 504,

505, 507, 520, 525, 527, 541, 545,

549, 590, 593, 595, 600, 602, 605,

611, 614, 618-620, 623, 628, 635,

638, 644, 645, 648, 649, 655, 658,

660-662, 668, 672, 674, 675, 686,

690, 696, 702-704, 708

AMI, see amphetamine

amitriptylene, see amphetamine

amobarbital, see depressants/barbiturates

amphetamine, 7, 9, 17, 22, 61, 66, 80, 106,

114, 120, 126, 129, 130, 134, 135, 143,

149, 158, 160, 161, 166, 167, 187, 190,

191, 202, 204-206, 224, 225, 229, 230,

237-239, 245, 247, 249, 254, 259,

262, 267, 268, 272, 280-282, 287,

293, 299, 301, 310, 314, 317, 318,

323-327, 332, 333, 335-341, 343,

344, 346, 356, 360, 380, 386, 390,

391, 393, 396, 400, 401, 406, 415-

419, 424, 428-430, 432, 435, 437,

438, 443-445, 447, 452, 453-455,

457, 460, 461, 465, 477, 480, 481,

483-486, 488-502, 495-498, 502-

504, 508, 511-513, 519-521, 526, 534,

535, 540, 544, 552, 553, 560, 571,

573, 581, 588, 589, 596, 606, 623,

640, 644, 645, 654, 658, 666, 672,

684, 685

AMI, 346

amitriptyline, 24, 152, 153, 201

314, 357

chlorimipramine, 280

D-amphetamine (D-AMP), 60,

158, 165, 172, 188, 169, 205, 206,

229, 230, 259, 260, 262, 267, 271,

272, 274, 275, 287, 288, 298, 299,

318, 321, 335, 343, 344, 356, 357,

359, 361, 371, 387, 392, 404, 407,

409, 411, 424, 428-433, 436, 439,

440, 444-446, 452-455, 457, 460,

462-464, 466, 471, 477, 481, 488,

491, 492, 495, 496, 499, 500, 503,

505, 512, 516, 520, 521, 541, 547,

550, 559, 564, 575, 582

desmethylimipramine (DMI), 162,

344, 357, 462

dextroamphetamine, 24, 25, 243,

279, 335, 380, 439, 446, 483,

544, 614, 615, 646, 647

tlextromethamphetamine, 360

DL-p-hydroxyamphetamine, 502

fenfluramine, 24, 25, 134, 243,

280, 447, 516, 519, 584

hydroxyamphetamine, 137, 360,

457, 463

imipramine, 24, 25, 37, 152, 153

223, 244, 290, 314, 335, 338,

348, 357, 368, 370, 371, 379,

400, 401, 439, 462, 495, 508,

512, 557, 595

L-amphetamine, 134, 172, 187,

299, 321,’ 335, 344, 356, 359,

380, 387, 445, 466, 481, 500,

512, 516, 521, 547

levo-methamphetamine, 380

methamphetamine, 106, 134, 160,

189, 218, 224, 237, 293, 299,

334, 336, 387, 400-402, 415-

419, 424, 455, 462, 468, 482,

489, 521, 547

methedrine, 106, 235, 236, 415,

417, 525, 570 (see also methamphetamine)

methylphenidate (Ritalin), 120, 160,

233, 336, 338, 350, 424, 447,

457, 516, 517, 533, 584, 697,

708, 709

n-ethylamphetamine (NEA), 503

p-chloramphetamine (PCA), 134,

209, 331-333, 335, 347, 392, 543

384xxiii
p-chloromethamphetamine, 333, 419

p-hydr,oxyamphetamine, 134, 160,

246, 249, 338, 424

p-methoxyamphetamine, 64

phenmetrazine, 336, 338, 371, 424,

516, 517

phenothiazine, 7, 81, 85, 111, 126,

143, ,167, 173, 174, 201, 299,

527, 547, 649, 658, 701, 726

Surmontil (trimipramine), 290, 368

1-amphetamine, 54, 134

(+)-amphetamine, 264, 317, 422,

437, 552

analgesics, 16, 19, 36, 53, 68, 69, 97,

99, 100, 152, 205, 217, 232

acetaminophen, 692

aspirin, 482

D(-)-levorphanol, 321

dextropropoxyphene, 6

phenylbutazone (PB), 294

propoxyphene (Darvon), 6, 7, 21,

32, 162, 415, 636, 692

anesthetics

dichloromethane, 144

eugenol, 408

halothane, 170, 218-220, 358

ketamine, 218-220, 473, 480

lidocaine, 220

procaine, 320

promazine, 81, 173, 357

tetracaine, 192, 193, 196

trichloroethanol (TCE), 163

Animal toxicity, 212, 220, 228, 283,

331, 357, 529, 531, 532, 541, 542,

545, 548, 553, 559

anhalonidine, see hallucinogens

anileridine, 162

aniline hydroxylase, 178

Antagonists /clinical chemotherapy, 19

26, 46, 48, 50, 68, 76, 77, 100

110, 156, 165, 181, 200, 204, 205,

213, 219-223, 228-230, 232, 237,

242-245, 252, 257, 262, 263, 265,

270, 271, 277, 280, 284-287, 289

309, 311, 323, 337, 349, 354, 355,

358, 361, 362, 366, 373, 375, 381,

407, 409, 413, 415, 440-442, 447,

465, 475, 477, 488, 496, 500, 508,

510, 519, 525, 526, 532, 541, 565,

566, 571-580, 596, 606, 608-613,

617, 619, 626

antidepressants, 243, 244

benactyzine, 326

desipramine, 104, 152, 153, 249,

252, 290, 314, 335, 338, 357,

368, 595

nortiptyline, 104, 357

perphenazine, 247, 316, 339, 488

phenelzine, 95, 214, 294

protriptylene, 153, 161, 314,335, 338

tranylacypromine, 95, 126, 183, 196,

253, 254, 541, 575, 576, 611

tricyclic antidepressants, 148, 335

antihistamines, 696, 704

dextromethorphan, 6, 33, 162, 253,

611

diphenhydramine, 508

doxylamine, 352

methscopolamine, 411

phenylephrine, 250, 276, 296, 451,

463, 464

tripelennamine, 212

apomorphine (APO), see narcotics

aprobarbital, see depressants/barbiturates

aromatic beta-carboline, see inhalants

artane (trihexyphenidyl), see sedatives

aspirin, see analgesics

atropine, see sedatives

azide, 127

barbital, see depressants /barbiturates

barbitone, see depressants /barbiturates

barbiturates, see depressants

Basic research, 5-564

adverse effects,, see Adverse effects

behavioral effects, 385-522

biochemistry/metabolism, 79, 80,

83-89, 91-95, 97, 98, 100, 101,

103-105, 107, 109-114,

118-127, 129, 132, 137-144, 148-

157, 159, 162, 165, 168, 169, 173-

175, 179-183, 215

chemistry, 80-82, 87, 88, 90-92, 97,

101, 109, 112, 115, 116, 118, 125, 128,

130, 131, 133, 134,137, 140-142,

144, 146-148, 151, 153, 157, 158, 161,

163, 165, 171, 176-179, 182, 184,

304

detection, see Methodological developments

effects, 79-81, 84-87, 90, 92, 94,

95, 97 -99, 102, 103, 105-107, 109,

110, 122, 124-129, 134, 135, 138, 139

141, 143-146, 148, 152-155, 157-163,

165, 166, 168-170, 172, 174, 175, 177,

178, 181-183, 185-384 (see also

Adverse effects, behavioral effects

and Reproductive effects)

mechanisms of action, 79, 82, 84, 149,

158, 160, 165, 173, 185-384

reproduction, see Reproductive effects

384xxiv
sites of action, 20, 26, 31, 37, 54,

63, 72, 79, 81, 85, 87, 88, 94,

104, 108, 109, 113, 120, 123, 127,

135, 136, 142, 143, 145, 148, 150,

152,154, 159, 162-164, 166, 167,

171, 173, 181, 183, 186, 193-195,

200, 203, 223, 257, 263, 264,

27,3, 278, 296, 298, 302,, 305,

316,’ 320, 338, 344, 351, 360,

361,: 378

Behavioral effects, see Basic research

Behavioral etiology, see Etiology

belladonna, see sedatives

benactyzine, see antidepressants

benzene, see inhalants

benzodiazepines, 40, 239

benzomorphan, see narcotics

benzophenone, 34

benztropine, 85, 204, 335, 336, 489,

508, 531, 607, 639

berberine, 12

beta-diethylaminoethyl diphenylpropylacetate, see SKF-525A

bethanechol, 207, 260

Biochemistry/metabolism, see Basic

research

Biological etiology, see Etiology

biperiden, 252

Botanical, 20, 47-49, 58 59, 61

70, 108, 109, 118, 138, 139,

151, 176, 177, 259, 540, 557

641

brom-lysergic acid diethylamide, see

hallucinogens

bromide, 478

bufotenine, see hallucinogens

bulbocapnine, ,,318, 361, 505

butaperazine, 134

butyrophenone, see tranquilizers

caffeine, see stimulants

canadine, 12

cannabis, 69; 79, 80, 105, 106, 109,

118, 129, 146, 151, 174, 201, 208,

235, 241, 244, 281, 293, 303, 308,

360, 364, 365, 395, 397, 404, 412

414, 423, 448, 453, 472, 474, 509,

538, 545, 562, 584, 641, 645

cannabidiol, 79, 124, 208, 282,

283, 304, 346, 362, 404

cannabinoid, 5, 50, 58, 107, 112,

115, 122, 132, 133, 138, 139,

147, 148, 158, 163, 168, 182,

196, 200, 208, 268, 282, 283,

299, 302-305, 346, 377, 390, 557

cannabinol, 208, 261, 267, 282,

304

Cannabis Sativa L,, 20, 22, 47, 48

59, 64, 70, 108, 162, 165, 176,

177, 303, 530, 557, 641, 674

hashish, 115, 125, 147, 148, 158,

168, 244, 250, 303-305, 365,

402, 500, 509, 549, 551, 591

marihuana, 7, 9, 22, 34, 43, 56-

58, 61, 63, 64, 66-68, 84, 87,

90, 100, 104, 106, 108, 118, 124-

126, 131, 133, 139, 140, 144-

147, 157, 162, 170, 176, 185, 198,

201, 202, 204, 208, 209, 211,

213, 214, 221, 222, 234, 235,

241, 244, 267, 269, 281, 293,

299, 301-304, 306, 308, 313,

315, 322, 327, 360, 363, 365,

385, 389, 392, 394, 396, 397,

399, 402, 403, 411, 412, 414,

420, 433, 436439, 447, 457,

458, 466-470, 472, 475, 476,

478, 480, 482, 486, 494, 496,

497, 501, 502, 504, 508-510,

522, 523, 525-527, 530, 540,

542-545, 547-553, 557, 560,

561, 566, 568, 573, 581, 584,

592, 593, 598, 602, 628, 630-

633, 636-638, 640, 644-651,

653, 654, 658-660, 666-669,

675-681, 683, 685, 686, 688,

689, 707, 709, 722,

THC, 9, 10, 13, 21, 27, 29, 30, 43,

47, 56, 57, 59, 67, 70, 83, 84,

90, 100, 102-104, 106-109, 112-

115, 122, 124, 125, 131-133, 135,

138-142, 144-148, 153, 158, 162,

163, 170, 174, 176, 182, 184-186,

197, 200 -203, 205, 208-211, 222,

225, 228, 233-235, 244, 250,

260, 261, 265, 267-269, 273,

279, 282-284, 293-295, 297-

299, 301-305, 307, 308, 313-

315, 322, 331, 346, 350, 356-

358, 361-365, 377, 385, 388,

394, 395, 397, 399, 400, 403,

404, 408, 409, 412, 414, 415,

420, 421, 425, 436, 437, 447,

457-459, 461, 467-469, 473-

476, 482, 486, 489, 494, 498-

501, 504-510, 522, 525, 530, 532,

542-551, 557, 561, 621, 632, 646,

648

cannabis, other constituents, 49, 57,

83, 101, 124, 144, 208, 225, 267,

303, 304, 346

384xxv
caramiphen, 326

carbachol, see stimulants

cardiolipin, 376

catapressan, see clonidine

catecholamine, 14, 59, 60, 75, 98, 120,

126, 128, 136, 141, 143, 159, 165-

167, 172, 174, 187, 190, 191, 194,

195, 205, 216, 217, 224, 226,

228, 231, 259, 267-271, 280, 294

29’5, 302, 315, 318, 326, 327, 332,

336, 337, 340, 342, 344, 347, 350,

353-356, 358, 360, 367, 386, 393,

407, 417, 428, 432, 441, 465, 471,

490, 498, 502, 505, 531, 550, 552,

559, 577, 592, 658, 703, 718

Chemistry, see Basic research

chloral hydrate, see depressants/barbiturates

chloralose, see depressants /hypnotics

chlordiazepoxide((Librium), see

depressants/barbiturates

chlorimipramine, see amphetamines

chlormethazanone, 695

chloroform, see inhalants

chloromercuribenzoate, 154, 316

chlorpromazine, see tranquilizers

chlorprothixene, 338, 725

chymotrypsin, 154

cigarettes, see tobacco

cinanserin, 207, 252, 373, 428

Clinical drug free therapy, 572, 590,

599, 601, 620

clonidine, 86, 160, 203, 337, 338, 567

clozapine, 428, 611

cocaine, see stimulants

codeine, see narcotics

corticosterone, 235, 294, 382, 383

cortisol, 189, 269, 381, 386, 489

Criminal justice, 18, 568, 584, 598,

601, 637, 638, 640, 641, 646, 663,

673, 675, 676, 707, 709

cyanide, 95

cyclazocine, see narcotic antagonists

cycloheximide, 68, 217, 240, 266,

311, 359

cyclophosphamide, 240

cyproheptadine, 207, 277, 285

cytoxan, see cyclophosphamide

D(-)-levorphanol, see analgesics

DAC, 593

D-AMP, see amphetamines

D-amphetamine, see amphetamines

Darvon, see analgesics

depressants

barbiturates, 7, 9, 13, 17, 24,

35, 39, 40, 42, 61, 66, 76, 88,

110, 177, 190, 191, 199, 220, 227,

231, 238, 266, 331, 358, 359, 379,

398, 401, 410, 435, 438, 482, 520,

524-527, 529, 532, 541, 564, 566,

596, 634, 666, 668, 672, 684

amobarbital, 25, 29, 115, 218-

221, 243, 250, 396-399, 443

520, 540, 569, 603, 714

aprobarbital, 42

barbital, 177, 191, 199, 253,

300, 358, 359, 368, 386,

510, 520, 524, 560

barbitone, 190, 191

chloral hydrate (CH), 163, 218-

220, 463

chlordiazepoxide (Librium), 20

37-39, 233, 373, 388, 389, 400,

410, 411, 443, 455, 463, 482,

512, 528, 533, 632

diazepam (Valium), 25, 169, 178,1

218-220, 357, 442, 463, 495

ethchlorvynol, 40, 463

glutethimide, 7, 17, 39

hexobarbital, 177, 283, ,302

hydroxyamobarbital, 29

levarterenol, 202, 239

mephobarbital, 13, 90

meprobamate, 178, 410, 495,

695

metharbital, 13, 90

methohexital, 520

pentobarbital, 7, 35, 57, 62, 74,

82, 124, 135, 177, 193, 194, 199,

202, 203, 209-211, 258, 265,

266, 302, 312, 313, 320, 322,

328, 331, 369, 371, 389, 402,

410, 430, 455, 456, 462-464,

468, 476, 482, 495, 512, 520,

525, 543, 555

pentobarbitone, 190

phenobarbital, 13, 51, 81, 90, 110,

115, 132, 177, 178, 253, 283, 401,

456, 471, 482, 483, 521, 548, 564

secobarbital, 177, 352, 482

thiopental, 177, 343, 520

hypnotics, 11, 391

aliphatic hypnotics, 220

chloralose, 24, 202, 341

flurazepam, 231, 408

methaqualone, 8, 39,82, 170, 482

524, 535, 635, 659, 670

methyprylon (Noludar), 524

paraldehyde, 218-220

pellotine, 132, 171

quaalude, 205, 526, 630

384xxvi
desipramine, see antidepressants

destrorphan, 181

dexamethasone, 381, 382

dextroamphetamine, see amphetamine

dextromethorphan, see antihistamines

dextropropoxyphene, see analgesics

dextrorphan, 38, 69, 99, 127, 154, 159,

328,, 351, 372, 532, 700

DHPG, see 3,4-dihydroxyphenylglycol

diacetylmorphine (heroin), see narcotics

diazepam, see depressants/barbiturates

dibutyryl cyclic AMP, 220, 221, 397-

399, 569, 603

dichloromethane, see anesthetics

digoxin, 30

diethyldithiocarbamate DDC, 340, 407,

490

diethyl ether, see inhalants

diisopropylfluorophosphate, 193, 194

196, 565; 595, 696

Dilaudid (hydromorphine), see narcotics

dimethoxyphenyletylamine, see DMPEA

diphenylhydantoin, 88, 132, 178, 283,

362, 411

diphenhydramine, see antihistamines

diprenorphine (M-5050), see narcotic

antagonists

disulfiram, 238, 254, 418, 619

Ditran, 24, 242, 345, 496, 537, 557

DL-isoproterenol, see stimulants

D-lysergamide, see hallucinogens

DMPEA, 28, 113, 374, 518

DMPH, 333,

DOPA, see L-Dopa

DOPEG, 86, 153, 161

doxapram, 218

doxepin, 24, 25, 30, 109, 115

doxylamine, see antihistamines

DPH, se’e diphenylhydantoin

dTC, see tubocurarine

ECHO, see echotheopate

echotheopate, 295

Education, 555, 572, 581, 587, 590, 598

618, 661-664, 668, 675

EMY, 593

Effects, see Basic research

ephedrine, 120, 463, 464

Epidemiology, 665-690

addict populations, 28, 62, 65,

66, 566, 598-602, 607, 612,

615, 634, 635, 638, 642, 643,

646, 654-657, 665, 666, 670,

672, 6,73, 681-683, 689

general populations, 9, 21, 396,

466, 629, 633, 637, 651-653

667, 678, 689

high risk populations, 10, 42, 66,

392, 438, 480, 541, 566, 567,

581, 593, 628-630, 633, 637, 638

640, 643-645, 647-650, 653,

658, 660, 667-669, 675, 676,

678, 680, 681, 683, 685-688,

690

minority populations, 566, 628,

630, 636, 637, 667, 670, 679

special populations, 637-639,

648, 663, 672, 683-686

epinephrine, 75, 269, 295, 309, 334,

342, 352-355, 378, 489, 587

eserine, 473

ETA, see etonitazene

ethanol, 56, 163, 185, 202, 220, 227,

253, 301, 343, 350, 353, 402, 483,

495, 646, 702-704, 707 (see also

alcohol, with other drugs)

ethchlorvynol, see depressants/

barbiturates

ethopropazine, 85

Etiology

behavioral, 19, 28, 386, 401, 410,

415, 436, 458, 478, 492, 514,

583, 591, 628, 636, 638, 641, 643,

654, 657, 659, 668, 673

biologic al

18, 116, 251, 420, 448, 515, 516

554, 636, 685

multiple factors, 16, 52, 65, 338, 493

502, 534, 535, 566, 590, 629,

643, 645, 647, 650, 651, 667, 675

376, 678; 684, 686, 688

pharmacological, 18, 55, 116, 281,

436, 458, 478, 514, 533, 627, 632,

641, 653, 675

psychosocial, 9, 21, 21, 31, 42, 43,

62, 281, 392, 438, 439, 480, 514,

525-527, 541, 566-568, 570, 628,

630-633, 635-644, 646, 648-655,

657-660, 668, 669, 675, 676, 680

683, 687, 689

etonitazene, 53, 438, 472, 515, 516

etorphine, 99, 117, 127, 137, 164, 264, 278

eucatropine, 133

eugenol, see anesthetics

Evaluation

drug education, 5, 10, 662, 676, 686

drug treatment/rehabilitation, 64, 407,

578, 604, 607, 609, 616-618, 622,

624, 676, 685, 715

384xxvii
fencamfamin, 372, 419

fenfluramine, see amphetamines

FLA-63, 191, 252, 307, 386

floropipamide, 246

flourouracil, 75

fluphenazine, 600, 623, 649, 658

flurazepam, see depressants/hypnotics

flurothyl, 6

furazolidone, 143

gallamine, 202

gasoline sniffing, 211

GHB, see gamma-hydroxybutrate

gamma-hydroxybutrate, 348

glue sniffing, 211, 637, 696

glutethemide, see depressants/

barbiturates

hallucinogens, 23, 25, 27, 43, 52, 67,

108, 116, 211, 242-244, 272, 282, 283

300, 374 422, 423, 540, 544, 602,

645, 650, 666, 672, 688

anhalonidine, 132, 171

brom-lysergic acid diethylamide,

199, 334, 489, 540

bufotenine, 375, 518

D-lysergamide, 178

DOM, see STP

Lophophora williamsii, see peyote

LSA, 76

LSD, 9, 18, 20, 63, 70, 76, 80, 85,

105, 108, 116, 130, 131, 141, 173,

178, 182, 186, 187, 189, 197, 199,

202, 211, 227, 233-235, 247, 254,

256, 259, 261, 264, 268, 271, 272,

279, 280, 313, 334, 335, 341, 345,

366, 367, 372, 375, 402, 403, 414,

424, 438, 446, 473, 482, 489, 493

496, 506, 507, 518, 526, 530, 533,

536, 540-542, 544, 549-551, 557,

558, 561, 562, 564, 606, 611, 614,

615, 618-620, 625, 627, 647, 679,

689, 699, 713, 719

MDA, 170, 688

mescaline, 9, 18, 28, 60, 82, 102,

114, 126, 130-132, 155, 159, 163,

202, 259, 264, 268, 335, 343,

345, 374, 375, 402, 438, 489,

496, 518, 540, 550, 556

PCP, 170, 591, 660, 688

peyote, 82, 132, 155

phenyclidine, see PCP

psilocin, 131

psilocybin, 170, 268, 501, 537, 591,

659, 688

STP, 123, 127, 142, 170, 211, 268,

272, 439, 445, 501, 505, 507,

560, 659

tryptamine, 116, 123, 178, 226,

252, 254, 326, 353, 373, 375,

403, 467, 518, 538, 594

haloperidol, see tranquilizers

halothane, see anesthetics

harmsline, 196, 462

hashish, see cannabis

HC-3, see hemicholinum-3

hemicholinium-3, 196, 273, 354,

379, 565, 699

heroin, see narcotic’s

hexamethonium, 127, 276, 698

hexobarbital, see depressants/barbiturates

High risk populations, see Epidemiology

hydroxyamobarbital, see depressants/

barbiturates

hydroxyamphetamine, see amphetamines

hydroxynorephedrine, 134, 249

hyoscyamine, 92, 133

hypnotics, see depressants

hyoscyamine, 326, 411

imipramine, see amphetamines

indolealkylamines, 130, 142

indoleamine, 165, 167, 331, 353

Information systems, 22, 24, 33, 36, 40

41, 50, 74, 694, 701, 720-723

inhalants

aerosols, 696

aromatic-beta-carboline, 123

benzene, 304

chloroform, 257, 353

chloroform methanol, 316

diethyl ether, 202, 253, 429

gasoline fumes, 211

glue, 211, 637, 696

isoproterenol, 209, 250, 260,

276, 342, 378

lighter fluid, 211

mace, 696

nasal inhalers, 696

nitrous oxide, 105, 296

nutmeg, 696

oxymetazoline, 378

solvents, 696

thinners, 211

insulin, 461, 692

iodoacetamide, 127

iodoacetic acid, 154, 316

iprindole, 104, 239, 249

384xxviii
ketamine, see anesthetics

KSW 3019, 424

LAAM(levomethady1), see narcotics

L-amphetamine, see amphetamine

L-Dopa, 11, 14, 34, 41, 94, 98, 119,

152, 153, 161, 172, 173, 182,

183, 188, 191, 228, 246, 247,

252, 265, 271, 307, 309, 314,

317, 325, 326, 339, 340, 361,

379, 393, 443, 473, 552, 718

levallorphan, see narcotic antagonists

levarterenol, see depressants/

barbiturates

levodopa, see L-Dopa

levomethadyl (LAAM), see narcotics,

levorphanol, see narcotic antagonists

Librium (chlordiazepoxide), see

depressants/barbiturates

lidocaine, see anesthetics

lighter fluid, 211

lithium, 101, 107, 134, 348, 497, 697

LSA, see hallucinogens

LSD, se’e hallucinogens

L-3,4-dihydroxyphenylaianine, see

L-Dopa

mace, 696

MAO inhibitors, 143, 148, 196, 227,

300, 309, 340, 348, 356

marihuana, see cannabis

MDA, see hallucinogens

mecamylamine, 204, 320, 350, 508

Mechanisms of action, see Basic

Research

meperidine (MEP), see narcotics

mephentermine, 245, 259, 463

mephobarbital, see depressants/

barbiturates

meprobamate, see depressants/

barbiturates

mescaline, see hallucinogens

metanephrine, 75

methaqualone, see depressants/

hypnotics

metharbital, see depressants/

barbiturates

methadone,, see narcotics

methamphetamine, see amphetamine

methanol, 220, 257, 304 (see also

alcohol, with other drugs)

methedrine, see amphetamines

Methodological developments, 5-78

methohexital, see depressants/

barbiturates

methoxamine, 202, 260

methscopolamine, see antihistamines

methylphenidate, see amphetamines

methylscopolamine, 331, 473, 488

methyprylon, see depressants/

hypnotics

methysergide, 280, 373, 470,

584, 692

Minority populations, see Epidemiology

modaline, 143

molindone, 546

monoamine oxidase, 294, 337, 466,

547

monoterpenes, 47

MOPEG, 11, 86, 153, 161, 203, 567

MOPET, 11, 203

morphine, see narcotics

morphine glucuonide, see narcotics

morphine sulfate, see narcotics

MPH (methyl phenidate), see

amphetamines

multiple drugs, 5-8, 11, 12, 14, 17-

19, 21, 25, 26, 30, 32, 33, 35,

37-39, 46, 51-53, 57-60, 66, 69,

71, 75, 76, 81, 82, 85, 86, 88,

91, 92, 94, 95, 99, 100, 104-107,

110, 114, 116, 120-122, 126, 127,

129-136, 148, 149, 151-154, 156, 159,

160-162, 165, 168, 171-174, 177-179,

187-191, 195, 198, 199, 202-205, 212,

214, 215, 218-224, 227, 229,

230, 233, 235, 236, 238, 239,

243-247, 249, 250, 252, 254-256,

258-260, 262, 265, 267, 270-273,

275-278, 280, 281, 284, 285,

287-289, 293-298, 301, 302, 304,

305, 307, 309, 311, 312, 314, 316-

318, 320-323, 325, 326, 328, 331-

342, 344, 345, 347, 348, 350-363,

365,-383, 386-389, 393, 395-398,

401, 402, 404, 405, 407-411, 413-

415, 419, 420, 424, 428-431, 433-

435, 439-441, 443, 444, 447, 451,

452, 455-457, 460, 462-465, 467,

473, 474, 476-478, 480, 482, 483,

488-490, 492, 494, 495, 497-503,

508, 509, 511, 512, 516-521, 525, 526,

531-533, 537, 538, 540, 541, 544, 545,

548-552, 557, 558, 563-567, 570-

573, 575, 577, 580, 582, 584-588,

592, 593, 595-597, 602, 608, 611,

613, 614, 618, 623, 639, 643-648, 651,

658, 660, 672, 685; 686, 692, 693,

695, 696, 698, 700, 719, 726

muscarine, 58, 204

myristicin, 408

M99, see etorphine

384xxix
nalodine, see narcotics

nalorphine, see narcotic antagonists

naloxone, see narcotic antagonists

naltrexone (EN-1639), see narcotic

antagonists

narcotics, 18, 22, 43

anti-carboxymethylmorphine, 363

apomorphine (APO), 7, 59, 160,

191, 230, 255, 264, 310, 314,

315, 323, 336-338, 340, 361,

362, 407, 429, 431, 437, 483,

489, 5,05, 588, 589

benzomorphan, 148, 244, 302, 305,

465

carboxymethylmorphine, 6

codeine, 6, 7, 14, 19, 21, 71, 79,

121, 162, 178, 179, 198, 221,

223, 395, 413, 519, 692;

dihydrocodeine, 363

dextro-methadone, 127, 150, 306

diacetylmorphine, see heroin

dihydromorphine (DHM), 6, 99,

100, 156, 162

diphenoxylate, 6

ethylmorphine, 81, 162, 177, 178

heroin, 14, 21, 26, 32, 33, 65, 66,

71, 78, 80, 84, 91, 106, 118, 122,

162, 226; 234, 245, 295, 296,

311, 327, 363, 365, 366, 380, 381,

423, 435, 436, 456, 458, 478, 510,

521, 523, 526-528, 531, 537, 552-555,

574, 579, 580, 583, 586, 592, 594,

599-601, 605, 606, 609, 611-613,

615-617, 621, 622, 625-628, 633, 637

638, 642, 643, 646, 650, 654, 657,

658, 661, 666, 672, 677, 681, 683,

684

hydromorphine (Dilaudid), 178, 179, 363,

478, 565, 596

isomorphine, 15

LAAM, 241, 296, 309, 320, 381, 458,

474, 476, 521, 608, 617, 626

levo-methadone, 127, 149,-152, 306

(also spelled laevo-methadone)

levomethadyl acetate (LAAM)

meperidine (MEP), 6, 7, 53, 71, 99,

110, 140, 171, 205, 220, 221, 223,

252-254, 273, 405, 409, 541, 544,

575, 576, 611

methadone, 5-7, 15, 17, 34, 50, 51, 53,

58, 59, 69, 99, 100, 106, 110, 116, 122,

127, 142, 149-151, 156, 162, 168, 170,

179, 205, 213, 221, 223, 225, 226, 234,

241, 244, 245, 256, 283-285, 287, 289,

292, 296, 298, 305, 306, 309, 311, 315,

328, 330, 354, 355, 370, 371,381, 389,

391, 401, 405, 435, 453, 456, 474,

478, 483, 487, 499, 519, 521

methadone (continued)

523, 525, 526, 528, 530, 531,

537, 543, 545, 553, 555, 559,

561, 563, 575, 577, 579, 582-

585, 595, 597, 599-602, 604-

606, 608, 611-616, 619, 622,

624-627, 638, 643, 650, 657,

659, 665, 669-671, 673, 689

morphine, 5-7, 9, 10, 12, 14-18,

21, 25, 26, 30-33, 36, 37, 44-46,

49, 50, 52, 53, 65, 66, 68, 69,

71-79, 80, 84, 87, 91-100, 102,

104, 106, 107, 109, 110, 116-118,

121-124, 127, 128, 134, 135, 138,

140, 141, 144, 149, 150, 154, 155,

159, 162, 165, 171, 175, 179-182,

186, 189-192, 197, 198, 200, 204,

205, 207-209, 213, 215, 217, 221-

223, 225, 226, 228-234, 236-238

240, 247, 248, 251, 254-256, 258,

260, 262, 263, 265, 266, 270, 273,

274, 277, 280, 282, 284-299, 392,

305, 307, 309, 311-313, 316, 318-322,

328-330, 332, 336, 341-343, 346,

348-353, 356-359, 361-364, 367-

371, 376, 377, 379, 381-387, 389,

391, 392, 395, 396, 399-401, 404-407,

409, 410, 413, 415, 420, 424, 426-

430, 432, 434, 438, 439, 441-443,

446, 449, 450-453, 457-459, 461, 463,

465, 471, 472, 474-476, 480, 481, 483,

487, 492-494, 496-505, 509, 511,

515-517, 519, 522, 524, 529, 531, 532,

534, 539, 540, 543, 544, 546,

550, 553, 554, 556, 558, 560,

563-566, 568 573, 576, 577, 580-583

585-587, 589-593, 616, 623; 654, 692

morphine glucuonide, 380

morphine sulfate, 228, 230, 231, 236,

240, 248, 258, 287, 288, 290, 306

311, 316, 319, 321, 322, 364, 382, 387,

405, 406, 432, 457, 471, 472, 481, 487,

498, 539, 540, 556

nalodine, 198

N-phenethyl-morphine, 141

normorphinr, 14, 149, 150, 162, 579, 613

opium, 12-14, 87, 88, 684

oxymorphine, 156, 689

poppy seeds, 6

3 carboxymethylmorphine, 363

6 alpha-OH-dihydromorphine, 157

6-monoacetylmorphine, 21

14-hydroxynoroxymorphine, 579

narcotic antagonists, 25, 43, 46, 50, 67-

69, 76, 77, 102, 110

cyclazocine, 19, 24, 25, 41, 42, 48, 76,

110, 129, 130, 162, 221, 242-245, 271

384xxx
cyclazocine (continued)

284, 320, 370, 409, 422, 423, 441,

442, 465, 478, 513, 532, 573-575,

578, 579, 583, 588, 589, 608, 610,

611, 613, 621, 622, 626, 643

diprenorphine (M-5050), 69, 415, 588

levallorphan, 19, 32, 100, 156, 232, 296,

330,351, 354, 358, 420, 441, 500, 588,

591,’ 596

neostigmine, 194, 320, 447

neurine, 58, 151

nialamide, 129, 135, 183, 281, 335, 339,

340, 447, 490

levorphanol, 31, 53, 69, 92, 93, 99,

100, 110, 121, 127, 154, 156, 159, 165,

181, 197, 205, 207, 213, 233, 234,

257, 258, 264, 278, 298, 316, 328,

330, 342, 343, 351-355, 372, 376,

377, 384, 405, 435, 496, 532,

577, 590, 700

nalorphine, 19, 20, 69, 71, 72, 100,

105, 110, 141, 156, 162, 198, 221,

223, 256, 270, 284, 287, 328, 363,

415, 420, 424, 434, 441, 451, 465,

573, 576, 577, 588

naloxone, 15, 18: 19, 26, 50, 52, 53,

65, 68, 69, 71, 73, 74, 76, 84, 93,

100, 104, 106, 109, 110, 117, 122,

123, 127, 140, 141, 154-157, 162,

165, 169, 181, 198, 204, 207, 213,

221, 223, 225, 233, 236-238, 244,

245, 257, 266, 270, 271, 278, 284,

287, 289, 298, 311, 321-323, 342,

348, 349, 354, 355, 358, 359, 361,

362, 366, 367, 369, 381 -383, 389,

391, 395, 399, 407, 415, 428, 432,

434, 438, 440, 441, 446, 461, 472,

475, 505, 510, 511, 519, 532, 565,

566, 568-575, 577-580, 582, 583,

585, 586, 588-590, 592-594, 596,

606, 608-610, 613, 614, 617, 619,

626

nicotine, see tobacco

nikethamide, 424

nitroglycerin; 340

nitrous oxide, see inhalants

noradrenaline, see norepinephrine

norpinephrine (NE), 19, 60, 75, 86, 88,

94, 95, 98, 99, 101, 107, 120, 128,

136, 149, 151-153, 158, 161, 164-166,

172, 174, 187, 191, 203, 215, 220,

222, 224, 225, 227, 238, 246, 250,

251, 255, 256, 260, 262, 263, 265,

267, 270, 271, 276, 281, 285, 302,

307, 309, 310, 314, 315, 317, 318,

321, 325, 326, 329, 332, 334, 335,

337, 338, 340, 344, 354-356, 358-360,

365, 367, 377-379, 387 398-400,

407, 429, 440, 441, 451, 463, 464,

467, 471, 485, 488-490, 492, 502,

504, 511, 552, 563, 569, 587, 589,

590, 595, 658

normetanephrine, 129, 224, 263, 335,

338, 340, 360

normorphine, see narcotics

nortiptylene, see antidepressants

nutmeg, 696

naltrexone (EN-1639), 15, 17, 92, 101,

110, 157; 289, 415, 532, 566, 578,

579, 587, 588, 593, 613

noradrenaline, 252

norcyclazocine, 41, 42

norephedrine, 137

norketobemidone, 46

normetanephrine, 263

pentazodine, 7, 19; 21, 110, 148, 162,

205, 212, 221, 232, 270, 274, 305,

320, 405, 409, 413, 415, 440-442,

465, 519, 529, 572, 582, 583, 677,

692

opium, see narcotics

orap, see pimozide

ouabain, 305, 700

OXO, see oxotremorine

oxotremorine, 204, 337, 350

oxymetazoline, 378

oxymorphine, 156, 689

oxypertine, 246

oxytocin, 212

384xxxi

p-ADE, see acetyldeoxyephedrine

para-chlorophenylalamine, see p-chlorophenylanine

paraldehyde, see depressants/hypnotics

paregoric, 456

pargyline, 95, 135, 161, 183, 196, 204,

224, 265, 271, 317, 338, 340, 380,

nasal inhalers, 696

Natural history, see Treatment of drug

abuse

n-ethylamphetamines (NEA), see amphetamine

490, 582, 692

parpanit, see caramiphen

p-chloroamphetamine (PCA), see

amphetamines

p-chlorometamphetamine, see

amphetamines
p-chlorophenylalanine, 63, 92, 204, 212,222,

251, 254, 262, 265, 271, 275, 323, 333,

347, 396, 421, 427, 437, 465, 483, 497,

541, 575, 576, 582

PCP, see hallucinogens

p-CPA, see p-chlorophenylalanine

PCPA, see p-chlorophenylalanine

pellotine, see depressants /hypnotics

pempidine, 204

pentaerythrol tetranitrate, 340

pentaphen, see caramiphen

pentazocine, see narcotic antagonists,

pentobarbital, see depressants/

barbiturates

pentylenetetrazol (PTZ), see stimulants

perphenazine, see antidepressants

peyote, see hallucinogens

Pharmacological etiology, see Etiology

phencyclidine, 202, 218, 220, 330, 482

phenelzine, see antidepressants

pheniprazine, 95, 214

phenitrone, 168, 357, 500, 591

phenmetrazine, see amphetamines

phenobarbital, see depressants/

barbiturates

phenothiazine, see amphetamines

phenoxybenzamine, 86, 94, 185, 203,

250, 276, 281, 314, 329, 339, 354,

378, 488, 567

phentolamine, 94, 186, 219, 276, 285,

334, 398, 452, 603, 698

phenylbutazone, see analgesics

phenylephrine, see: antihistamines

phenylquinone, 284, 593

p-hydroxyamphetamine, see amphetamines

physostigmine, 82, 194, 204, 252, 270, 309,

331, 336, 337, 447, 496, 508, 531, 565,

573, 587, 590, 592, 607, 639, 647

picrotoxin, see stimulants

pilocarpine, see stimulants

pimozide, 22, 59, 199, 264, 272, 315,

338, 362, 362, 437, 453, 460, 461,

477, 588, 620

piperacetazine, 26

piperazine, 275, 649

piperidine, 58

pipradrol, 160, 336, 338, 371, 517

p-methoxyamphetamine, see amphetamines

PMZ, see pimozide

polyvinylpyrrolidone, 391

poppy seeds, 6

prednisolone, 253

Prevention, 565-594

behavioral, 391, 440, 441, 569, 572,

576, 579, 581, 589

educational, 555, 566, 568, 570, 572,

581, 584, 587, 590, 591, 598, 608,

637, 662, 668, 675, 676, 684, 690

primidone, 81, 192

probenecid, 201, 597

procaine, see anesthetics

profadol, 440, 582

prochlomperazine, 111, 173

promazine, see anesthetics

pronithalol, 354

propanol, 40

propoxyphene, see analgesics

propranolol, 94, 213, 229, 276, 334,

378, 414, 452, 463, 571, 582

propylene-glycol, 331

protriptylene, see antidepressants

psilocybin, see hallucinogens

psilocin, see hallucinogens

Psychobehavioral, 385-522, 627-660

Psychosocial etiology, see Etiology

puromycin, 353, 355

pyrazole, 88

pyridine, 173, 193

quaalude, see depressants/hypnotics

quinine, 7, 17, 32, 327, 696

Reproduction effects, 89, 104, 189, 214,

234, 235, 313, 315, 353, 383, 406,

456, 471, 521, 523, 525-528, 531,

536, 537, 539, 540, 542-547, 551,

553, 554, 559, 560-562

reserpine, see tranquilizers

rho-chlorophenylalanine, see p-chlorophenylalanine

Ritalin (methylphenidate), see

amphetamines

safrole, 408

secobarbital, see depressants/

barbiturates

salicylic acid, 39

scopolamine, see sedatives

sedatives, 18, 105, 388, 397, 629, 634,

651, 667, 672, 692

atropine, 20, 24, 85, 91, 92, 133,

202, 205, 207, 209, 211, 212, 230,

242, 277, 285, 295, 320, 331, 336,

337, 350, 388, 411, 451, 452, 508,

516, 536, 698

belladonna, 194, 602

dihydroergotamine, 488

scopolamine, 51, 82, 92, 105, 133,

192-194, 235, 252, 281, 326, 336,

337, 339, 388, 390, 393, 414, 419,

430, 431, 473, 487, 488, 508, 565

trihexyphenidyl (Artane), 85, 508

384xxxii
Sites of action, see Basic research

SKF-525A, 57, 104, 107, 284, 301, 302,

457, 4’99, 549

Sociocultural, 392, 627-660, 665-690

solvents, 696

somatostatin, 218, 219, 397, 398

SPA, 372, 419, 494, 517

Special populations, see Epidemiology

SP-1, 394

stimulants, 18

bethanechol, 207, 260

caffeine, 218, 404, 424, 464, 482, 719

carbachol, 192-196, 295

cocaine, 7, 32, 40, 66, 75, 92,133,

170, 183, 188, 189, 252, 254, 285,

293, 335, 341, 363, 371, 372, 387,

412, 413, 419, 424, 428, 433-435,

439, 446, 447, 459, 481, 482, 489,

494, 501, 503, 517, 566, 575, 593,

6,02, 625, 659, 671, 672, 689

cocainesterase, 91, 133

dichloroisoproterenol, 378

dimethylphenylpiperazinium (DMPP),

207’; 260

Dinitrophenol, 127

DL-isoprdterenol, 276, 354

doxapram, 218

harmaline, 196, 462

muscarine, 58, 204

oxytocin, 212

pentylenetetrazol (PTZ), 202, 282,

362

picrotoxin, 193, 202, 218, 565

pilocarpine, 130, 133, 205, 431

theophylline, 218, 260, 265, 334,

719

tropacocaine, 91, 133, 157

STP, see hallucinogens

strychnine, 168, 202, 218

succinylcholine, 296

sulfonamides, 39

sulthiame, 708

Surmontil (trimipramine), see amphetamines

Talwin (pentazocine), see narcotic antagonists

tetrabenazine (TBZ), see tranquilizers

tetracaine, see anesthetics

tetrahydrocannabinol, see cannabis

thetahydroisoquinoline (THIQ), 227

tetrahydropapaveroline (THP), 101, 180,

227

tetrodotoxin, 207

THC, see cannabis

theophylline, see stimu1ants

Therapeutic uses of abusable drugs,

132, 167, 232, 261, 282, 283, 294,

361, 362, 402, 533, 611, 614, 619,

621, 623, 679, 689, 692, 695, 697,

701, 713, 719

thiopental, see depressants/barbiturates

thioproperazine, 173, 174

thioridazine, 81, 726

thiothixene, see tranquilizers

THIQ, see tetrahydroisequinoline

THP, see tetrahydropapaveroline

thymidine, 20, 262

thyroxine, 75

tobacco, with other drugs, 541, 593, 668

cigarettes, 112, 363, 526, 643, 686

nicotine, 7, 79, 194, 207, 350, 404,

482, 645, 658

tolbutamide, 482

tranquilizers, 9, 37, 53, 275, 397, 457,

541, 629, 653, 666, 692

butyrophenone, 126, 167, 229, 246,

275, 318

chlormezanone, 695

chlorpromazine, 7, 9, 21, 25, 27, 33,

37, 54, 69, 70, 81, 85, 88, 89, 110-

113, 126, 143, 144, 148, 173-175, 177,

178, 199, 202, 206, 246, 247, 249,

254, 258, 259, 268, 293, 312, 338,

371, 393, 400, 415, 430, 431, 439,

455, 463, 467, 476, 488, 495, 500,

507, 508, 517, 525, 527, 537, 538,

541, 575, 576, 595, 702, 703

chlorprothixene, 338, 725

haloperidol (HAL), 66, 206, 229, 230

246, 259, 277, 339, 343, 356, 361,

362, 407, 428, 431, 488, 494, 498

571, 583, 589, 611

oxypertine, 246

prochloperazine, 111, 173

reserpine, 63, 86, 129, 135, 161, 164,

188, 191, 207, 224, 226, 228, 238,

245, 246, ‘252, 254, 255, 263, 267,

281, 290, 307, 317, 318, 323, 324,

336, 338-340, 344, 350, 354, 355,

393, 420, 422, 462, 465, 480, 490,

492, 495

tetrabenazine (TBZ); 281, 339, 447,

462, 464, 490

thiothixene, 23-25, 725, 726

trifluperidol, 275

tranylcypromine, see antidepressants

Treatment of drug abuse, 595-626

acute medical, 40, 41, 134, 218, 526,

‘531, 558, 602, 603, 609, 638, 639

384xxxiii
Treatment of drug abuse (continued)

behavior patterns of treated, 595-

597, 599-603, 606, 607, 616, 625

behavioral treatment, 577, 596, 597,

600, 601, 606, 612, 618-620, 623

natural history, 525, 526, 572, 598,

600, 601

pharmacological, 229, 230, 381, 569,

580, 596, 597, 602, 603, 608-611,

613, 615, 617, 621, 625, 626, 642,

649, 658

treatment systems, 525, 526, 555, 572,

595, 597-602, 604-614, 616-621, 624-

626, 638, 640, 641, 646, 650, 656,

657, 663, 672, 684, 695

tremorine, 204

trichloracetic acid, 367

trichloroethanol, see anesthetics

trifluperazine, 262, 371, 488

trifluperidol, 275

triflupromazine, 81

trihexyphenidyl (Artane), see sedatives

trimipramine, see amphetamines

tripelennamine, see antihistamines

tryptamine, see hallucinogens

tubocurarine, 193, 194, 196, 511

Tween, 56, 282, 301, 307, 414, 470, 548

tybamate, 245, 306, 549, 625

tyramine, 107, 178, 239

uridine, 316

Valium (diazepam), see depressants/

barbiturates

xylamidine tosylate, 373, 375, 518, 594

yohimbine, 317, 345, 480, 496

(1)-1-2-diphenyl-1-dimethylaminoethane,

see SPA

2-phenyl-3-ethylaminobicylo-(2,2,1)-

heptane, see fencamfamin

2,5-dimethoxy-4-methylamphetamine,

see hallucinogens/STP

3-methoxy-4-hydroxyphenylethanol,

see MOPET

3-methoxy-4-hydroxyphenylglycol,

see MOPEG

3,4 dihydroxyphenyleneglycol, see

DOPEG

3,4 dihydroxyphenylglycol (DHPG), 227

3,4 dimethoxyphenyletylamine, see

DMPEA

6 methylene, 579

384xxxiv