Phencyclidine:

An Update

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse and Mental Health Administration
Phencyclidine: An Update

Editor:

Doris H. Clouet, Ph.D.

Division of Preclinical Research

National Institute on Drug Abuse

and

New York State Division of

Substance Abuse Services

NIDA Research Monograph 64

1986

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administratlon

National Institute on Drug Abuse

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For sale by the Superintendent of Documents, U.S. Government Printing Office

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NIDA Research Monographs are prepared by the research divisions of the

National lnstitute on Drug Abuse and published by its Office of Science The

primary objective of the series is to provide critical reviews of research problem

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

integrative research reviews. its dual publication emphasis is rapid and targeted

dissemination to the scientific and professional community.

Editorial Advisors

MARTIN W. ADLER, Ph.D.

Temple University School of Medicine

Philadelphia, Pennsylvania

SYDNEY ARCHER, Ph.D.

Rensselaer Polytechnic lnstitute

Troy, New York

RICHARD E. BELLEVILLE, Ph.D.

NB Associates, Health Sciences

Rockville, Maryland

KARST J. BESTEMAN

Alcohol and Drug Problems Association

of North America

Washington, D.C.

GILBERT J. BOTV N, Ph.D.

Cornell University Medical College

New York, New York

JOSEPH V. BRADY, Ph.D.

The Johns Hopkins University School of

Medicine

Baltimore, Maryland

THEODORE J. CICERO, Ph.D

Washington University School of

Medicine

St Louis, Missouri

SIDNEY COHEN, M.D.

Los Angeles, California

MARY L. JACOBSON

National Federation of Parents for

Drug Free Youth

Omaha, Nebraska

REESE T. JONES, M.D.

Langley Porter Neuropsychiatric lnstitute

San Francisco, California

DENISE KANDEL, Ph.D

College of Physicians and Surgeons of

Columbia University

New York, New York

HERBERT KLEBER, M.D.

Yale University School of Medicine

New Haven, Connecticut

RICHARD RUSSO

New Jersey State Department of Health

Trenton, New Jersey

NIDA Research Monograph Series

CHARLES R. SCHUSTER, Ph.D.

Director, NIDA

JEAN PAUL SMITH, Ph.D.

Acting Associate Director for Science, NIDA

Acting Editor

Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857
Phencyclidine: An Update
This monograph is based upon papers and discussion from the

technical review on phencyclidine which took place on May 7-9,

1985, at Rockville, Maryland. The review was sponsored by the

Divisions of Preclinical Research, Clinical Research, and

Epidemiology and Statistical Analysis of the National Institute on

Drug Abuse.

COPYRIGHT STATUS

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Williams and Wilkins to reproduce the figure on page 156. Further

reproduction of this figure without specific permission of the

copyright holder is prohibited. All other material in this volume

except quotea passages from copyrighted sources is in the public

domain and may be used or reproduced without permission from the

Institute or the authors. Citation of the source is appreciated.

Opinions expressed in this volume are those of the authors and do

not necessarily reflect the opinions or official policy of the

National Institute on Drug Abuse or any other part of the U.S.

Department of Health and Human Services.

The United States Government does not endorse or favor any specific

commercial product or commodity. Trade names or suppliers' names

appearing in this publication are used only because they are

considered essential in the context of the studies reported herein.

DHHS Publication No. (ADM)87-1443

Printed 1986 Reprinted 1987

NIDA Research Monographs are indexed in the Index Medicus. They

are selectively included in the coverage of American Statistics

Index, BioSciences Information Service, Chemical Abstracts. Current

Contents, Psychological Abstracts, and Psychopharmacology Abstracts.

iV
Foreword

This volume comes at an especially important time. PCP continues

to be a significant problem in the U.S. with reports of epidemic

levels of use in certain localities. Since 1978, NIDA has supported a substantial research program on this drug. The results

of these studies demonstrated the biological and behavioral toxicity of PCP. Furthermore, PCP abuse presents a considerable hazard not only to the abuser, but to those in social contact with

him/her. Particularly disconcerting were reports concerning the

widespread occurrence of PCP-induced psychoses and neurological

deficits and the number of PCP-abusing pregnant women.

In view of this, NIDA felt that it was important to convene a conference and prepare a monograph on a wide variety of issues relating to PCP. The present volume represents input from the preclinical, clinical, and epidemiological programs of the Institute. It

is hoped that this state-of-the-science report on the basic biological mechanisms underlying PCP's action and current, as well as

potential, treatment approaches to PCP abuse will prove useful to

both researchers and health care personnel. This monograph also

serves to document, once again, the harmful effects of PCP and

should be useful in the development of specific prevention programs.

I would like to express my appreciation to Dr. Doris Clouet who

undertook to organize the conference and edit the monograph while

a Visiting Scientist at NIDA.

Marvin Snyder, Ph.D.

Director, Division of Preclinical

Research

v

Preface

Since the last Technical Review on phencyclidine (PCP) held by the

National Institute on Drug Abuse was published in the NIDA

Research Monograph series in 1978, there has been an explosion of

new knowledge about drug actions in brain, including those of

phencyclidine and related compounds, and during the same period, a

new epidemic of PCP abuse has arisen in a few population centers

in the country, resulting in greater clinical expertise in treating PCP abuse and PCP psychoses. In reports published in this

Monograph, based on a Technical Review that was held May 7-9,

1985, at NIDA, both basic and clinical aspects of PCP abuse are

discussed in detail by leading experts in each area.

In the first section of the Review, the basic neurobiology of PCP

was emphasized. Studies on the binding of PCP to specific receptor molecules in brain have been confounded by the presence of two

types of PCP-binding molecules. GUNDLACH reported that he was

able to distinguish a PCP-binding site from an opiate-binding site

that also binds PCP. The two sites had different localizations in

brain and produced different behaviors. ZUKIN also separated the

two receptors and reported on the early development of the PCP

receptor in brain. He described the isolation from brain of a

substance that reacts specifically with the PCP receptor.

O'DONAHUE has isolated a naturally occurring peptide from brain

that can produce responses similar to PCP when administered to

animals. The results are reminiscent of the early studies of the

opiopeptides that interact with opiate receptors and produce

effects like narcotic drugs when administered to animals.

The binding of PCP to its receptor initiates a series of coupled

neurochemical events eventually leading to the expression of behavior. One such coupling reaction was described by BLAUSTEIN as

a blockade of transmembrane channels that transport K+ into the

neuronal cells. Since K+

 movements are part of the process of

neurotransmission between neurons, this effect of PCP may explain

the results of studies by MARWAH and by JOHNSON, in which several

neurotransmitter systems were shown to be involved in the actions

vii
of PCP. BUTERBAUGH also involved the K+

 channel in the dosedependent convulsant and anticonvulsant actions of PCP. MORETON

elaborated on the specific electrophysiological responses to PCP

administration. JACOBSON has synthesized many components related

to PCP, one of which, metaphit, was able to bind at the PCP receptor and display responses similar to PCP itself. CONTRERAS showed

that metaphit had a dose-dependent effect on ataxia in rats acting

like both agonist and antagonist.

OWENS has prepared antibodies to PCP in goats. When administered

to mice the PCP levels in blood rose tenfold as an antibody-bound

form that was readily excreted in urine. BROWNE tested the selfadministration by rats of 1,000 compounds related (and not related) to PCP, some of which produced PCP-like effects. One compound

that was self-administered prevented the entrance of PCP into

brain. BALSTER gave a general review of the effects produced by

PCP in laboratory animals and showed that some effects were similar to those produced by amphetamine , some to barbiturates, and

some to antipsychotics. This response profile makes PCP a unique

drug that stands alone in its complex effects and toxicity.

An epidemiological report by CRIDER showed high PCP abuse in Los

Angeles, the Baltimore-Washington area and New York City, with

part of the increase due to higher use by inner-city black males.

WISH reported that urine tests on prison admissions show a high

use of PCP, alone or in combination with alcohol and cocaine, in

the New York City prison population. Signs of brain damage and

motor impairment were found by LEWIS in PCP users subjected to a

battery of psychological and motor tests. These subjects did not,

in general, have toxic responses to PCP, raising the question of

whether the symptoms preceded drug use. Many legal questions

arise from incidents occurring while the PCP user is under the

drug's influence or during psychotic episodes, including acts

committed by police or others trying to restrain the psychotic

individual. LERNER described three such cases that went to trial.

In the last section, clinicians discussed the treatment strategies

for PCP abusers. MCCARRON described the presenting symptoms in

prison admissions or emergency room admissions of over 1,000 PCP

abusers with PCP toxicity. She divided responses in adults into

four major patterns and suggested treatment for each group of

symptoms. GORELICK explored the reasons for choosing PCP for use

in a population entering a V.A. Hospital. The feelings of power,

invulnerability, and great strength, followed by dysphoria, were

the principal reasons. HOWARD showed the unfortunate condition of

babies born to mothers using PCP. The babies at birth were

smaller than usual, shaking and unconsolable. Some motor and

mental deficits were seen in some of these babies after 6 months

and 5 years. FRAM stated that the most successful treatment of

middle-class adolescent PCP abusers was in a peer-group meeting

attended daily. PAUL LUISADA of the Northern Virginia Institute

of Psychiatry summed up the Technical Review meeting in a masterly

fashion, blending basic and clinical reports into a coherent

viii
whole. Unfortunately, this off-the-cuff summary was not recorded

for publication.

Selecting from these presentations those that will prove most

useful in the future, either clinically or mechanistically, is not

easy. However, the potential value of some studies may be mentioned: (1) the separation and characterization of two PCP receptors; (2) the discovery of a naturally occurring brain substance

with which PCP competes; (3) the synthesis of a long-lasting PCP

analog; and (4) the successful preparation of antibodies to PCP.

Clinically, we may mention: (1) the discovery that motor and psychological deficits are found in PCP abusers; (2) the categorization of responses in man to psychosis-producing doses of PCP,

which has led to different treatment regimes depending on the

group of presenting symptoms; and (3) the relative success of

peer-group therapy programs in treating adolescent and young adult

PCP abusers.

The editor would like to thank the participants, all of whom

provided timely and complete reports in their areas of expertise,

and Dr. J. Michael Walsh (Division of Clinical Research) and

Nicholas J. Kozel (Division of Epidemiology and Statistical.

Analysis) who cochaired the Technical Review. Special thanks

go to Dr. R. Stanley Burns, who made a major contribution by

suggesting suitable clinical investigators.

Doris H. Clouet, Ph.D.

Neuroscience Research Branch

Division of Preclinical Research

ix

Contents

Foreword

Preface

Characterization of Phencyclidine and Sigma ReceptorBinding Sites in Brain

Andrew L. GundZach, Brian L. Lurgent, and

Solomon H. Snyder

Further Evidence of Phencyclidine/Sigma Opioid Receptor

Commonality

Ratna Sircar and Stephen R. Zukin

Isolation and Identification of an Endogenous Ligand

for the Phencyclidine Receptor

Debora A. DiMaggio, Patricia C. Contreras,

Remi Quirion, and Thomas L. O' Donohue

Phencyclidine (PCP) Selectively Blocks Certain Presynaptic

Potassium Channels

Mordecai P. Blaustein, Dieter K. Bartschat, and

Roger G. Sorensen

Involvement of Dopaminergic, Cholinergic, and Glutamatergic

Mechanisms in the Actions of Phencyclidine-Like Drugs

Kenneth M. Johnson and Lawrence D. Snell

Anticonvulsant Properties of Phencyclidine and Ketamine

Gary G. Buterbaugh and Hillary B. Michelson

Agonistic and Antagonistic Effects of PCP-Derivatives

and Sigma Opioids in PCP Behavioral and Receptor Assays

Patricia C. Contreras, Remi Quirion, and

Thomas L. O’Donohue

xi

Page

V

vii

1

14

24

37

52

67

80
Page

Electroencephalographic (EEG), Psychopharmacological,

and Receptor-Binding Profiles of 'Phencyclinoids'

Antonia Mattia, Arthur P. Leccese, Karen L. Marquis,

Esam E. El-Fakahany and J. Edward Moreton 94

Modulation of Phencyclidine (PCP) Pharmacokinetics

With PCP-Specific Fab Fragments

S. Michael Owens and Michael Mayersohn ll2

Psychopharmacology of Phencyclidine

Joe Marwah and David K. Pitts 127

Discriminative Stimulus Properties of PCP Mimetics

Ronald G. Browne 134

Clinical Implications of Behavioral Pharmacology Research

on Phencyclidine

Robert L. Balster 148

Phencyclidine: Changing Abuse Patterns

Raquel Crider 163

PCP and Crime: Just Another Illicit Drug?

Eric D. Wish 174

Neuropsychological Assessment of Phencyclidine Abusers

James E. Lewis and Robert B. Hordan 190

Phencyclidine Intoxication

Margaret M. McCarron 209

Diagnosis and Treatment of Chronic Phencyclidine (PCP)

Abuse

David A. Gorelick, Jeffrey N. Wilkins, and Carl Wong 218

Legal Issues Associated With PCP Abuse--The Role of the

Forensic Expert

Steven E. Serner and Richard S. Burns 229

The Long-Term Effects on Neurodevelopment in Infants

Exposed Prenatally to PCP

Judy Howard, Vickie Kropenske, and Rachelle Tyler 237

Clinical Observations in the Treatment of Adolescent

and Young Adult PCP Abusers

David H. Fram and Nancy Stone 252

List of NIDA Research Monographs 261

xii
Characterization of Phencyclidine

and Sigma Receptor-Binding Sites

in Brain

Andrew L. Gundlach, Brian L. Largent, and Solomon H. Snyder

INTRODUCTION

Introduced in the late 1950s as a dissociative anesthetic, phencyclidine (PCP) has since become a major drug of abuse. PCP has

strong, centrally mediated behavioral effects in animals and man

and influences many different neuronal systems. PCP inhibits the

uptake and increases the release of monoamines in brain (Smith et

al. 1977; Doherty et al. 1980; Vickroy and Johnson 1983; Marwaha

1982; Johnson and Snell, this volume), interacts with cholinergic

(Aronstam et al. 1980; Maayani et al. 1974) and serotonergic

(Nabeshima et al. 1984) systems and antagonizes the neuronal stimulation caused by the excitatory amino acid, N-methyl aspartate

(Anis et al. 1983). PCP may produce a general enhancement of neurotransmitter release by blocking voltage-sensitive potassium

channels (Blaustein and Ickowicz 1983; Blaustein et al., this

volume) and thus might act at several different loci.

Several groups have described specific receptor binding sites for

PCP in brain, with a pharmacological selectivity consistent with

effects of PCP and PCP analogues in animal behavioral tests

(Vincent et al. 1979; Zukin and Zukin 1979). Classical neurotransmitters and neuropeptides fail to interact with 3

H-PCP binding sites. However, recently, a putative endogenous ligand for

PCP receptor sites has been described (Quirion et al. 1984;

DiMaggio et al., this volume; Sircar and Zukin, this volume).

Psychotomimetic effects of certain opioids in man (Keats and

Telford 1964; Haertzen 1970) and unique behavioral effects of

these drugs in animals have suggested the existence of specific

receptor sites, designated sigma receptors (Martin et al. 1976).

Many pharmacological and behavioral effects of the "sigma benzomorphans," such as N-allylnormetazocine (SKF-10,047) and cyclazotine, are not blocked by opioid antagonists, such as naloxone or

naltrexone (Iwamoto 1981; Cowan 1981; Vaupel 1983; Young and

Khazan 1984), suggesting that these drugs interact at sites very

different from more classical opiate receptors. Furthermore,

1
other studies have suggested that the ability to produce "sigma"

or psychotomimetic-like behavioral effects resides more in the (+)

isomer of drugs such as SKF-10,047, with the (-) isomer being much

weaker or inactive (Brady et al. 1982; Slifer and Balster 1983;

Katz et al. 1985). This stereoselectivity is opposite to that at

opiate receptors.

Assays of tritium-labeled (+) and (-) SKF-10,047 binding to brain

membranes have suggested that the two isomers bind to distinct

sites with different pharmacological profiles and regional distributions (Martin et al. 1984). Other behavioral and biochemical

studies have suggested a commonality of effects of the sigma opioids and PCP and have suggested that these common actions are

mediated through a common receptor binding site (Zukin and Zukin

1981; Shannon 1983). However, the regional distribution and pharmacology of (+)3

H-SKF-10,047

sites labeled with 3

labeled sites appears to differ from

H-PCP (Tam 1983; Tam 1985; Martin et al.

1984).

3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) produces behavioral and biochemical effects in animals that are consistent with

its having agonist actions at dopamine autoreceptors (Hjorth et

al. 1981; Hjorth, et al. 1983; Arnt et al. 1983). However, in

vitro assays reveal 3-PPP as a weak inhibitor of dopamine release

and tyrosine hydroxylase activity, mechanisms thought to be under

dopamine autoreceptor control (Sminia and Mulder 1983; Markstein

and Lahaye 1983; Haubrich and Pflueger 1981; Mulder et al. 1985).

Recently, specific binding sites in brain for (+) 3H-3-PPP have

been described (Largent et al. 1984). These apparently nondopaminergic binding sites have a distinctive pharmacological profile

and regional distribution

tor sites labeled with (+)3H-SKF-10,047

similar to that of putative sigma recep-

(Tam 1983; Tam 1985;

Martin et al. 1984).

This study compares the pharmacological specificity and autoradiographic lotcalization of binding sites in brain for (+)3

H-SKF10,047, (+) 3

H-3-PPP and 3H-TCP (1-[l-(2-thienyl) cyclohexyl]

piperidine), a PCP analogue that labels PCP receptor sites with

high affinity (Vignon et al. 1983). Equilibrium-saturation and

drug-inhibition binding studies using rat brain homogenates reveal

that (+)3H-SKF-10,047 binds to two sites on brain membranes and

that (+)3H-3-PPP and 3H-TCP are selective radioligands for the

high and low affinity (+)3H-SKF-10,047 labeled sites respectively.

Autoradiographic studies reveal a similar distribution of (+)3H-3-

PPP and high affinity (+)3H-SKF-10,047 binding sites and the differential localization of these and 3

H-TCP (PCP-receptor) sites.

CHARACTERISTICS OF (+)3H-3-PPP, (+)3H-SKF-10,047 AND 3H-TCP

BINDING

Binding studies were carried out as previously described (Largent

et al. 1984), except that in experiments utilizing (+) 3

H-SKF10,047 or 3

H-TCP the incubation buffer was Tris pH 8.0 at a

2
concentration of 5 mM rather than 50 mM, as used in (+)3

H-3-PPP

studies. All three ligands bind saturably and with high affinity

to rat brain membranes. (+)3H-3-PPP binds with an apparent dissociation constant (KD) of 30 nM to a maximal number of binding

3

H-TCP

sites (Bmax) equal to 30 pmol/g wet wt (Largent et al. 1984).

(0.5 - 50 nM) binds to a single population of sites with a

KD of 8 ± 1 nM and a Bmax of 44 ± 4 pmol/g wet wt (n = 4). Computer-assisted analysis of saturation data suggests that (+)3

H-SKF10,047 labels two sites in brain membranes with KD values of 42 ±

12 and 615 ± 430 nM and Bmax values of 18 ± 7 and 80 ± 25 pmol/g

wet wt (n = 5) (see figure 1). In the presence of haloperidol (5

μM), a potent inhibitor of high affinity (+)3H-SKF-10,047 binding

(see figure 2), (+)3H-SKF-10,047 labels a single low affinity site

(KD, 300 ± 24 nM) with a Bmax of 74 ± 18 pmol/g wet wt (n = 3).

PHARMACOLOGY OF (+)3H-3-PPP, (+)3H-SKF-10,047 and (+)3H-TCP

BINDING

The drug specificity of sites labeled by (+)3H-3-PPP has been extensively described previously (Largent et al. 1984) with binding

being potently inhibited by haloperidol, phenothiazines such as

perphenazine and psychotomimetic opioids such as pentazocine, SKF10,047, and cyclazocine (see table 1). Stereoselectivity for different isomers of drugs at the binding site is seen for 3-PPP and

many opioid derivatives, with the (+) isomer being a more potent

inhibitor than its corresponding (-) isomer. However, little

stereoselectivity occurs for isomers of PCP-like drugs, with dexoxadrol and levoxadrol having similar potency (see table 1).

Furthermore, other potent PCP analogues have very low affinity for

(+) 3H-3-PPP labeled sites (data not shown).

3

H-TCP binding is inhibited potently by PCP and is stereoselective, with the potency of dexoxadrol exceeding that of levoxadrol

by a factor of 400, in contrast to that seen at (+)3H-3-PPP

labeled Sites. Benzomorphans differ widely in their potency

against 3H-TCP binding with (+)SKF-10,047 being eight-fold more

potent than pentazocine, a reversal of their relative potencies at

(+)3

H-3-PPP labeled sites. Haloperidol and (+)3-PPP are very weak

inhibitors of 3H-TCP binding (see table 1).

The drug inhibition profile of (+)3H-SKF-10,047 binding is similar

in many ways to that of (+)3H-3-PPP binding, but has some important differences. While pentazocine and SKF-10,047 are both

potent inhibitors of (+)3

H-SKF-10,047 binding, haloperidol and

(+)3H-3-PPP inhibit only a portion of total specific (+)3H-SKF10,047 binding with high potency (see figure 2 and table 1). If

(+)3H-SKF-10,047 binding is measured in the presence of 5μM

haloperidol to block binding to the haloperidol/(+)3-PPP-sensitive

sites, the drug specificity of the remaining specific binding is

similar to that for 3H-TCP binding (see table 1). The decreased

potency of pentazocine and the higher potencies of phencyclidine

and dexoxadrol against (+)3H-SKF-10,047 binding, relative to

their potencies at (+)3H-3-PPP sites, merely reflects the

3
contribution of the low-affinity PCP-like sites to the total specific (+)3

H-SKF-10,047 binding (see table 1). Although overall

IC50 values are given in table 1, inhibition of (+)3H-SKF-10,047

binding by drugs such as phencyclidine and pentazocine is consistent with displacement of binding from two sites (see figure 2).

FIGURE 1. Scatchard plot of equilibrium-saturation binding of

(+)SKF-10,047 to rat brain membranes. Membranes were

incubated with 8 nM (+)3H-SKF-10,047 and various concentrations (1 - 64,000 nM) of (+)SKF-10,047 for 45

min at room temperature. Results are from a single

experiment and values are the average of duplicate

determinations. Lines indicate the high (K D 45 nM;

Bmax 22 pmol/g) and low (K D 110 nM; Bmax 86 pmol/g)

affinity components of total specific binding. Also

shown is the computer-generated curve of best fit for

the data points.

4
FIGURE 2. Drug inhibition of (+)3H-SKF-10,047 binding to rat

brain membranes. The data shown are from a typical

experiment and represent the mean of duplicate determinations, replicated twice. Lines represent

computer generated curves of best fit for drug displacement from one site (haloperidol , Ki

 4 nM) or

two sites (pentazocine , Ki values 13 and 1550 nM;

phencyczidine , Ki values 31 and 457 nM).

AUTORADIOGRAPHIC LOCALIZATION OF (+)3H-3-PPP, (+)3H-SKF-10,047 AND

3H-TCP BINDING SITES

Studies of the regional distribution of (+)3H-3-PPP binding sites

in brain homogenates reveals highest levels in the hindbrain, midbrain, cerebellum, and hypothalamus, with lower levels in cerebral

cortex, corpus striatum, and olfactory tubercle. Similar studies

reveal high levels of (+)3H-SKF-10,047 binding site in hypothalamus, midbrain, pons, and medulla (Tam 1985), while 3

H-PCP binding

is highest in hippocampus and cerebral cortex (Zukin and Zukin

1979). Autoradiographic studies provide details of these binding

site localizations and alloy a better comparative analysis of the

structures labeled by each 3H-ligand. Slide mounted brain sections (8 microns) were incubated with 5 nM (+)3

H-3-PPP, 10 nM

(+)3H-SKF-10,047, or 5 nM 3H-TCP for 45 minutes at room temperature, washed in buffer for the appropriate amount of time, rinsed

in water, and dried. Autoradiograms were produced by apposing the

labeled brain sections to tritium-sensitive film for 3 to 5 weeks

at 4°C.

5
TABLE 1. Drug inhibition of specific binding of various 3Hligands to sigma and PCP receptor sites in brain

IC5 0 (nM)

(+) 3 H-SKF-10,047

Drug (+) 3 H-3-PPP (+) 3 H-SKF-10,047 (+ 5μH haloperidol) (+) 3H-TCP

(+)SKF-10,047 340 ± 30 75+ 3 375 + 30 420 ± 7

(-)SKF-10,047 1350 ± 110 895 ± 175 530 ± 25 840 ± 35

(+)3-PPP 30 ± 2 49 + 6 * >100,000 >100,000

Haloperidol 2 ± 1 5 ± 1 *

23± 285 ±

>50,000 >50,000

Pentazocine 2 50 1520 ± 220

Phencyclldine 710 ± 330 ± 48 ± 12

3,200

85 40 63 ± 6

Dexoxadrol 1880 ± 510 569 ± 140 46 ± 9 42 ± 5

Levoxadrol 2080 ± 490 3790 ± 70 9,500 17,000

NOTE: Membranes were Incubated with 10-12 concentrations of drug and 2-4 nM

(+)3H-J-PPP, 8-10 nM (+)3H-SKF-10,047, or 1-3 nM 3H-TCP respectively. The

IC50 (concentration that inhibited 50% of specific binding) was calculated

using an iterative curve fitting program (McPherson 1983). Nonspecific

binding was determined in the presence of 1 μM haloperidol for (+)3H-3-PPP,

100μM PCP for (+)3H-SKF-10,047, and 100 μM (+)SKF-10,047 for 3

H-TCP.

*IC50 values for (+)3-PPP and haloperidol against the portion of specific (+)3HSKF-10,047 binding displaceable by these drugs.

(+)3H-3-PPP labels a number of different areas in the brain, including a major group of structures associated with the limbic

system, and another with the brainstem motor-regulatory system.

Binding sites are concentrated in the pyramidal cell layer of the

hippocampus and the granular layer of the dentate gyrus, with lower levels in the remaining hippocampal areas (see figure 3). Most

of the cerebral cortex has low levels of binding, but the pyramidal cell layer of the pyriform cortex and a superficial layer of

the cingulate cortex have higher levels. The hypothalamus, septal

nuclei, diagonal band, and central grey also display high amounts

of (+)3H-3-PPP binding sites. Likewise several cranial nerve

nuclei, reticular, and pontine nuclei all have high levels of

binding. In the cerebellum the Purkinje and granule cell layers

are heavily labeled, while high levels are also seen in the deep

cerebellar nuclei and vestibular nuclei (see figure 4).

The distribution of 3H-TCP labeled sites is similar to that described previously for 3

H-PCP (Quirion et al. 1981). Binding is

densest in cortical regions, the strata oriens and radiatum of the

hippocam us and the molecular layer of the dentate gyrus (see

figure 3). There is negligible binding over the pyramidal cell

layer of the hippocampus and the granular layer of the dentate

gyrus. Moderate levels of binding sites are present in thalamic

areas, the corpus striatum, nucleus accumbens, olfactory tubercle,

septum, and interpeduncular nucleus, while low levels are found

throughout the cerebellum, pons-medulla, midbrain, and hypothalamus (see figures 3 and 4).

6
FIGURE 3. Autoradiograms of (+)3H-3-PPP, (+)3H-SKF-10,047 and 3HTCP binding sites in coronal sections of guinea pig

brain. Increased grain density is indicated by

increased whiteness in the photograph. Distribution

of (A) (+) 3H-3-PPP sites, (B) (+) 3H-SKF-10,047 sites,

(C) 3H-TCP sites. Nonspecific binding of each ligand

was not significantly above film background to yield

an image at a comparable exposure. Cingulate cortex,

CC; dentate gyrus, DC; hippocampus, Hi (pyramidal

Cell layer, arrows; Stratum oriens, asterisks); ventral thalamus, VT; zona incerta, Zi. (Bar = 2 mm).

7
FIGURE 4. Autoradiograms of (+)3H-3-PPP, (+)3H-SKF-10,047

and 3H-TCP binding sites at the level of the midbrain

(A-C) and cerebellum/hindbrain (D-F). (+)3H-3-PPP

binding is highest in the pontine nuclei and central

grey (A), over the Purkinje and granular layers of

the cerebellum and to cranial nerve nuclei (D). The

distribution of (+) 3H-SKF-10.047 bindina sites is

similar to that for, (+) 3H-3-PPP (B,E). Very low

levels of 3H-TCP associated arains are found at the

level of the cerebellum and pons-medulla (C,F).

Central grey, CG; cerebellum, Purkinje cell layer,

arrows; entorhinal cortex, EC; facial nucleus, Fn;

pontine nuclei Pn; Superior colliculus, SC; vestibutar nuclei, Ve. Bar = 2 mm.

8
In several brain areas the distribution of (+)3

H-SKF-10,047 binding sites is strikingly similar to that of (+)3

H-3-PPP labeled

sites.

PPP

Structures labeled by both (+)3H-SKF-10,047 and (+)3H-3-

(but not by 3H-TCP) include the pyramidal cell layer of the

hippocampus, the granular layer of the dentate gyrus, the Purkinje

cell layer of the cerebellum, cranial nerve and pontine nuclei,

the central grey, the zona incerta and hypothalamic areas, among

others (see figures 3 and 4). Additionally, (+)3

H-SKF-10,047

labels to some extent certain brain areas labeled heavily by 3HTCP, but not by (+)3

H-3-PPP. These include the thalamus, olfactory tubercle, and nonpyramidal layers of the hippocampus. One complicating methodological problem associated with (+)3

H-SKF-10,047

binding to brain slices is the somewhat low affinity of specific

binding and high levels of nonspecific binding of the ligand,

which makes interpretation of the autoradiograms more difficult.

Initial attempts to examine sites labeled by (+)3H-SKF-10,047

which are lower affinity and not labeled by haloperidol or (+)3H3-PPP, failed to produce visually convincing images. However,

depletion of the concentrated binding over the pyramidal cell

layer of the hippocampus, Purkinje cell layer of the cerebellum,

and cranial nerve nuclei was apparent (data not shown). Likewise,

examination of (+) 3H-SKF-10,047 binding in the presence of a drug

selective for PCP sites should give further confirmation of the

similarity of high affinity (+)SKF-10,047 and (+)3-PPP/haloperidol

labeled sites.

CONCLUSIONS

These studies have implications for research on both PCP and psychotomimetic opioids, as well as perhaps dopaminergic function. A

major finding, which goes against previous suggestions, is that

PCP and psychotomimetic opioid binding sites in brain are not

identical with regard to pharmacology or distribution, at least

when examined in an in vitro system. The benzomorphan, (+)SKF10,047, labels at least two populations of nonopiate sites in

brain. Sites for which (+)SKF-10,047 has higher affinity have a

characteristic pharmacology having high affinity and selectivity

for benzomorphans, haloperidol, and (+)3-PPP (this study, see also

Martin et al. 1984; Tam 1985). Their distribution can be visualized autoradiographically, revealing high levels in hypothalamus,

midbrain, cerebellum, pons, and medulla. Overall, the pharmacology and distribution of (+)3-PPP labeled sites and high affinity

(+)SKF-10,047 sites are very similar, suggesting that these drugs

at least label the same receptor-binding site complex, although

there is not, as yet, conclusive evidence that they label the

exact same site on the molecule. Further studies examining possible allosteric interactions and agonist-antagonist roles of the

two types of drug are required to decide this issue.

The relative selectivity of drugs such as haloperidol for the

higher affinity (+)SKF-10,047 labeled sites allowed the determination of the pharmacological profile of the low affinity sites,

which was very similar to that of 3H-TCP labeled sites. PCP and

9
PCP analogues had high affinity for the haloperidol-insensitive

(+)SKF-10,047 binding, and stereoselectivity for dexoxadrol over

levoxadrol was greater than that seen against total specific

(+) 3H-SKF-10,047 binding.

Although PCP has high affinity for 3H-TCP labeled sites, it also

has moderate potency against (+)3H-3-PPP and (+)3H-SKF-10,047

binding, suggesting that it may still have pharmacological activity at these sites, in vivo, when present at appropriate concentrations. This may explain the apparent contradiction between these

in vitro results, revealing different binding sites for these two

groups of drugs and differences in distribution of these sites,

and the evidence cited in the introduction to this study, from in

vivo behavioral and biochemical studies, which demonstrates common

actions of PCP ard psychotomimetic opioids. For example, the number and regional concentration of PCP binding sites in the ponsmedulla and hypothalamus is lower than that of (+)SKF-10,047 (and

(+)3-PPP) sites in these same areas. Yet both SKF-10,047 and PCP

produce effects-on cardiovascular parameters (Vaupel 1983), presumably through central actions at cardiovascular regulatory loci

in these brain areas. Furthermore, in light of the common psychotic effects of PCP and SKF-10,047, it is possible that sites

that are labeled by both PCP (TCP) and (+)SKF-10,047 such as in

nonpyramidal cell areas of the hippocampus and in cortex may represent at least some of the sites at which these drugs mediate

these effects. However, it is also possible that sites labeled

with high affinity by (+)SKF-10,047 (and (+)3-PPP) throughout the

brain, particularly in the hippocampus, hypothalamus, and brainstem reticular formation, are "psychotomimetic sites."

Experiments based on our results could be conducted to test the

physiological and pharmacological relevance of these findings.

Autoradiographic mapping studies should assist future work towards

this end, as they provide new information that allows "sitedirected experiments." The examination of the effects, in vivo

and in vitro, of sigma and/or PCP drugs on biochemical, physiological, and behavioral parameters in discrete brain areas will best

improve our knowledge of the true sites and mechanisms of action

of PCP-like and psychotomimetic opioid drugs.

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ACKNOWLEDGEMENTS

This work was supported by USPHS grant DA-00266 and Research

Scientist Award DA-00074 to S.H.S., National Institutes of Health

Traning Grant GM-07626 to B.L. Largent, and a grant from the

McKnight Foundation. A.L. Gundlach is the recipient of a National

Health and Medical Research Council (Australia) C.J. Martin

Fellowship.

AUTHORS

Andrew L. Gundlach, Ph.D.

Brian L. Largent, B.S.

Solomon H. Snyder, M.D.

Departments of Neuroscience, Pharmacology and Experimental

Therapeutics, Psychiatry and Behavioral Sciences

The Johns Hopkins University School of Medicine

725 North Wolfe Street

Baltimore, MD 21205

13
Further Evidence of

Phencyclidine/Sigma Opioid

Receptor Commonality

Ratna Sircar and Stephen R. Zukin

Phencyclidine (1-[1-phenylcyclohexyl]piperidine HCl; PCP) and its

active derivatives produce unique behavioral effects in animals

and psychotomimetic effects in humans. Drugs of this class have

been demonstrated to bind saturably, reversibly, and with high affinity to specific binding sites in brain (Hampton et al. 1982;

Quirion et al. 1981; Sircar and Zukin 1983; Vincent et al. 1979;

Zukin and Zukin 1979). These sites have been shown to exhibit a

characteristic heterogeneous regional distribution pattern

(Quirion et al. 1981; Sircar et al., submitted for publication;

Zukin and Zukin 1979) distinct from that of any other receptor

type.

A variety of evidence suggests that PCP-like drugs and sigma

opioids may bring about their common behavioral effects via activation of the same receptors. The existence of sigma opioid receptors was postulated by Martin to account for the behavioral pharmacology of the drug N-allylnormetazocine (SKF-10,047) and related

benzomorphans, such as cyclazocine, which can produce psychosis in

humans and "canine delirium," tachycardia, and tachypnea in animals (Martin et al. 1976). Sigma opioid receptors differ from mu,

delta, and kappa receptors in terms of ligand selectivity. Specific sigma receptor ligands, such as (+)SKF-10,047, have very little affinity for mu, delta, or kappa receptors (Zukin et al.

1984), while prototypic mu, delta, and kappa opioids exhibit little or no affinity for sigma opioid receptors (Zukin and Zukin

1981a). Sigma opioid receptors labeled by 3

H-cyclazocine (ibid.)

or 3H-(-)SKF-10,047 (Zukin et al., submitted for publication) in

homogenate binding studies under conditions blocking radioligand

access to mu, delta, and kappa opioid receptors do, however, exhibit a ligand selectivity pattern in which not only sigma opioids

but also PC and its derivatives are active. Similarly, receptors

labeled by 3H-PCP exhibit high affinity for sigma opioids (Zukin

et al. 1983). Regional distributions of 3

H-PCP and 3H-cyclazocine

homogenate binding are similar (Zukin and Zukin 1981a). Behavioral studies utilizing the drug discrimination paradigm (Shannon

1981; Shannon 1982; Teal and Holtzman 1980; Holtzman 1980; Brady

et al. 1982; Katz et al. 1985) have demonstrated cross-generaliza14
tion between PCP derivatives and sigma opioids. Such biochemical

and behavioral findings have suggested the hypothesis that the

sigma opioid and PCP receptors may represent the same entity

(Zukin and Zukin 1981b; Quirion et al. 1981).

A problem in previous studies of sigma opioid receptors has been

that racemic or (-) sigma opioid isomers interacted at multiple

opioid receptor sites, requiring special blocking techniques to

permit targeting of sigma receptors (Zukin and Zukin 1981b). The

(+) isomers of sigma opioids, essentially devoid of mu, delta, and

kappa activity (Zukin et al. 1984), thus seemed the ligands of

choice for studies of sigma opioid receptors. This report documents the binding characteristics of 3

H-(+)SKF-10,047 to rat and

mouse brain.

Among PCP derivatives, TCP (N-(1-[2-thienyl]cyclohexyl)piperidine)

has been shown to be more potent than PCP itself (Vincent et al.

1979; Zukin and Zukin, 1979). In homogenate binding studies 3H-TCP

binds to brain PCP receptor sites more potently than 3H-PCP

(Vignon et al. 1983). Such findings raise the possibility that

3

H-TCP might prove a superior molecular probe of PCP/sigma opiate

receptors.

In this chapter, the binding characteristics of the prototypical

sigma opioid H-(+)SKF-10,047 are described, and the quantitative

localization patterns of bits binding sites in brain are compared

with those of 3H-PCP and 3H-TCP, the prototypic PCP receptor

ligands, to address the questions of the extent and nature of

PCP-sigma opioid receptor commonalities, and which radioligands

constitute the best molecular probes of brain PCP/sigma opioid

receptors.

CHARACTERIZATION OF 3H-(+)SKF-10,047 BINDING IN RAT BRAIN

Specific binding of 3H-(+)SKF-10,047 proved saturable with respect

to increasing radioligand concentration. Scatchard analysis of

3

H-(+)SFK-10,047 binding gave a curvilinear plot suggestive of multiple 3

H-(+)SKF-10,047 binding sites or cooperativity of binding.

Computer-assisted analysis (Munson and Rodbard 1980) revealed the

best fit to be to a two-site model with apparent KD values of 3.6

nM and 153 nM, and BMax values of 40 fmol and 1.6 pmol/mg protein

for the apparent high- and low-affinity binding sites, respectively. Scatchard analysis of complete binding isotherms in each

of the four dissected brain regions (hippocampus, frontal cortex,

cerebellum and pons-medulla) similarly gave curvilinear plots,

which, in each case, displayed a good fit to a two-site model. For

each of these regions, as well as for the whole-brain preparation,

a valid fit to a one-site model could not be obtained (Sircar and

Zukin, in press).

3

H-(+)SKF-10,047 binding was also measured in the presence of 100

nM haloperidol. This approach yielded a Scatchard plot in which

the density of the apparent high-affinity sites was decreased by

15
greater than 90 percent (to 0.5 fmol/mg protein) relative to the

value obtained in the absence of haloperidol, while the density of

the apparent low-affinity binding sites showed little alteration

(1.08 pmol/mg protein). This finding suggested that the curvilinear Scatchard plot was the result of independent interactions

of 3H-(+)SKF-10,047 with two distinct binding sites. To test this

hypothesis, ligand selectivities of the two apparent classes of

sites were characterized. The rank order of potency (PCE>dexoxadrol>PCP>pentazocine>ketamine>levoxadrol) of ligands for displacement of 100 nM 3

H-(t)SKF-10,047 from the predominant lower-affinity sites (in the presence of 100 nM haloperidol) was similar to

that reported for displacement of 3H-PCP (Zukin and Zukin 1979;

Zukin et al. 1983). By contrast, the rank order of drugs inhibiting the binding of 3

H-(+)SKF-10,047 to the higher-affinity site

(haloperidol>dexoxadrol>pentazocine>PCP>levoxadrol) proved distinct from the pattern for PCP receptors.

CHARACTERIZATION OF 3H-(+)SKF-10,047 BINDING SITES IN MOUSE BRAIN

To assess possible species specificity of our findings, 3H-(+)SKF10,047 binding was carried out in mouse brain. Scatchard analysis

of the binding data resulted in a biphasic Scatchard plot similar

to that observed in rat brain. Computer-assisted analysis of the

apparent two-site fit of the binding data yielded apparent KD values of 4 and 227 nM, and BMax values of 86 fmol and 3.8 pmol/mg

protein, respectively. As in the rat, 100 nM haloperidol significantly reduced the high-affinity site while leaving

ity site unaffected.

 the low-affinOur finding of two distinct 3

H-(+)SKF-10,047

binding sites in mouse as well as rat brain is at variance with a

recent study (Martin et al. 1984), which had reported mouse brain

to possess a homogeneous population of haloperidol-sensitive 3H-

(+)SKF-10,047 binding sites. It may be that our extending the

binding isotherm to higher radioligand concentrations (500 nM for

our study as opposed to 100 nM for Martin et al.) was responsible

for revealing the lower-affinity PCP/sigma opioid receptors.

VISUALIZATION OF PCP/SIGMA OPIOID RECEPTORS BY LIGHT HICROSCOPY

AUTORADIOGRAPHY

The quantitative distribution patterns of PCP/sigma opioid receptors identified here from 3

H-TCP autoradiograms(Sircar and Zukin,

in press), 3

H-(+)SKF-10,047 autoradiograms and 3H-PCP autoradiograms (Sircar et al., submitted for publication) were remarkably

similar (table l), and resembled the qualitative pattern of 3H-PCP

binding sites previously reported (Quirion et al 1981). Hippocampus was the most heavily labeled region in all 3 autoradiograms

(figure 1). Dentate gyrus and hippocampal fields CA1 and CA2 were

noticeably darker than hippocampal field CA3 in PCP, TCP and

(+)SKF-10,047 autoradiograms. Distinct laminar patterning in the

hippocampus was seen with PCP and TCP, while lamination was less

distinct in the case of (+)SKF-10,047. Diencephalic structures

manifested moderate to low amounts of binding. In the thalamic

region, the intermediodorsal nucleus had the highest concentration

16
of both 3

H-PCP and 3H-(+)SKF-10,047 binding, while in the hypothalamus the dorsomedial nucleus had the highest levels of both.

Midbrain/pontine areas also showed moderate to low levels of 3

H -

PCP and 3H-(+)SKF-10,047 binding. The superficial layer of the

superior colliculus was substantially darker than the deeper layers.

both 3H-PCP and 3H-(+)SKF-10,047 binding was the interpeduncular

Another region in this area showing high concentrations of

nucleus. Cerebellym had moderate levels of PCP binding, but fairly high levels of 3

H-(+)SKF-10,047 binding. In comparison, there

were significantly lower levels of 3H-TCP binding in central gray,

TABLE 1. Receptor density values obtained from autoradiograms

labeled with 3H-PCP, 3H-TCP and 3H-(+)SKF-10,047 in

rat brain

Receptor Density (fmol/mg Tissue)

Anatomical Region PCP TCP (+)SKF-10,047

Hippocampus 296 91

CA 1 284 104

CA 2 272 105

CA 3 225 66

Dentate 378 111

Dorsomedial hypothalamus 284 40

Superior colliculus 260 65

Interpeduncular n. 248 40

Frontal cortex 225 83

Basolateral amygdaloid n. 225 42

Substantia nigra 225 1 4

Central gray 213 2 6

Nucleus accumbens 177 52 94

Cerebellum 154 47

Locus coeruleus 154 46

Striatum 154 46 94

Pons reticular formation 12 8

Corpus callosum 0 0

194

194

211

167

194

156

128

117

128

117

139

161

139

134

78

0

NOTE: 20-Micron sectlons from specific regions of rat brain were prepared and incubated with 10 nM H-PCP (49.9 Cl/mnol), 5 nM 3

H-TCP (58.2 Cl/mmol) and 10

nM 3H-(+)SKF-10.047 (25.5 Cl/mmol) respectively. Sections were juxtaposed

against trltlum-sensltlve film along with tritium standards, and-optical

densities determined (Geary and Wooten 1983: Kuhar 1982: Sircar and Zukin.

in press; Tempel et al. 1984). Optical density values from different brain

regions were converted to receptor densities (nCl/mg tissue) using the

tritium standards. The receptor density values have been expressed in

fmol/mg tissue using the formula:

CI/mg tissue

speclflc actlvity

= mmol/mg tissue.

Values represent mean readings from six sections for each region, derived

from two Independent experiments. Readings have been normalized to nonspecific binding and to blank tissue.

1 7
FIGURE 1. Anatomical distrubtion of 3H-PCP, 3H-TCP,

and 3H-(+)SKF-10,047 bindings in rat brain

NOTE: Brain sections are at the level of bregma -3.8 mm of the rat

brain atlas (paxinos and Watson 1982). 20-Micron thick coronal sections of frozen rat brain were cut, thaw-mounted onto

gelatin-coated slides, and incubated with (a) 10 nM 3H-PCP

(49.9 Ci/mmol) for 45 minutes; (b) 5 nm 3H-TCP (58.2 Ci/mM)

for 1 hour; (c) 10 nM 3H-(+)SKF-10,047 (25.5 Ci/mmol) for 1

hour. Adjacent sections were incubated with the same radioligand concentrations, but in the presence of 1,000-fold excess of nonlabeled PCP, TCP or (+)SKF-10,047, respectively,

for nonspecific binding. Sections were washed, dried, and

exposed to tritium-sensitive film for 2 to 6 weeks. Note the

dense labeling in CA1, CA2, and dentate gyrus of the hipocampus with all three radioligands. TeUnlike PCP and TCP,

(+)SKF-10,047 labeled stratum pyramidale.
substantia nigra, dorsomedial hypothalamus, and interpeduncular

nucleus. PCP is known to bind very weakly to mu opiate receptors

(Vincent et al. 1978) but this property is not related to its discriminative stimulus behavioral effects or to its interaction with

PCP/sigma opiate receptors. Areas such as central gray, substantia nigra, and interpeduncular nucleus are known to be rich in mu

opiate receptors (Herkenham and Pert 1982). The fact that 3H-TCP

does not bind significantly in these areas suggests that, besides

being a more potent analog of PCP than PCP itself (Vignon et al.

1983), it may also be a more specific PCP/sigma opioid receptor

ligand, devoid of significant cross-activity at other classes of

receptors.

The remarkable similarity in the regional distribution of binding

sites for the arylcyclohexylamines PCP and TCP and those of the

chemically unrelated benzomorphan (+)SKF-10,047 supports the

hypothesis that PCP derivatives and sigma opioids may act via a

common receptor site. The sigma opioid/PCP receptors are concentrated primarily in the limbic areas of the brain, including hippocampus, amygdala, striatum, and frontal cortex--regions that are

involved in higher nervous functions, including memory, emotion,

and behavior (Kimura 1958; Milner 1968). Autoradiograms obtained

with 3H-(-)SKF-10,047 in the presence of mu and delta blockers

(Zukin et al., Submitted for publication are generally similar to

those obtained with 3H-( +)SKF-10,047 or 3

H-PCP. By contrast

to 3H-PCP, 3H-TCP, and 3

H-(+)SKF-10,047 autoradiograms, 3H-

(-)SKF-10,047 autoradiograms show striosomes in the striatum and

denser labeling in central gray, locus coeruleus, and nucleus

accumbens, whereas hippocampus showed a lower relative concentration of 3

H-(-)SKF-10,047 binding. 3H-(-)SKF-10,047 may thus label

not only sigma opioid/PCP receptors, but also residual mu opioid

receptors and other binding sites as well, perhaps including the

haloperidol-sensitive sites described above. The differences between the autoradiographic patterns of 3

H-PCP and 3H-(+)SKF-10,847

binding in the present study probably arise from the fact that 3HPCP, which gives a Scatchard analysis indicative of a single highaffinity site in binding studies (Vincent et al. 1979; Zukin and

Zukin 1979; Quirion et al 1981; Mendelsohn et al. 1984) reveals

the pattern of its homogenous class of PCP/sigma opioid receptors

in autoradiograms, while 3H-(+)SKF-10,047, which we have shown in

this study to bind to two independent sites, reveals the autoradiographic pattern of the pattern of PCP/sigma opioid receptors

plus that of the haloperidol-sensitive binding sites.

Our results suggest that the numerically predominant 153 nM 3H-

(+)SKF-10,047 site represents the PCP opioid receptor. The much

less abundant haloperidol-sensitive 3.6 nM 3H-SKF-10,047 binding

site that we have described appears to represent the same entity

as a class of sites reported by several other groups utilizing diverse strategies, including use of

3

H-SKF-10,047 in the presence

of etorphine (Su 1982); 3

H-ethylketoSyclazocine

ence of excess naloxone (Tam 1983);

(EKC) in the pres3

H-(+)SKF-10,047 or (+)3Hhaloperidol in guinea pig brain (Tam and Cook 1984); (+)3

H-3-PPP

19
(3-(3-hydroxyphenyl)-N-(1-propyl)piperidine) or 3

H-haloperidol

(Largent et al. 1984); 3H-EKC or 3H-SKF-10,047 in cultured NCB20

cells (McLawhon et al. 1981; West et al. 1983); and 3

H-(+)SKF10,047 in mouse brain (Martin et al. 1984). The pattern of areas

where we have found relatively higher 3H-(+)SKF-10,047 than 3H-PCP

binding, including central gray and cerebellum, is consistent with

areas enriched in (+)3H-3-PPP binding (Largent et al. 1984). As

noted above, the latter radioligand labels sites identical to the

haloperidol-sensitive 3

H-(+)SKF-10,047 sites but distinct from

3

H-PCP sites (ibid.). The behavioral significance of the haloperidol-sensitive (sigma) sites remains unknown. The striking

PCP-like behavioral effects of (+)SKF-10,047 thus appear to be

mediated at the haloperidol-insensitive sites, as well as at haloperidol-sensitive sites.

Because of its interactions with multiple binding sites, 3H-

(+)SKF-10,047 does not appear to be the ideal ligand for labeling

PCP/sigma opioid receptors in binding assays. While its interaction with the non-PCP/sigma opioid sites can

sion of haloperidol in the incubation medium,

be blocked by inclu3

H-TCP, which binds

exclusively and more potently to the nonhaloperidol-sensitive sigma opioid/PCP receptors (Vignon et al. 1983; Sircar and Zukin, in

press), is clearly preprable to 3

H-(+)SKF-10,047 for targeting

these sites. Indeed, 3

H-TCP appears to be the best ligand of

PCP/sigma opioid receptors currently available.

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L.S.; and Everette, M.L. Stereoisomers of 3

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Gilbert, P.E. The effects of morphine- and nalorphine-like

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McLawhon, R.W.; West, R.E., Jr.; Miller, R.J.; and Dawson, G.

Distinct high-affinity binding sites for benzomorphan drugs and

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Acad Sci USA. 78:4309-4313, 1981.

Mendelsohn, L.G.; Kerchner, G.A.; Kalra, V.; Zimmerman, D.M.; and

Leander, J.D. Phencyclidine receptors in rat brain cortex.

Biochem Pharmacol 33:3529-3535, 1984.

Milner, B. Visual recognition and recall after right temporal

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Munson, P.J., and Rodbard, D. LIGAND: A versatile computerized

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Quirion, R.R.; Hammer, P., Jr.; Herkenham, M.; and Pert, C.B. The

phencyclidine (angel dust)/sigma "opiate" receptor: Its visualization by tritium-sensitive film. Proc Natl Acad Sci USA

78:5881-5885, 1981.

Shannon, H.E. Evaluation of phencyclidine analogs on the basis of

their discriminative stimulus properties in the rat. J

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Shannon, H.E. Pharmacological analysis of the phencyclidine-like

discriminative stimulus properties of narcotic derivatives in

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Sircar, R., and Zukin, S.R. Characterization of specific sigma

opiate/phencyclidine (PCP) binding sites in the human brain.

Life Sci 33(1):259-262, 1983.

Sircar, R., and Zukin, S.R. Visualization of 3

H-TCP binding in

rat brain by quantitative light-microscopy autoradiography.

Brain Res, in press.

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Characterization and autoradiographic visualization of 3H-

(+)SKF-10,047 binding in rat and mouse brain: Further evidence

for sigma opioid/phencyclidine receptors commonality. Submitted

for publication.

Su, T.P. Evidence for sigma opioid receptor: Binding of 3

H-SKF10,047 to etorphine-inaccessible sites in guinea-pig brain. J

Pharmacol Exp Ther 223:284-290, 1982.

Tam. S.W. Naloxone-inaccessible sigma receptor in rat central

nervous system. Proc Natl Acad Sci USA 80:6703-6707, 1983.

21

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Tam, S.W., and Cook, L. Sigma opiates and certain antipsychotic

drugs mutually inhibit (+)3H-SKF-10,047 and 3H-haloperidol binding in guinea-pig brain membranes. Proc Natl Acad Sci USA

81:5618-5621, 1984.

Teal, J.J., and Holtzman, S.G. Discriminative stimulus effects of

cyclazocine in the rat. J Pharmacol Exp Ther 212:368-376, 1980.

Tempel, A.; Gardner, E-L.; and Zukin, R.S. Visualization of opiate receptor upregulation by light microscopy autoradiography.

Proc Natl Acad Sci USA 81:3893-3897, 1984.

Vignon, J.; Chicheportiche, R.; Chicheportiche, M.; Kamenka, J.M.;

Geneste, P.; and Lazdunski, M. 3

H-TCP: A new tool with high

affinity for the PCP receptor in rat brain. Brain Res

280:194-197, 1983.

Vincent, J.P.; Cavey, D.; Kamenka, J.M.; Geneste, P.; and

Lazdunski, M. Interaction of phencyclidine with the muscarinic

and opiate receptors in the central nervous system. Brain Res

152:176-182, 1978.

Vincent, J.P.; Kartalovski, B.; Geneste, P.; Kamenka, J.M.; and

Lazdunski, M. Interaction of phencyclidine ("angel dust") with

a specific receptor in rat brain membranes. Proc Natl Acad Sci

USA 76:4678-4682, 1979.

West, R.E., Jr.; McLawhon, R.W.; Dawson, G.; and Miller, R.J. 3

Hethylketocyclazocine binding in NCB-20 hybrid neurotumor cells.

Mol Pharmacol 23:486-492, 1983.

Zukin, R.S., and Zukin, S.R. Demonstration of 3

H-cyclazocine

binding to multiple opiate receptor sites. Mol Pharmacol

20:246-254, 1981a.

Zukin, R.S., and Zukin, S.R. Multiple opiate receptors: Emerging

concepts. Life Sci 29:2681-2686, 1981b.

Zukin, S.R., and Zukin, R.S. Specific 3

H-phencyclidine binding in

rat central nervous system. Proc Natl Acad Sci USA

76:5372-5376, 1979.

Zukin, S.R.; Brady, K.T.; Slifer, B.L.; and Balster, R.L. Behavioral and biochemical stereoselectivity of sigma opiate/PCP receptors. Brain Res 294:174-177, 1984.

Zukin, S.R.; Fitz-Syage, M.L.; Nichtenhauser, R.; and Zukin, R.S.

Specific binding of 3H-phencyclidine in rat central nervous tissue: Further characterization and technical considerations.

Brain Res 258:277-284, 1983.

ZuKin, S.R.; Tempel, A.; Gardner, E.L.; and Zukin, R.S. Interaction of 3

H(-)SKF-10,047 with brain sigma opioid receptors:

Characterization and autoradiographic visualization. Submitted

for publication.

ACKNOWLEDGEWENTS

3

H-TCP was a gift from New England Nuclear Corp., MA. Nonradiolabeled PCP and its derivatives were supplied by the National Institute on Drug Abuse. This research was supported by National

Institute on Drug Abuse research grant DA-03383 to S.R.Z. and by

the Department of Psychiatry, Albert Einstein College of Medicine/

Montefiore Medical Center, Dr. H.M. van Praag, Chairman. Ratna

Sircar is recipient of an N.R.S.A. fellowship under N.I.M.H.

Training grant number MH14627-09.

22
AUTHORS

Ratna Sircar, Ph.D., Research Fellow

Departments of Psychiatry and Neuroscience

Albert Einstein College of Medicine

1300 Morris Park Avenue, Bronx, NY 10461

Stephen R. Zukin, M.D., Associate Professor

Departments of Psychiatry and Neuroscience

Albert Einstein College of Medicine

1300 Morris Park Avenue, Bronx, NY 10461

23
Isolation and Identification of an

Endogenous Ligand for the

Phencyclidine Receptor

Debora A. DiMaggio, Patricia C. Contreras, Remi Quirion,

and Thomas L. O’Donohue

CLASSIFICATION OF OPIOID RECEPTORS

Opioid receptors comprise a heterogenous group that can be divided

into at least four biochemically and topographically distinct subtypes, designated mu, kappa, sigma, and delta. Martin et al.

(1976) proposed the existence of mu, kappa, and sigma opioid receptors based on observed differences in pharmacological profiles

of drugs seen with variably selective opioid agonists and

antagonists. Other groups have provided evidence for the delta

subtype (Hughes et al. 1975).

The mu opioid receptor has been extensively characterized (Lord et

al. 1976; Lord et al. 1977; Chang et al. 1979; Chang and

Cuatrecasas 1981). Classical opioid effects, such as analgesia

induced by morphine and its congeners, are thought to be mediated

by the mu opioid receptor, which preferentially binds the levorotatory isomer. This stereoselective binding of the (-) enantiomer, which has greater analgesic and respiratory depressant

properties than the (+) isomer, strongly supports the physiological relevance of specific mu opioid receptors. Delta receptors have also been well characterized (Simantov 1978). These

opioid receptors are believed to be involved in reward processes

and seizure. From the evidence available for kappa receptors

(Kosterlitz and Paterson 1980, Chang and Cuatrecasas 1979), it

appears that these sites are involved in mediating analgesia and

sedation. Finally, it has been postulated that sigma receptors

are involved in mediating the psychotomimetic actions seen with

some of the benzomorphans, PCP, and PCP analogs (Quirion et al.

1981a).

INTERACTION OF OPIOID RECEPTORS WITH ENDOGENOUS PEPTIDE LIGANDS

The mu, kappa, and delta opioid receptors have been found to

interact with endogenous peptide ligands that share certain pharmacologic properties with opioid drugs. These peptide ligands are

derived from at least three different prohormones located in both

24
the central and peripheral nervous systems and also in the endocrine system.

Delta receptors are relatively selective for two related pentapeptides, methionine enkephalin and leucine enkephalin (met- and

leu-enkephalin), which were isolated from porcine brain (Hughes

1975). Both met- and leu-enkephalin inhibit electrically induced

contractions of guinea pig ileum, an effect that mimics those

effects seen with opioid drugs, and is naloxone reversible. The

enkephalins are processed posttranslationally from proenkephalin,

and secreted from central and peripheral neurons and endocrine

cells in the adrenal medulla.

Neurons in the brain and spinal cord process peptides derived from

prodynorphin; these peptides appear to be kappa-preferring

ligands. Dynorphin 1-13 was isolated from porcine pituitary by

Goldstein et al. (1979). This pituitary opioid peptide contains

within its sequence leu-enkephalin, which appears to be one of the

products of posttranslational processing (Zamir et al. 1985;

Palkovits et al. 1983). Dynorphin 1-13 is 700 times more potent

than the enkephalins in inhibiting electrical contractions in

guinea pig ileum longitudinal muscle (Goldstein 1979).

The third prohormone from which opioid peptides are derived is

pro-opiomelanocortin, which yields a number of nonopioid and

opioid peptide products (O'Donohue and Dorsa 1982). Of these

products, beta-endorphin, an untriakontapeptide isolated from

camel pituitary gland by Li and Chung (1976)) is thought to

interact primarily with mu and delta receptors.

EVIDENCE OF SPECIFIC PCP BINDING SITES

In recent years, a number of groups have reported the presence of

a class of high-affinity binding sites for phencyclidine (1-(1-

cyclohexylphenyl)piperidine, PCP), a dissociative anesthetic with

psychotomimetic properties. This binding was shown to be saturable, reversible, and selective (Vincent et al. 1979; Zukin and

Zukin 1979; Quirion et al. 1981a; Vignon et al. 1982), as well as

stereospecific (guirion et al 1981b). Furthermore receptor

densities using 3H-PCP (Quirion et al. 1981a) and 3H-TCP (N-(1-(2-

thienyl)cyclohexyl)3,4-3(H)piperidine, (Contreras et al., submitted for publication) to label the binding sites were reported

to be highest in cortical regions and hippocampus, indicating that

the distribution of PCP binding sites correlates well with the

psychotomimetic properties of the drug. The pharmacological relevance of the PCP receptor is supported by the fact that only those

drugs with PCP-like properties in vivo, such as SKF-10,047 (Nallylnormetazocine),

binding of

cyclazocine, PCP, and PCP analogs inhibit the

3

H-PCP in vitro (Quirion et al. 1981a). Although PCP

appears to bind to muscarinic and mu opioid receptors with very

low affinity (Vincent et al. 1979), its action on these receptors

is not compatible with its pharmacological profile (Vincent et al.

1979). Binding of PCP to the PCP receptor is not antagonized by

25
mu, delta, or muscarinic receptor ligands (Vincent et al. 1979).

Finally, good correlation exists between the ability of PCP

analogs to bind to the receptor and pharmacological potency as

measured by a number of assays, including the rotarod assay

(Vignon et al. 1982) and stereotypy (Contreras et al., submitted

for publication).

Because the psychotomimetic benzomorphans, classed as sigma opioids, inhibit binding of 3

H-PCP and show PCP-like actions in several behavioral assays, it has been suggested that PCP and sigma

opioids act through the same binding sites. However, recent work

by a number of investigators (Su 1982; Tam 1983; Martin et al.

1984; Contreras et al., in press) indicate that PCP binding sites

and sigma opioid sites may be distinct due to differences in drug

selectivity and regional distribution.

ENDOGENOUS LIGAND FOR THE PCP/SIGMA RECEPTOR

The presence of highly specific and selective binding sites for

PCP in brain strongly supported the presence of an endogenous ligand for these receptors. Quirion et al. (1984) and O'Donohue et

al. (1983) have reported the isolation of an endogenous factor

from preparative scale porcine brain acid extracts that inhibited

the binding of 3

H-PCP in rat brain membranes. This paper summarizes those previous findings , and extends the data on this

endogenous factor which has now been purified to homogeneity and

has been given the name alpha-endopsychosin.

EXTRACTION AND PURIFICATION OF ALPHA-ENDOPSYCHOSIN

Porcine brains (200) were obtained from Gwaltney Co. and homogenized at 4 °C in five volumes of acid solution (Bennett et al.

1979) consisting of trifluoroacetic acid, formic acid, hydrochloric acid, and sodium chloride. Following centrifugation, the

homogenate was extracted 1:1 with petroleum ether. The resulting

supernatant (60 liters) was then filtered using a Minitan Ultrafiltration System, and chromatographed in a series of runs using

preparative and semipreparative liquid chromatography followed by

several analytical reverse phase high pressure liquid chromatography steps. Figure 1 provides an overview of the purification

procedure. Throughout the purification, a binding assay using 3HPCP and rat brain membranes was used to assess the progress of

this procedure.

ENZYMATIC INACTIVATION

The effects of various enzymes on the activity of HPLC fractions

that inhibited 3H-PCP binding were investigated. As shown in

table 1, pronase (0.5 μg/ml), carboxypeptidase A (0.1 unit/ml),

and trypsin (3.0 g/ml) markedly decreased the potency of 10 n

units of PCP-like activity. No significant change in activity was.

seen when fractions were incubated with alpha-chymotrypsin.

Boiled enzymes did not alter the ability of active fractions to

26
inhibit the binding of 3

H-PCP to its receptor. These data suggest

that the endogenous material is a protein or peptide.

FIGURE 1. Purification scheme of alpha-endopsychosin

TABLE 1. Effects of various enzymes on the activity of HPLC

fractions which inhibited 3H-PCP binding

Treatment

Control (Boiled Active Enzyme

Enzyme) n Unit n Unit PCPPCP-Like Activity Like Activity

Pronase 8.9 ± 1.4 0

Trypsin 8.1 ± 1.6 2.3 ± 0.7

-Chymotrypsin 7.7 ± 1.4 5.4 ± 1.0

Carboxypeptidase A 8.8 ± 1.3 3.1 ± 0.6

NOTE: 10 n units of PCP-like activity were incubated with various concentrations

of active or inactive (boiled at 80 °C for 10 min) enzymes. The remaining

activity was then evaluated by the 3H-PCP binding assay. One unit of activity is equivalent to 1 mole of PCP. Mean ± SEM of three determinations.

27
GEL FILTRATION STUDIES

Supernatants were chromatographed over a column of Sephadex G-10,

G-25, and G-50, and aliquots of collected fractions were assessed

for their ability to displace 3

H-PCP from binding sites in rat

brain preparations. Results indicated that the endogenous material has a molecule weight of about 3,000.

SELECTIVITY AND SPECIFICITY OF ACTIVE FRACTIONS

As Shown in table 2, a comparative dose of 10 n units of PCP-like

activity inhibited 3H-PCP binding in rat brain membranes, but did

not inhibit binding of 3H-dihydromorphine, 3H-D-ala2-D-leu5-

enkephalin, 3H-ethylketocyclazocine, 3H-diazepam, or 3H-neurotensin. These results indicate that the active material is

specific and selective from PCP receptors, as binding to the mu,

delta, and kappa opioid receptors was unaffected, as was binding

to benzodiazepine and neurotensin receptors.

Aliquots of fractions from an intermediate chromatography step

were assayed for their ability to inhibit 3H-PCP receptor binding. The endogenous material inhibited binding of 3

HPCP to rat

brain membranes and did so in a dose-related fashion, but did not

displace 3H-SKF-10,047 in a separate binding study. Similarly, no

displacement of 3H-dexoxadrol or 3H-haloperidol from rat brain

preparations was apparent with aliquots taken from these same

fractions.

TABLE 2. Effect of endogenous 3H-PCP displacing material on the

specific binding of various ligands

Specific Binding

Ligand

Control 10 n Units of

(CPM) Extract (CPM)*

3

H-PCP

3

H-Dihydromorphipe

3

H-D-ala2, D-leu5-enkephalin

3

H-Ethylketocyclazocine

3

H-Diazepam

3

H-Neurotensin

2172 ± 201 409 ± 158+

1737 ± ±

±

214 1664

±

291

2474 304 2435 347

2691 ± 237 2831 ± 352

7211 ± 315 7337 ± 366

1817 ± 207 1901 ± 291

Remaining specific binding (CPM) after incubation in presence of 10 n units of

PCP-like activity as determined in a binding assay.

+

p<0.001

NOTE: One unit of activity is equivalent to 1 mole of PCP. Mean ± SEM of at

least three determinations, each In triplicate.

28
REGIONAL DISTRIBUTION OF ACTIVE MATERIAL IN RAT BRAIN

The distribution of 3H-PCP-displacing material correlated well

with PCP receptor densities. Highest concentrations of endogenous

material can be found in hippocampus and cortex, while relatively

little material is detectable in striatum and brainstem (table 3).

TABLE 3. Distribution of the endogenous PCP-like material (as

measured in a PCP receptor assay) in porcine brain

Region

N Units PCP Equivalents/g

Wet Weight

Hippocampus 6.91 ± 1.31

Frontal cortex 5.80 ± 1.15

Cerebellum 1.27 ± 0.78

Striatum 0.12 ± 0.08

Brainstem 0.08 ± 0.04

BIOLOGICAL PROPERTIES OF PCP-LIKE FRACTIONS

Active fractions tested for electrophysiological actions on hippocampal and cortical cells mimicked the actions of PCP (Quirion et

al. 1984). Iontophoresis of PCP inhibited spontaneous cortical

and hippocampal cell firing, as did micropressure ejection of the

PCP-like material. Fractions that did not possess PCP-like

actions had no effect on spontaneous neuronal activity.

Similarly, using a behavioral paradigm where unilateral injection

of PCP into substantia nigra induces contralateral turning behavior (Quirion et al. 1984), PCP-like fractions also mimicked the

actions of PCP, producing significant rotational behavior contralateral to the injection site. Once again, inactive fractions

elicited no response in this test. These two in vivo experiments

demonstrate that the endogenous material is anagonist relative to

PCP.

CHEMICAL CHARACTERIZATION OF PCP-LIKE MATERIAL

Figure 2 shows the elution profiles of several neuropeptides and

the PCP-like material. When the PCP-active fractions were rechromatographed over a flatter gradient and in a different solvent

system, it was clear that bombesin- and substance P-immunoreactivity no longer coeluted with the PCP-like material.

29
Figure 3 shows the final chromatogram and activity profile of

purified alpha-endopsychosin. The first peak contained most of

the PCP displacing activity as measured by its ability to inhibit 3

H-PCP. An aliquot of the most active material was hydrolyzed

in acid and the amino acid composition was determined using OPA

detection. It was determined that the peptide contained approximately 26 amino acids, in close agreement with the molecular

weight predicted by Sephadex gel filtration studies. N-terminal

analysis revealed that the peptide was blocked at this site. The

nature of this blockade is yet to be determined. Studies are

under way to determine the amino acid sequence of the peptide.

FIGURE 2. Panel A: Elution pattern of endogenous PCP-like material from fractionated porcine brain. Activity is

expressed in terms of equivalents of PCP required to

inhibit 3H-PCP bindina to rat brain membranes. One

unit of activity is eqivalent to 1 mole of PCP.

Panel B: Activity profiles of bombesin, neuropeptide

Y, and substance p from the same HPLC fractions.

30
FIGURE 3. Chromatogram and elution pattern of the purified

material

DISCUSSION

The existence of high affinity and stereoselective binding sites

for PCP, a dissociative anesthetic with psychotomimetic properties, has been demonstrated in brain by a number of groups

(Vincent et al. 1979; Zukin and Zukin 1979; Quirion et al. 1981a;

Vignon et al. 1982). The identification of these PCP receptors in

central nervous tissue suggested the existence of an endogenous

ligand specific for these pharmacologically relevant binding

sites. We have identified what appears to be a selective peptide

ligand for the PCP receptor from porcine brain acid extracts and

have named this compound alpha-endopsychosin due to its similarity

in pharmacology to PCP. We have assigned the alpha designation to

this peptide, since it is the first endogenous PCP ligand to be

identified, and activity profiles of fractionated porcine brain

show that other fractions are also PCP-active, although they do

not appear to be as potent as the fraction characterized. This

putative ligand for the PCP receptor, which is regionally distributed throughout the CNS and inhibits 3

H-PCP binding in rat brain

membranes, appears to be an agonist relative to PCP, as indicated

by its actions in electrophysiological and behavioral tests. The

peptide appears to be selective for PCP receptors, since it does

not interact with mu, kappa, or delta opioid receptors; nor does

it interact with a number of other peptide binding sites.

31
Furthermore, the distribution of this peptide is compatible with

PCP receptor densities, with highest concentrations of both ligand

and receptor in areas that could be relevant to the psychotomimetic properties of PCP. Amino acid analysis of an aliquot of

the purified fraction shows the peptide to contain at least 26

residues. Because the peptide is blocked at the N-terminus,

enzyme fragments have been generated and purified over HPLC for

sequence determination.

Without a specific PCP antagonist, it cannot be stated unequivocally that the endogenous ligand and PCP act at the same receptor

to induce specific electrophysiological and behavioral actions.

The discovery of specific PCP antagonists will facilitate complete

characterization of the PCP-endogenous ligand system. Along this

line of investigation, Rafferty et al. (in press) have reported

the discovery of an acylating agent which specifically reacts with

PCP receptors. This agent effectively blocks PCP-induced stereotypic behavior and electrophysiological actions in rats (Contreras

et al. 1985). an effect that has been shown to be the result of

PCP receptor-binding. It will be interesting to study the effects

of this specific acylating agent on the interaction of PCP receptors with the endogenous ligand.

Although PCP affects several ion channels (Aguayo et al. 1982;

Albuquerque et al. 1980) and numerous neurotransmitter systems, it

is believed to exert its psychotomimetic effects via interaction

with a specific receptor. It has been suggested that PCP receptor

sites are actually sigma opioid sites, since SKF-10,047 and

Syclazocine, sigma opioid psychotomimetics, inhibit the binding of

3

H-PCP to membranes in vitro.

hibit binding of

PCP analogs have been shown to in3

H-cyclazocine and 3H-SKF-10,047 (Quirion et al.

1981b). Furthermore, sigma opioids generalize to PCP stimulus In

drug discrimination paradigms (Brady et al. 1982; Shannon 1981).

and PCP has been shown to generalize to sigma opioid stimulus

(Shannon 1983). However, Contreras et al. (1985) have shown that

Metaphit, an acylating agent specific for PCP receptors, inhibits

PCP-induced stereotypy but does not inhibit stereotyped behavior

typically seen with cyclazocine treatment. In addition, evidence

exists that suggests that PCP, SKF-10,047, and cyclazocine do not

bind to a homogenous population of receptors (Contreras et al., in

press). Recent work presented by a number of investigators (Su

1982; Tam 1983; Martin et al. 1984; and Contreras et al., in

press) also indicates that, due to differences in regional distribution of drug selectivity, PCP receptors and sigma opioid sites

represent different binding sites. Largent et al. (1984) have

shown that sites labeled with 3H-PPP (3-(3-hydroxyphenyl)-N-(1-

propyl)piperidine) are specific for sites that are distinct from

PCP sites. Finally, Pilapil et al. (in press) have delineated a

binding profile for dexoxadrol, a putative sigma agonist, that is

distinct from PCP binding. In this light, it is particularly

interesting to note that the PCP-like peptide inhibits binding of

3

H-PCP but not of 3H-(+)SKF-10,047, 3H-dexoxadrol or 3H-haloperidol. The endogenous ligand for the PCP receptor may therefore

32
be a far more selective ligand than any of the synthetic

compounds.

A controversial issue concerns whether PCP/sigma opioids are in

fact opioids at all, as their "sigma" psychotomimetic actions are

not antagonized by naloxone. The three known opioid peptide precursors share marked structural homology in that they all contain

multiple cysteine residues in the N-terminal region, they are all

approximately the same size, and they all contain an enkephalin

sequence (Douglass et al. 1984). It will be interesting to see

whether alpha-endopsychosin is the peptide product of a distinct

yet similar prohormone. If so, then perhaps alpha-endopsychosin

and PCP binding sites may belong to the superfamily of opioid peptides and receptors.

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76:4678-4682, 1979.

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ACKNOWLEDGEMENT

This work was supported in part by the Chemical Research and

Development Center, U.S. Army.

35
AUTHORS

Debora A. DiMaggio

Experimental Therapeutics Branch

National Institute of Neurological

and Communicative Disorders and Stroke

National Institutes of Health

Bethesda, MD 20205

Patricia C. Contreras

Experimental Therapeutics Branch

National Institute of Neurological

and Communicative Disorders and Stroke

National Institutes of Health

Bethesda, MD 20205

and

Howard University

Department of Medicine

Washington, DC 20059

Remi Quirion

Douglas Hospital Research Centre

and Department of Psychiatry

McGill University

Verdun, Quebec H4H 1R3 Canada

Thomas L. O'Donohue

Experimental Therapeutics Branch

National Institute of Neurological

and Communicative Disorders and Stroke

National Institutes of Health

Bethesda, MD 20205

36
Phencyclidine (PCP) Selectively

Blocks Certain Presynaptic

Potassium Channels

Mordecai P. Blaustein, Dieter K. Bartschat,

and Roger G. Sorensen

INTRODUCTION

Phencyclidine (1-[1-phenylcyclohexyl] piperidine; "PCP"; "angel

dust") is a major drug of abuse in the United States. It is a

particularly interesting pharmacological tool because it induces a

toxic confusional psychosis in man that reproduces many of the

primary symptoms of schizophrenia (Domino and Luby 1981). The

precise mechanism of action is not known, but many studies suggest

that the complex behavioral syndrome elicited by PCP is a consequence of altered central synaptic transmission (Petersen and

Stillman 1978). PCP is known to bind with high affinity to brain

membranes (Vincent et al. 1978: Zukin and Zukin 19791: however,

the physiological activity of these receptors has not-yet beenelucidated, nor have these receptors been identified. One effect

of low concentrations of PCP is a blockade of a portion of the

potassium-stimulated 86Rb efflux from rat brain presynaptic nerve

terminals (synaptosomes) (Albuquerque et al. 1981; Albuquerque et

al. 1983; Blaustein and Ickowicz 1983). These studies led to the

suggestion that PCP may selectively block certain potassium channels, and that this effect might account for the behavioral action

of the drug (Albuquerque et al. 1981; Albuquerque et al. 1983;

Blaustein and Ickowicz 1983).

ferent fractions of 86Rb efflux from synaptosomes (Bartschat and

Recently, we succeeded in separating four pharmacologically-difBlaustein 1985a; Bartschat and Blaustein 1985b), which correspond

to four different types of K channels. Submicromolar to micromolar concentrations of PCP and behaviorally-active congeners

selectively block one of these channels--a voltage-regulated, noninactivating (or very slowly inactivating) K channel in nerve

terminals. The rank order of potency for block of these K channels paralleled both the relative ability of these agents to produce characteristic behavioral deficits in rats (Shannon, 1983),

and their ability to displace 3

H-PCP from its high affinity binding sites in brain (Vincent et al. 1978; Zukin and Zukin 1979;

37
Sorensen and Blaustein 1985a). In view of the enhanced neurotransmitter release that would be expected to accompany block of

presynaptic K channels (Llinas et al. 1976), this mechanism could

explain the PCP-induced "dopamine storm" (Rappolt et al. 1980).

Such altered synaptic transmission at central synapses may underlie the disordered behavior characteristic of PCP intoxication.

The aforementioned observations imply that the high affinity PCP

binding sites in the brain are K channels. Therefore, as a prelude to the eventual isolation and characterization of these PCP

"receptors"/K channels, we employed a tritiated photo affinity

analogue of PCP, m-azido-3H-PCP (3H-Az-PCP) to label rat brain,

synaptic membrane proteins. The results indicate that this analogue binds specifically to two membrane polypeptides of a parent

MR 80,000 and 95,000 Daltons (Sorensen and Blaustein 1985b).

IDENTlFICATION OF K CHANNELS IN SYNAPTOSOMES WITH TRACER 86Rb

EFFLUX

Rb efflux from synaptosomes loaded with 86Rb was used to assess

the K permeability of the nerve terminals under "resting" conditions, and under conditions in which the terminals were depolarized by elevating the external

half-life 36 times longer than 42K,

k concentration, [K]o. With a

86Rb is a suitable tracer for

K because (Bartschat and Blaustein 1985a; Bartschat and Blaustein

1985b): (1) Rb, like K, is accumulated by synaptosomes via a

metabolically active, ouabain-sensitive route; (2) Rb permeates

most neuronal K channels nearly as well

(3) synaptosomes preloaded with both

as does K itself; and

42K and 86Rb have qualitatively similar K and Rb effluxes.

Voltage-regulated K channel activity in synaptosomes was measured

as described in the figure 1 legend. For further details, see

Bartschat and Blaustein (1985a).

[K]o; open circles in figure 1),

Under "resting" conditions (5 mM

86Rb efflux was about 0.3 to

0.4%/sec (component "R"), which corresponds to a resting K permeability of 2.4x10-7cm/sec (Bartschat and Blaustein 1985a). Rb

efflux under these conditions probably reflects the mechanism(s)

responsible for the normal K permeability of the resting

terminals.

Depolarization of the synaptosomes with Ca-free media containing

100mM K increased 86Rb efflux (figure 1, open squares); two

kinetically and pharmacologically distinct K conductances could be

discerned. Between 1 and 4 seconds, Rb efflux was linear and was

2.2 to 2.4%/sec (component "S"). Extrapolation of Rb efflux to

the

of 86Rb efflux (component "T").

ordinate ("zero time") exposed an additional, rapid component

Component T reflects a distinct K

channel that, unlike component S, appeared to inactivate in less

than 1 second (Bartschat and Blaustein 1985a).

38
FIGURE 1. Time course of 8 6Rb efflux from synaptosomes; the

NOTE:

effect of PCP

Synaptosomes were prepared as described (Krueger et al. 1979), were equilibrated with

late tracer 86Rb (20 μCi/ml in PSS) at 30 °C for 30 minutes. PSS contained

hysiologlcal salt solution (PSS). and were allowed to accumu-

(mM): KCI, 5; NaCl, 145; MgCI2, 2; glucose, 10; HEPES buffer, 10, titrated

to ph 7.4 with NaOH; Na2 HPO4, 0.5; and unlabelled RbCI, 0.1. Aliquots

(30 μl) of the synaptosomal suspension were then pipetted onto glass fiber

filters, were washed free of extracellular tracer, and then exposed to

efflux media for various lengths of time (1 to 4 seconds). Efflux was terminated by rapid addition of “stopping solution” containing the K channel

blockers tetraethylamnonium (145 mM) and tetrabutylamnonium (5 mM), but no

NaCl or KCI. Suction was rapidly applied, and the filters and filtrates

were counted by Iiquid scintillation spectroscopy; Rb efflux was expressed

as:

The efflux medium was similar to the loading medium; however, In experiments involving elevated [K]o, K replaced Na mole-for-mole. When drugs

were tested, they were Included In the wash media facilitate equilibration with the synaptosomes. Symbols correspond to Rb efflux in: 5 mM

K ( 0), 100 mM K (control; ), 100 mM K + 10 μM PCP ( ). or 100 mH K +

100 μM PCP . The data points are the means of six determinations.

The components of 86Rb efflux indicated in the figure represent: R = Rb

efflux in 5 mH K media (expressed in %/sec); S = Rb efflux between 1 and 4

seconds (%/set) in K-rich media minus component R; T = K-dependent increment (%) In Rb efflux when S is extrapolated back to zero time. SV =

component of S that is blocked by PCP; SR = PCP-lnsensltive portion of

component S.

Inclusion of Ca in the efflux media enhanced 86Rb efflux in 100 mM

[K]o but not 5 mM [K]o (data not shown). This Ca-dependent 86Rb

efflux (component "C") appears to be a manifestation of TEA-sensitive, Ca-regulated K channels (Bartschat and Blaustein 1985a;

Bartschat and Blaustein 1985b).

39
Pharmacological evidence indicates that components R, S, T, and C

correspond to distinct classes of K channels (Bartschat and

Blaustein 1985a; Bartschat and Blaustein 1985b). Component T is

blocked by low concentrations of 4-aminopyridine (4-AP); component

C is selectively blocked by micromolar quinine sulfate, but not by

4-AP. Components R and S are much less sensitive to both drugs.

EFFECTS OF PCP ON K CHANNELS IN SYNAPTOSOMES

To determine which of these K channels are inhibited by PCP, this

drug was tested for its ability to block the various components of

Rb efflux. In the experiment of figure 1, the effects of 10 μM

PCP (closed circles) and 100 μM PCP (closed squares) were examined

depressed

in nominally Ca-free solutions. In 100 mM [K]o medium, 10 μM PCP

86Rb efflux through S by about 35 percent, but had negligible effect on component T. Increasing PCP to 100 μM had no

additional effect on S, but blocked component T by about 45 percent. Although not shown here, component R and the Ca-dependent

component, C, were virtually unchanged by 100 μM PCP.

The dose-response curves for the effects of PCP on components S

and T are illustrated in figure 2. Note that low doses of PCP selectively blocked a portion (about one-third) of component S (SV);

higher doses inhibited T, as well, with but little additional effect on S.

FIGURE 2. PCP dose-response curves for the inhibition of components S ( ) and T ( )

NOTE: The data points are the means of 4 determinations, ± SEW. SimiIar results

were obtained in 3 other experlments.

40
EFFLUX COMPONENT S CAN BE DIVIDED INTO TWO FRACTIONS, SR AND SV,

WITH DIFFERENT PROPERTIES

Before trying to interpret this partial inhibition of S by PCP, we

need to consider the influence of membrane potential on the 8 6 R b

efflux. To obtain information about the relationship between component S and membrane potential, we measured S (increase in the

slope of 86Rb efflux between 2 and 4 seconds) as a function of

[K]o in the efflux solution, in the absence of drug. These data

are shown in figure 3 (solid circles); the calculated depolarization, due to increasing [K]o, is given in the upper abscissa

scale.

FIGURE 3. Effect of PCP on 8 6Rb efflux component S

NOTE: The magnitude of component S at the indicated [K] was expressed as the

slops of the least squares line fitting Rb efflox°between 2 and 4 seconds

for control (•) and 100 μM PCP-containing solution (o). The dotted line Is

the expected contrlbutlon of the "resting” K permeablllty (R) to component

S due to electrodiffusion effects (i.e., SR) when the synaptosomes are depolarized to the level lndicated In the upper abscissa (also see Bartschat

and Elsusteln 1985a). The data points are the means of 4 determinatlons.

As discussed previously (Bartschat and Blaustein 1985a), depolarization of

flux of 86Rb through the "resting" K permeability (component R),

the terminals should increase the driving force for efeven if there is no increase in conductance (i.e., no voltage gating of R). The magnitude of this calculated electrodiffusion component of 86Rb efflux through the "resting" K conductance, denoted

as SR, is shown as the dotted line in figure 3 (also see figure 6c

in Bartschat and Blaustein 1985a). The difference between this

41
dotted line (fraction SR) and the solid line (component S) presumably represents the voltage-regulated fraction of component S,

denoted as SV.

THE EFFECT OF PCP ON 86Rb EFFLUX THROUGH COMPONENT S

If two different types of K conductances contribute to component

S, we might anticipate that some drugs will affect the two conductances differently. Indeed, the dose-response curves for inhibition of S by tetra-alkylamines and 4-AP appear to be biphasic

(Bartschat and Blaustein 1985a), which is consistent with this

prediction. The obviously biphasic dose-response curve for PCP

inhibition of component S (figure 2, open circles) provides further evidence for this view.

Note that the magnitude of component S measured as a function of

[Klo

in the presence of 100 μM PCP (figure 3, open circles) corresponds very closely to the calculated magnitude of SR (figure 3,

dotted line). These data clearly indicate that components SR and

Sv are different. Component SV

voltage-regulated, noninactivat

apparently is a manifestation of

ing K channels, and is blocked

selectively by low concentrations of PCP. Since the "resting" 8 6Rb

efflux is unaffected by these conc

we would not expect PCP to affect

entrations of PCP (not shown),

86Rb efflux component SR if this

flux is mediated by the resting K conductance, as described.

The concentration of PCP that inhibits SV by 50 percent (IC50) is

about 1 μM (figure 2, open circles). This is within the range of

doses that produce confusional psychosis (0.1 to 1.0 mg/kg, corresponding to about 0.1 to 1 μM) (Burns and Lerner 1981). Higher

concentrations of PCP induce convulsions and coma (Burns and

Lerner 1981). Assuming that block of the K channels corresponding

to SV does cause the behavioral deficit, it is important to consider the possibility that block of only a small fraction of these

K channels may be sufficient to induce behavioral change.

THE EFFECTS OF PCP ANALOGUES ON COMPONENT Sv

If the behavioral activity of PCP is related to its block of presynaptic K channels (Albuquerque et al. 1981; Albuquerque et al.

1983; Blaustein and Ickowicz 1983), PCP-like analogues should

block these same K channels with a rank order of potency that

parallels their relative in vivo psychotomimetic activity. One of

the most behaviorally potent PCP-like agents is TCP (1-[1-(2-

thienyl)-cyclohexyl] piperidine) (Shannon 1983). Figure 4 illustrates the dose-response curves for the block of components S and

T by this drug. The data indicate that TCP is a more potent

blocker of Sv than is PCP (figure 2). TCP blocked component T

only at high concentrations (>1O-5 M), and in this respect was

approximately equivalent in potency to PCP (figure 2).

42
FIGURE 4. Dose-response curve illustrating the effects of the PCP

analogue TCP on components ( ) and T (o)

NOTE: The experiment was carried out as described in the figure 1 legend. The

data points are the means of 6 determinations.

Figure 5 compares the ability of PCP and two of its congeners,

meta-amino-PCP (m-NH2-PCP)

block component S. All

and meta-nitro-PCP (m-NO2-PCP), to

three drugs selectively blocked Sv, but

with very different affinities. The rank order of potency for

block of Sv by these three drugs and TCP (figure 4) was: TCP, mNH2-PCP>PCP>m-NO2-PCP. This same sequence was observed when these

agents were examined in various behavioral impairment paradigms

that have been used to assess the psychotomimetic liability of

these and related agents (Albuquerque et al. 1981; Shannon 1983;

Aguayo et al. 1984). In contrast, all of these agents blocked T

only at higher concentrations (IC5O's=100-500 μM; data not shown).

The similarity between the relative potency of block of Sv by PCPlike drugs and the effects of these drugs in the behavioral

impairment paradigms strongly supports the view that blockade of

voltage-regulated, noninactivating K channels may be directly

involved in the psychotomimetic actions of these drugs.

THE EFFECTS OF "SIGMA OPIATES" ON COMPONENT SV

Several "sigma opiates," which differ structurally from PCP, are

known to induce a PCP-like toxic psychosis, and to displace PCP

from rat brain membranes (Zukin 1982; Hampton et al. 1982;

43
FIGURE 5. The effects of the PCP ( ), m-NH2

-PCP (o), and m-NO2-

PCP ( ) on component S

NOTE: The experiments were carried out as described in the figure 1 legend. The

data points are the means of SiX determinations.

Mendelsohn et al. 1984; Murray and Leid 1984). Of particular interest are several stereoisomer pairs of "sigma opiates," one

isomer of which produces PCP-like behavioral effects and displaces

bound 3H-PCP more potently than the other. These agents should be

especially well suited for a test of the hypothesis mentioned in

the preceding section, namely, that induction of the PCP-like behavioral deficit can be correlated with block of SV.

We examined the

opiates" on 86Rb efflux in synaptosomes in the presence of 10 μM

effects of three such stereoisomer pairs of "sigma

naloxone (to avoid classical opiate effects). Our data show

(Bartschat et al. 1985) that dexoxadrol blocks Sv at onethousandth the concentration of its stereoisomer, levoxadrol;

(+)NANM (N-allyl-normetazocine or SKF-10,047) is tenfold more

potent than (-)NANM; and (-)cyclazocine is two- to threefold more

potent than (+)cyclarocine. This stereoselectivity for block of

SV closely parallels the effects of these stereoisomers in behavioral and binding experiments (table 1). Furthermore, block of Sv

occurs at nano- to micromolar concentrations of the more potent

"sigma opiates"-- comparable to the concentrations at which PCP and

its more potent congeners act.

44
TABLE 1. Comparison of actions of stereoisomer pairs of "sigma

opiates"

Relative Potency for

Drug Pair

Block

of SV

Displacement of PCP-Like

Bound 3H-PCP Behavior

Dexoxadrol:

Levoxadrol ~1,OOO:1 418: 1

(+)NANM:(-)NANM ~1O:1 6.4:1

(-)Cyclazocine:

(+)Cyclazocine 1-2:1 1.8:1

SOURCES: a

Cone et al. 1984; bShannon 1982a; cShannon 1982b.

>1,OOO:1a

3:1b

5:1C

IDENTIFICATION OF THE RAT BRAIN PCP RECEPTOR

The aforementioned results are consistent with the view that the

rat brain PCP/"sigma opiate" high-affinity receptor is associated

with the voltage-regulated, noninactivating K channels in the presynaptic terminals. Thus, we reasoned that the elucidation of the

molecular composition of this PCP "receptor" might provide direct

information about the subunit composition of these K channels.

This could also prove to be a very useful first step in the effort

to purify and characterize the channel protein. To label and

identify the brain PCP receptor, we synthesized a tritiated photo

affinity analogue of PCP, m-azido-3H-phencyclidine (3H-Az-PCP)

(Haring and Kloog 1984). This photolabile ligand binds with high

affinity (K0.5 0.9 μM) to the rat brain PCP receptor (Sorensen

and Blaustein 1984) As illustrated by the fluorogram in figure

6, when rat brain sinaptic membranes were incubated with 3H-Az-PCP

and irradiated, several polypeptides incorporated the label. However, when excess unlabelled PCP was added before the samples were

irradiated, incorporation of the label was markedly reduced in

only two of the polypeptides, MR=80 kD (80,000 Daltons; P80) and

95 kD (P95). respectively. P95 was labelled more heavily than

P80, and may, therefore, include the primary PCP binding site;

however, we have not yet ruled out the possibility that P80 is a

product of proteolytic cleavage (Sorensen and Blaustein 1985b).

Covalent labelling of these two polypeptides was also specifically

blocked by other PCP analogues such as TCP, by some K channel

blockers (4-AP and tetrabutylammonium ions), and stereoselectively

by certain PCP-like "sigma opiates" (dexoxadrol >> levoxadrol)

(not shown). The latter results parallel the ability of these

ligands to displace 3H-PCP from rat brain membranes and to block

86Rb efflux component Sv in synaptosomes (Sorensen and Blaustein

1985a; Bartschat et al. 1985).

45
FIGURE 6. Fluorogram showing the covalent attachment of 3H-Az-PCP

to rat brain synaptic membrane polypeptides

NOTE: Synaptic membranes were incubated in the dark for 60 minutes at 0 °C in

either 54 mM3Tris-HEPES (A) or 5 mM sodium phosphate (B) buffers at pH 7.0,

with 1.0 μM H-Az-PCP, without (-) or with (+) a five hundredfold excess of

unlabelled PCP. The samples were then Irradiated with 366 nm UV light for

15 minutes (irradiation at 254 nm UV light for 5 minutes gives similar results) to pnotolyze the Az-PCP. The membranes were solubilized in sodium

dodecyl sulfate (SDS) dissociation buffer overnight. and subjected to SDSpolyacrylamide gel electrophoresis. The resulting geIs were impregnated

with “Fluore-Hance” (RPI, Mt. Prospect, III.) dried, and exposed to Kodak

X-Omat AR film for several weeks to obtain fluorographic patterns of the

labelled polypeptides. Several polypeptldes that incorporate label are

lndlcated as PN where N is defined as the apparent molecular weight (kD) of

the polypeptlde x 10-3. Molecular weight standards are also Indicated.

The acetylcholine receptor (AChR) of Torpedo electric organ is

also a PCP "receptor." However, this nicotinic AChR has about

one-tenth the affinity for PCP than that of the rat brain PCP receptor [K0.5 0.3 μM , versus 4-6 μM for Torpedo (Heidmann et

al. 1983; flaring et al. 1984)]. Moreover, the nicotinic AChR has

subunits of MR<66 kD, and these are the subunits that are specifically labelled with 3

H-AZ-PCP in the Torpedo electroplax membranes

(Heidmann et al. 1983; Haring and Kloog 1984; Haring et al. 1984).

These data indicate that the nicotinic AChR-PCP receptor differs

from the rat brain PCP receptor. Furthermore, our findings are

46
consistent with the view that the rat brain PCP receptor is the

voltage-regulated, noninactivating K channel in the nerve terminals, and that this channel consists of at least two subunits of

MR=80 kD and 95 kD.

HOW DOES PCP PRODUCE ITS BEHAVIORAL EFFECTS?

The

of 86Rb efflux component SV,

striking correlation between behavioral potency and block

for PCP analogues and the stereoisomer pairs of "sigma opiates," provides strong circumstantial

evidence that the K channel block may underlie the behavioral

effects of these drugs. Block of K channels at the nerve tetminals should prolong the nerve action potential and thereby enhance

Ca entry into the terminals. This would in turn, alter synaptic

transmission by increasing Ca-dependent neurotransmitter release;

virtually all neurotransmitter types might be affected, depending

upon the distribution in the brain of these PCP-sensitive, voltage-regulated K channels. Such disruption of synaptic transmission at central synapses could induce the disordered behavior that

is characteristic of PCP intoxication. Thus, our observations may

provide the physiological link between the binding of PCP to its

high-affinity receptor in the brain and the ultimate behavioral

effects of PCP intoxication.

It should be pointed out that PCP analogues also have a prominent

postsynaptic action: they block the channels associated with the

nicotinic cholinergic receptors (Albuquerque et al. 1981;

Albuquerque et al. 1983). However, many of the analogues that

display potent antinicotinic activity are behaviorally inactive

(Albuquerque et al. 1983), whereas our data demonstrate that there

is a direct relationship between block of certain presynaptic K

channels and behavioral potency; the stereoselective effects of

the "sigma opiates" are particularly striking in this regard

(table 1). This supports the view that presynaptic K channels are

the primary sites of action of these drugs in the brain. Moreover, our data indicate that the voltage-regulated, noninactivating K channels may be the high-affinity PCP binding sites, and

that PCP may be a useful ligand to help identify and isolate these

K channels.

The behavioral effects of PCP have been associated with excessive

release of a wide variety of neurotransmitters: in particular, a

massive dopamine release may underlie some of the most prominent

symptoms of PCP intoxication (Rappolt et al. 1980). Our results

readily explain the genesis of such an effect, because activation

of presynaptic K channels is one of the primary factors that influences Ca entry into nerve terminals and Ca-dependent transmitter release by limiting action-potential duration and regulating

excitability.

47
There is ample precedent for a modulatory role of K channels in

behavior. The K channel blocker, 4-AP, selectively blocks component T (Bartschat and Blaustein 1985a). prolongs nerve action

potentials, and enhances neurotransmitter release (Llinas et al.

1976). In man, intoxication with this agent may lead to dissociative behavior, agitation, confusion, convulsions, and coma (Spyker

et al. 1980). However, the behavioral aberrations induced by 4-AP

differ qualitatively from those induced by PCP. This implies that

block of various types of presynaptic K channels may modify behavior and mental activity; however, the precise nature of the behavioral manifestations is likely to depend upon the specific type of

K channel that is affected.

In man, PCP intoxication causes a profound perceptual and cognitive disturbance that resembles the primary symptoms of schizophrenia (Domino and Luby 1981). According to the popular

"dopamine hypothesis," the positive symptoms (e.g., thought disorder and delusions) of schizophrenia are associated with an

excessive release of dopamine (by an unknown mechanism). These

symptoms can often be curtailed by treatment with neuroleptics,

agents that block dopamine receptors (Seeman 1980). However, the

negative symptoms (e.g., flattened affect and anhedonia) are not

alleviated by the neuroleptics, and are likely to be associated

with other, nondopaminergic pathways (Crow 1980). PCP intoxication reproduces both the positive and negative symptoms of schizophrenia (Domino and Luby 1981). In view of the evidence that

schizophrenia may be an inherited disorder (Kety et al. 1978), and

that neurotransmitter pathways other than dopaminergic pathways

may be involved in producing some of the behavioral aberrations

(Hornykiewicz 1982; Henn 1983), recent findings (Albuquerque et

al. 1981; Albuquerque et al. 1983; Blaustein and Ickowicz 1983)

raise the possibility that the inherited defect could involve a

primary alteration in the ion channels responsible for the maintenance of normal electrical activity in the nervous system. For

example, a defect in K channel activation could lead to prolongation of action potentials at nerve terminals and, thus, to excessive release of a wide variety of neurotransmitters, including

dopamine.

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Cone, E.J.; McQuinn, R.L.; and Shannon, H.E. Structure-activity

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Hornykiewicz, O. Brain catecholamines in schizophrenia--a good

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Kety, S.S.; Rosenthal, D.; Wender, P.H.; and Schulsinger, F. The

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1985a.

Sorensen, R.G., and Blaustein, M.P. The rat brain phencyclidine

receptor consists of two polypeptides (MR = 95 kD and 80 kD)

that are specifically labelled by 3H-azido-phencyclldine. Soc

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16:487-497, 1980.

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Lazdunski, M. Interaction of phencyclidine with the muscarinic

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1982.

Specific [ 3H] phencyclidine binding

in rat central nervous system. Proc Natl Acad Sci USA 76:5372-

5376, 1979.

ACKNOWLEDGEMENTS

Dr. E.X. Albuquerque provided helpful discussion and Dr. P. Von

Voightlander (the Upjohn Company, Kalamazoo, MI) supplied samples

of dexoxadrol and levoxadrol. Supported by NIH grant NS-16106 and

NIH NRSA NS-07611.

AUTHORS

Mordecai P. Blaustein, M.D.

Professor and Chairman

Dieter K. Bartschat, M.D., Ph.D.

Research Associate

Roger G. Sorensen, Ph.D.

Research Fellow

Department of Physiology

University of Maryland School

of Medicine

655 West Baltimore Street

Baltimore, MD 21201

51
Involvement of Dopaminergic,

Cholinergic, and Glutamatergic

Mechanisms in the Actions of

Phencyclidine-Like Drugs

Kenneth M. Johnson and Lawrence D. Snell

INTRODUCTION

Although there is good evidence that administration of phencyclidine (PCP) to rodents alters the synthesis, metabolism, release,

or reuptake of several neurotransmitters, including serotonin,

norepinephrine, GABA, acetylcholine (ACh), and methionine enkephalin, most of the research in this area has been on dopamine (DA).

The reasons underlying the interest in DA are several. Perhaps

the most important is the similarity seen by most investigators

between schizophrenia and PCP-induced psychosis in humans. This

has been coupled with the observation that PCP-induced stereotypy,

locomotor activity, and rotational behavior can be blocked by

antischizophrenic agents that are DA receptor antagonists. The DA

connection has been strengthened substantially by studies from

several laboratories showing that PCP, like amfonelic acid, enhances DA synthesis and release, and blocks its subsequent reuptake (Johnson 1983). However, because of the complexity of the

neuronal systems subserving even relatively simple behaviors such

as stereotypy or circling behavior in rats with unilateral destruction of the nigrostriatal dopaminergic pathway, it is possible that the dopaminergic properties of PCP are not the primary

factors that underlie these behavioral properties. One of the

primary goals of the studies presented here was to determine the

relevance of the known dopaminergic properties of PCP to the

ipsilateral turning produced by PCP administration to rats.

Another characteristic of PCP which has been studied with great

interest over the last 5 years, is the ability of PCP to produce a

discriminative stimulus in monkeys, rats, and pigeons. As discussed elsewhere in this volume, by Browne, the discriminative

stimulus properties of PCP are shared not only by other members of

the arylcycloalkylamine class, but by psychotomimetic benzomorphans and substituted dioxolanes. The structure-activity

relationships (SAR) within and between these classes are virtually

identical to those found when studying the displacement of 3H-PCP

from its binding site in rat brain membranes. This correlation

52
between the behavioral and binding data suggests that this binding

site could be part of a physiologically relevant receptor.

Although some progress is being made toward the identification of

an endogenous ligand for this receptor (DiMaggio et al., this

volume), many questions remain unanswered. For example, on what

kinds of neurons are these receptors located? What is their

function? How is this function carried out? A more specific

question, which we sought to answer, was whether facilitation of

DA release or blockade of its reuptake could be mediated by an

action at this receptor.

One of the difficulties in the pharmacological analysis of druginduced behavior is that the same behavior may be affected in a

similar fashion by a variety of drugs. For example, PCP-induced

turning is inhibited by alpha-methyl-p-tyrosine (an inhibitor of

tyrosine hydroxylase) and arecoline (a muscarininc agonist)

(Finnegan et al. 1976). Similarly, PCP-induced behaviors are

facilitated by amphetamine (Balster and Chait 1978) and physostigmine (Finnegan et al. 1976). Thus, behaviors such as turning,

which are thought to be largely mediated in the striatum, are

somewhat difficult to analyze because of the balance between

cholinergic and dopaminergic neurons in that area (Pycock et al.

1978). That balance may be influenced considerably by the excitatory (presumably glutamatergic) input from the cortex. The potential importance of this input was revealed by studies that showed

that PCP and several drugs with PCP-like discriminative stimulus

properties selectively antagonized spinal neuron excitation by Nmethyl-D-aspartate (NMDA), an agent believed to selectively activate one of three putative glutamate receptors (Lodge et al. 1982;

Berry et al. 1984a; Berry et al. 1984b). In addition, this laboratory recently reported that PCP potently inhibited NMDA-induced

ACh release from the rat striatum (Snell and Johnson 1984; Snell

and Johnson, in press). Therefore, another goal of the studies

reported here was to determine whether ACh release could be influenced by PCP, either by virtue of its ability to release DA or by

antagonism of glutamate, in a way that was correlated with turning

behavior. By using the SAR approach, we also hoped to determine

whether PCP/sigma receptors might be mediating any of the effects

we observed on DA or ACh function in the striatum.

METHODS

Male Sprague-Dawley rats (200-300 gm) were used in all experiments. Dopamine uptake was measured using the accumulation of

tritium into a striatal synaptosomal fraction in the presence of

an MAO inhibitor following a 5-minute incubation period with

10 nM 3

H-DA at 37 °C. Uptake at 2 °C was used as a control for

uptake by diffusion and was subtracted from uptake at 37 °C.

Other details have been published previously (Johnson and Snell

1985).

To measure the spontaneous efflux of DA, we preincubated striatal

slices (0.4 mm) in a modified Tyrode's buffer containing pargyline

53

185-466 0 - 87 - 3
and 10 nM 3

H-DA for 30 minutes. Slices were loaded into plexiglas

superfusion chambers (0.4 ml) and superfused with buffer at a constant rate of 0.7 ml/min. Superfusate was collected in 5-minute

fractions and radioactivity estimated by liquid scintillation

spectrometry. Fractional release was calculated as the percent of

radioactivity in each fraction, relative to that which was in the

slice at that time (radioactivity in the slice was counted at the

end of the experiment). Fractional release reached a stable baseline of about 1 percent after 30 minutes of superfusion. Drugs

were added in various concentrations 15 minutes later, for a period of 15 minutes. Drug-induced increases in spontaneous 3

H-DA

efflux were estimated by subtracting the average of the fraction

before addition of drug and the fraction collecting 25 minutes

after the removal of drug from each of the eight fractions in

between. This technique is published in detail elsewhere (Snell

et al. 1984).

The effects of various PCP-like drugs on K+ and NMDA-induced ACh

release were studied in a similar superfusion paradigm. KCl (30

mM) was used as a depolarizing stimulus as previously described

(Leventer and Johnson 1983). As with K+

 stimulation, in the study

of NMDA-induced ACh release, slices were loaded with 3H-choline

(50 nM) and then superfused

(to prevent the reuptake of

with buffer containing hemicholinium-3

3

H-choline formed from the extraneuronal hydrolysis of newly synthesized and released 3

H-acetylcholine), until a stable baseline was reached (60 minutes).

Superfusion was continued and the collection of 3-minute fractions

was begun. Buffer containing test drug or vehicle was added 9

minutes prior to the addition of an excitatory amino acid (usually

1 mM NMDA) for 2 minutes. Fractional release over baseline was

estimated in a manner similar to that described above for 3H-DA

release. This paradigm was slightly modified to allow the study

of NMDA-induced 3H-DA release as well.

The effect of PCP-like drugs was also studied in vivo. In these

experiments, the ability of these drugs to enhance haloperidolinduced DA metabolism was assessed by measuring DA and homovanillic acid (HVA) concentrations in the striatum. In this paradigm,

saline or drug was administered (SC) immediately after the administration of 0.1. mg/kg haloperidol. The rats were killed 45

minutes later, and DA and HVA levels were estimated fluorometritally (Snell et al. 1984).

Turning behavior in rats was measured after unilateral administration of 8 μg of 6-hydroxydopamine into the substantia nigra.

Details of the injection procedure and experimental protocol were

described in Johnson and Snell, 1985.

In order to determine the potential correlation between any of

these variables and affinity for the PCP/sigma receptor, we determined the concentration of these drugs required to displace specific binding of 3

H-PCP to rat cortical membranes (Johnson and

Snell 1985). In other experiments, we determined the effect of

54
NMDA on the affinity and binding site density by Scatchard

analysis, as described in the note with table 4.

RESULTS

Turning Behavior

All the drugs tested in these experiments were administered (IP)

at doses ranging from 3 to 10 mg/kg (except for ketamine, which

was tested at 10, 30, and 100 mg/kg). All the rats used had

previously turned contralaterally in response to 0.05 mg/kg apomorphine HCl. Net ipsilateral rotations were counted in two

consecutive 15-minute bins, immediately following drug (or saline)

administration.

PCP produced a dose-related increase in ipsilateral turning, as

reported previously (Fessler et al. 1979). However, the effects

of N-ethyl-phenylcyclohexylamine (PCE) and ketamine were related

to dose in an inverse manner. This inverse dose-relationship was

apparent in both 15-minute periods, and appeared to be due to a

general motor incapacitation. With PCE, ipsilateral posturing was

apparent, but hindlimb coordination was grossly impaired. Ketamine, on the other hand, seemed to reduce turning by virtue of

gross sedation (after 100 mg/kg, the rats were totally akinetic).

N-Allylnormetazocine (NANM) produced results virtually identical

with those of PCP (about 25 turns in the first 15-minute period

after 10 mg/kg). Cyclazocine was a little more potent than PCP,

and etoxadrol was more potent than cyclazocine, although turning

was impaired by ataxia at the higher dose of each. Neither ketocyclazocine nor ethylketocyclazocine (EKC) produced any significant rotation at the doses tested. If these drugs are ranked for

effectiveness in the first 15-minute period (without regard to

dose), one obtains the following rank: PCE, etoxadrol > cyclazotine, NANM, PCP > ketamine >> EKC, ketocyclazocine (Johnson and

Snell 1985).

The ineffectiveness of the latter two kappa agonists suggested

that this effect might be partially mediated via the PCP/sigma

receptor. To test this notion further, we utilized three related

pairs of drugs, each of which has one member that is more potent

than the other in displacing 3H-PCP from its binding site, and in

eliciting PCP-like responding in rats trained to discriminate PCP

from saline. These data are shown in table 1. In the first 15

minutes following administration, 1-[1-(napthyl)cyclohexyllpiperidine, (m-NH2-PCP), dexoxadrol and (-) cyclazocine induced significant ipsilateral turning, while their counterparts, 1-[(mnitrophenyl)cyclohexyl]piperidine, (m-NO2-PCP), levoxadrol, and

(+) cyclazocine did not. (-) Cyclazocine and m-NH2-PCP caused

significant ataxia, as evidenced by reduced turning rates in the

second 15-minute time period. Ataxia produced by dexoxadrol and

etoxadrol (data not shown) was less severe. Although (-) cyclazocine was clearly more effective than (+) cyclazocine in the first

15-minute period, it was somewhat less active than (+) cyclazocine

55
TABLE 1. Effect of some PCP-like drugs on turning behavior

Drug

Net Ipsilateral Turns

Mg/ Kg (N) O-15 Min 15-30 Min

m-NH2-PCP 10 (3) 63 ± 2 1_+l

m-N02-PCP 10 (3) 8.0 ± 3.5 5.3 ± 2.9

Dexoxadrol 10 (6) 50 ± 15* 105 ± 17**

Levoxadrol 10 (6) 4.0 ± 1.0

(6) ±

2.5 ± 1.5

(-) Cyclazocine 5 48 13* 11 ± 6.0

(+) Cyclazocine 5 (3) 6.3 ± 5.3 19 ± 0.9**

*Slgniflcantly different from the turning rate produced by 0.9% NaCl (6.8 ± 2.1).

**Slgniflcantly different from the turning rate produced by 0.9% NaCl (5.0 ± 1.1);

P<.05 (Mann-Whitney U test).

in the second time period. This was probably due to the greater

ataxia produced by the (-) isomer. Thus, the differences between

dexoxadrol and levoxadrol, and between m-NH2-PCP and m-N02-PCP are

obvious, while the difference between the enantiomers of cyclazocine are more subtle, in that each produces turning at different

times following administration. Similar differences between the

enantiomers of dioxadrol and cyclazocine in producing stereotypy

are presented elsewhere in this volume (Contreras et al.).

Uptake of 3H-DA

PCP is a

3

H-DA,

potent, competitive inhibitor of synaptosomal uptake of

3

H-norepinephrine, and 3H-serotonin) (Garey and Heath 1976;

Smith et al. 1977). In addition, we found that PCP administration

in vivo resulted in a time- and dose-dependent inhibition of 3H-DA

uptake into striatal slices (Vickroy and Johnson 1980). More

recently, we compared the effects of amphetamine and representatives from each of the three chemical classes known to produce

PCP-like behavioral effects in rats on high-affinity, synaptosomal

uptake of H-DA (Johnson and Snell 1985). IC50 values (x10-6M)

were as follows: amphetamine

cyclohexylamine (PCE)

(0.06), PCP (O.58), N-ethyl-phenyl-

(9.4), ketamine (24), etoxadrol (38), and Nallylnormetazocine (NANM or SKF-10,047) (46). Cyclazocine and EKC

were extremely weak inhibitors, producing minimal inhibition even

at 1x10-4 M. Thus, although PCP unquestionably can inhibit DA

reuptake, other drugs with similar behavioral effects (and similar

potency) like PCE, etoxadrol, and cyclazocine are either much

weaker inhibitors or simply lack this property entirely. Further,

the abilities of these drugs to inhibit 3H-DA uptake and to displace 3

H-PCP from its binding site in brain membranes were not

significantly correlated (Johnson and Snell 1985).

56
Release of 3

H-DA

Complete concentration-response curves for representatives from

several chemical classes with PCP-like behavioral properties were

obtained using the in vitro release of 3

H-DA from striatal slices

(Snell et al. 1984). Every agent tested produced a significant

increase in spontaneous 3H-DA efflux at 30-100x10-6M. Since none

of the compounds tested appeared to exhibit a maximal effect even

at 1x10-4M, potency was difficult to estimate. In lieu of an

estimate of potency, we report here a simple comparison between

these drugs at the somewhat arbitrary concentration of 1x10-5 M

(table 2). This shows that drugs that are approximately equipotent with PCP in producing turning are much less effective at

this concentration than PCP. Further, the differences between

m-NH2-PCP and m-NO2-PCP, and between dexoxadrol and levoxadrol are

insignificant.

Inasmuch as the effects of PCP can be distinguished from those of

amphetamine, at a biochemical level, by measuring the effect of

each on haloperidol-induced DA metabolism, we also determined the

effect of these same drugs, in combination with haloperidol, on

the ratio of HVA to DA, which was used as an index of DA metabolism. In preliminary experiments, 0.1 mg/kg haloperidol increased

the striatal concentration of HVA from 1.20 ± 0.05 μg/g to 2.94 ±

0.26 μg/g while not significantly changing the concentration of DA

(7.95 ± 1.65 μg/g). Thus, the HVA/DA ratio was increased from

0.12 to 0.36 by haloperidol. The data presented in table 2 represent the percent of the HVA/DA ratio for a haloperidol control

group run the same day for the indicated drug (given immediately

after haloperidol). Amfonelic acid, PCP, and m-NH2-PCP significantly enhanced haloperidol-induced DA metabolism as indicated by

an increased HVA/DA ratio. Amphetamine reversed the effect of

haloperidol on HVA/DA, primarily by increasing the concentration

of DA. EKC decreased the HVA level and increased the DA level

significantly. All other drugs tested had no significant effect

on this index of haloperidol-induced DA metabolism.

ACh Release: Depolarization with K+

 and Excitatory Amino Acids

The effects of PCP and related compounds on ACh release have been

studied using two modes of depolarization: high K+

 and excitatory

amino acids. Both modes result in Ca++-dependent release, but

only the mode of excitatory amino acids is sensitive to tetrodotoxin, suggesting that excitatory amino acids elicit an action

potential that is requisite for ACh release. Using K+ (30mM KCl)-

stimulated AC release as the dependent variable, we found that

PCP (3-10x10-6M) and amphetamine (1x1O-6M) inhibited release by 17

to 28 percent, in a manner that was reversible by haloperidol

(Leventer and Johnson 1983). We postulated that PCP inhibited K+

-

stimulated ACh release via a release of DA. Later, we found that

(+) NANM and EKC, but not (-) NANM or morphine, also inhibited K

+

-

stimulated release. This was reversed by naloxone as well as by

haloperidol (Leventer and Johnson 1984). This led us to amend our

57
hypothesis to include the possibility that PCP was acting through

delta or possibly kappa opiate receptors to release DA, which then

inhibited ACh release. Although an action at these sites has not

been ruled out, it is apparent from our work with (+) and (-) NANM

and EKC that DA release is probably not a relevant intermediate

(table 2) (Snell et al. 1984).

TABLE 2. Comparative effects of several aryLcycLoalkylamines,

benzomorphans, and substituted dioxolanes on striatal

release of’ 3H-DA and hatoperidol-induced DA metabolism

Drug*

Fractional Release

of 3H-DA (x100)

at 1x10-5 M**

HVA/DA

(% Haloperidol

Control)

Amphetamine 34.0 ± 3.7

Amfonelic acid 5.9 ± 0.5

PCP 8.9 ± 1.4

PCE 0.53 ± 0.19

Ketamine 0.44 ± 0.28

m-NH2-PCP 4.14 ± 0.55

m-NO2-PCP 2.68 ± 0.29

NANM 0.91 ± 0.33

EKC 0.47 ± 0.15

Etoxadrol 0.68 ± 0.28

Dexoxadrol 0.86 ± 0.25

Levoxadrol 1.9 ± 0.28

65.1 ± 1.4***

197.0 ± 13

139.0 ± 3.8***

113.0 ± 4.7

92.4 ± 15

126.0 ± 5.1***

88.6 ± 7.7

88.5 ± 8.5

45.4 ± 3.0

114.0 ± 11

108 ± 2.7

83.8 ± 2.7

*All drugs were administered at a dose of 10 mg/kg (except ketamine, dexoxadrol,

and levoxadrol, which were used at 30 mg/kg).

**At 1x10-5 each of the drugs tested, except ketamine and etoxadrol, signiflcantly enhanced release above buffer controls (-0.38 ± 0.23).

***Significantly different from haloperidol control (p<0.05, Student’s t-test).

Since there is a cortico-striatal glutamatergic pathway that provides excitatory input onto both dopaminergic terminals and cholinergic interneurons, we followed the lead of Lodge and coworkers

(Lodge et al. 1983), and determined the effect of PCP on glutamate-stimulated ACh and DA release. We found that glutamateinduced release of ACh was mediated primarily through a glutamate

receptor subtype characterized by a selective affinity for the

antagonist 2-aminophosphonovalerate (2-APV) and the agonist, NMDA.

ACh release induced by NMDA is apparently mediated by a Mg++-gated

conductance, as 1.2mM MgCl2 inhibited ACh release stimulated by

NMDA by about 80 percent. Release induced by the prototypic agonists of the other receptor subtypes (quisqualate and kainate)

were unaffected by physiologic concentrations of Mg++. PCP inhibited ACh release induced by NMDA, but not that induced by

58
quisqualate or kainate. Since PCP enhances the spontaneous efflux

of DA, and DA is known to inhibit ACh release, we examined the

possibility that DA release may be involved in the inhibition of

NMDA-induced ACh release by PCP. We believe that it is not

involved, for the following reasons: (1) the concentrations of

PCP required to inhibit NMDA-induced release of ACh are at least

one-thirty-third of those required to elicit DA release, (2) DA

antagonists such as haloperidol, chlorpromazine, and clozapine do

not reverse the inhibition of ACh release by PCP, and (3) drugs

like etoxadrol, which have little or no potency as indirect DA

agonists, are potent inhibitors of NMDA-induced ACh release. The

concentration of several representatives from the drug classes

with PCP-like behavioral properties required to inhibit NMDAinduced ACh release by 50 percent are shown in table 3.

TABLE 3. Inhibition of NMDA-induced transmitter release

Drug

IC50(nM)

ACh DA

PCP 69

Etoxadrol 98

(-)Cyclazocine 120

(+)Cyclazocine 630

Dexoxadrol N.D.*

Levoxadrol N.D.

N-allylnormetazocine 940

Ketamine 1,600

Ethylketocyclazocine 8,300

Morphine 30,000

290

590

220

1,900

1,700

5,700

N.D.

N.D.

N.D.

N.D.

*N.D. = not determined

Two points need to be emphasized concerning the data on ACh

release. First, PCP, etoxadrol, and cyclazocine are very potent,

being effective in the same range in which they compete with 3

H -

PCP for binding to the PCP/sigma receptor recognition site.

Second, the rank order potency of these drugs in this preparation

correlates very highly with their ability to compete for 3H-PCP

binding sites (r=0.98, unpublished observation) and to mimic the

discriminative stimulus and reinforcing properties of PCP

(Balster, this volume; Browne, this volume). In addition, using

a single concentration of 1x10-7M, we found that the paired drugs

shown in table 1, which produced significant ipsilateral turning,

significantly inhibited NMDA-induced release. Their inactive

counterpart was also inactive at this concentration in inhibiting

ACh release.

59
In other experiments, we found that PCP also inhibited ACh release

induced by the amino acid transmitter candidates, L-glutamate and

L-aspartate. Release of ACh by these amino acids had a similar

Mg++sensitivity to that induced by NMDA, suggesting an action of

these amino acids on the N-type receptor. No inhibition of release by PCP could be seen in the presence of Mg++

.

Although inhibition of NMDA-induced DA release by all the drugs

studied was one-sixth to one-half that of inhibition of ACh release (table 3), the rank order potencies and stereoselectivity of

the effect was similar. One major difference, however, was noted

in our characterization of the response of dopaminergic nerves to

excitatory amino acids. That is, the responses to quisqualate and

kainate were inhibited by both Mg++ and PCP. Thus, the receptor

mediating the response of excitatory amino acids is less selective

in that quisqualate and kainate apparently can stimulate N-type

receptors on dopaminergic terminals (or other neurons modulating

DA release), to cause the release of DA. Further, even in the

presence of Mg++, PCP (1x10-6M) can inhibit release induced by Lglutamate, quisqialate, and kainate. This could mean that PCP is

somewhat less selective than one would predict from the ACh release experiments, or that the presence of Mg++ does not totally

inactivate the conductance channel activated by NMDA on these

neurons. Alternatively, since Mg++ completely abolishes NMDAinduced DA release, PCP may also block quisqualate and kainate

receptors in this preparation.

Analysis of PCP-NHDA Interactions

Since the actions of PCP and related compounds in blocking the response to NMDA appear to be well correlated with their affinity

for the PCP/sigma receptor, we wondered whether NMDA and PCP might

compete for the same binding site. Although glutamate had been

shown not to inhibit 3H-PCP binding (Zukin and Zukin 1979), we

thought that glutamate might not have a very high affinity for the

NMDA (PCP?) receptor.

NMDA on the specific,

The effects of several concentrations of

saturable binding of 3

H-PCP at equilibrium

to rat cortical membranes were analyzed according to Scatchard;

the results are shown in table 4.

These data show that NMDA does not compete for 3H-PCP binding

sites at co centrations that elicit significant ACh release

(EC50=5x10-5M). The apparent competition observed at the higher

concentrations may be irrelevant to this question, as significant

inhibition of the ACh or DA release can be observed using 3x10-5M

MDA. However, the competitive inhibition observed at higher NMDA

concentrations may indicate that NMDA binding can influence the

conformation of the PCP/sigma recognition site via an allosteric

mechanism.

In perhaps a more physiologic assessment of the nature of the PCPNMDA interaction, we determined the effect of fixed concentrations

of PCP and a classic NMDA antagonist (2-APV) on both ACh and DA

60
release stimulated by increasing concentrations of NMDA. As shown

in figure 1, 2-APY (3x10-4M) produced a parallel shift to the

right in the concentration response curve, while PCP (1x10-7M)

produced a nonparallel shift to the right. This suggests that

TABLE 4. Effect of NMDA on 3H-PCP binding to rat cortex

NMDA KD(nM) Bmx(p moles/mg protein)

0 ± ±

3x10-5M

256

±

26 5.83 0.35

3x10-4M

261 17 6.38 ± 0.16

3x10-3M

376 ± 26 6.21 ± 0.59

515 ± 68 6.66 ± 1.1

NOTE: Each value is the mean ±S.E. of 3 independent experiments,

Ic binding of 3H-PCP (defined as that displaceable by 3x10-5M PCP)

 in which specifmeasured at six concentrations ranging from 10 to 1,000 nM.

FIGURE 1. Effect of 2-APV and PCP on NMDA-induced ACh release

(upper panel) and DA release (lower panel). Each

point is the mean ±S.E. of 4-7 experiments.

61
PCP is not acting as a competitive inhibitor at the NMDA receptor;

thus, PCP and NMDA probably do not share a common recognition

site. Examination of the effect of PCP on NMDA-induced DA release

(figure 1, lower panel) tends to support this conclusion, but is

compromised somewhat by the slightly nonparallel shift produced by

2-APV. This may be due to the fact that NMDA may partially activate quisqualate and kainate receptors on those neurons that are

not antagonized by 2-APV.

DISCUSSION

This laboratory, as well as others, has shown unequivocally that

PCP affects a variety of parameters related to neurotransmission

in several neuronal systems. This paper has focused on evidence

for the involvement of dopaminergic, cholinergic, and glutamatergic pathways, and evidence of their interactions in the rat

striatum. However, the effects of PCP undoubtedly involve other

neuronal systems in other brain areas. Thus, it must be borne in

mind that the data discussed in this paper cannot possibly account

for the more complex behavioral effects of PCP.

On the other hand, restriction of our experimental paradigms to

the striatum does have some advantages. First, the involvement of

the striatum in locomotor activity, stereotypy, and circling

behavior are relatively well understood on anatomical, physiological, and neuropharmacological grounds. Although these behaviors are in no way selectively affected by PCP, the relatively

circumscribed anatomical and physiological substrates underlying

these behaviors make their study seem attractive. Our approach

has been to determine, using structure-activity relationships, the

correlation between circling behavior and a variety of neurochemical indices of transmitter function. Once the structure-activity

relationships have been established for a given parameter, one can

determine the correlation with other behaviors, or with other

measures of biological function, in an attempt to identify cause

and effect relationships. However, the urge to jump from a simple

correlation between a given neurochemical parameter and a more

complex behavior such as drug discrimination should be resisted

until appropriate hypotheses can be constructed and tested.

Another advantage in studying the striatum, with particular emphasis on dopaminergic mechanisms, is that we may gain some insight

into the factor underlying the production, by PCP, of schizophrenic symptoms in humans.

In this regard, considerable evidence shows that PCP increases

dopaminergic transmission in the striatum (Johnson 1983) and, more

recently, evidence indicates that DA function is increased in the

mesolimbic and mesocortical pathways as well. For example, PCP

administration has been shown to inhibit the firing of cells found

in the ventral tegmental area (Freeman and Bunney 1984) similar to

that observed in the substantia nigra (Raja and Guyenet 1980).

This effect was reversed by haloperidol. On the other hand, lower

doses of PCP (and NANM) increased cell firing in both areas in a

62
manner that is insensitive to haloperidol, suggesting significant

nondopaminergic influences on dopamine cells as well (Freeman and

Bunney 1984). In spite of the fact that PCP is a competitive

inhibitor of 3H-DA uptake, which also enhances impulse-dependent

release of DA (Doherty et al, 1980; Johnson and Oeffinger 1981) in

a manner similar to nonamphetamine stimulants such as amfonelic

acid (Doherty et al. 1980; Vickroy and Johnson 1982), the apparent

increased dopaminergic tone produced by PCP administration may not

be a major factor in behavioral alteration. The major argument in

favor of dopaminergic involvement in PCP-induced behaviors (aside

from the neurochemical data) is that DA antagonists reversed the

behavior. Unfortunately, the effects of DA antagonists on behaviors such as stereotypy and turning (which are strongly influenced

by DA) could dampen the behavior by acting at a site distinct from

that of the primary site of PCP action. The very weak dopaminergic properties of drugs like NANM, cyclazocine, and dexoxadrol

(Snell et al. 1984; Johnson and Snell 1985), which elicit turning

behavior (Johnson and Snell 1985; Snell and Johnson, in press) and

stereotypy (Contreras et al. 1984; Contreras et al., this volume),

argue in favor of this interpretation of the haloperidol-induced

inhibition of these behaviors. Haloperidol has also been shown to

antagonize PCP- and NANM-induced increases in locomotor activity

(Iwamoto 1981). Destruction of the nucleus accumbens and ventral

tegmental area with 6-OHDA prevented the increased locomotor

activity produced by PCP, but not that produced by caffeine or

scopolamine (French et al. 1984). Administration of 6-OHDA in

either area resulted in a decrease in the binding site density

found for 3H-PCP. These authors have suggested that PCP and NANM

may induce locomotor activity by interacting with PCP/sigma receptors located presynaptically on terminals of the mesolimbic DA

system (Iwamoto 1981; French et al. 1984). There may, therefore,

be a better case for the involvement of DA in PCP-induced locomotor activity than for stereotypy or rotational behavior, but

more detailed SAR studies are need to confirm this.

A final comment on the DA studies reviewed here: although PCP

does act as an indirect DA agonist similar to methylphenidate and

amfonelic acid, the effects are apparently not mediated via an

action on PCP/sigma receptors. This conclusion is based on the

absence of a significant correlation between (1) the effects of

several drugs from three chemical classes on DA reuptake, DA

release, or haloperidol-induced DA metabolism, and (2) either drug

discrimination behavior or affinity for the site labelled by 3HPCP. This does not rule out the possibility that nonstriatal

dopaminergic mechanisms are important in the general pharmacology

of PCP and related drugs.

The most interesting aspects of the studies reviewed here are that

the drugs having discriminative stimulus properties similar to PCP

also produce ipsilateral turning; and that this behavior is well

correlated with both affinity for the PCP/sigma receptor and the

ability to inhibit the effects of NMDA on transmitter release in

the striatum. Although inhibition of NMDA-induced DA release was

63
not as extensively characterized from an SAR standpoint as was the

inhibition of NMDA-induced ACh release, similar rank order potency

and stereoselectivity were apparent. Since striatal DA neurons

inhibit cholinergic interneurons, blockade of an excitatory input

onto both neurons would effectively cancel any effect on net output from the striatum. However, two points should be considered.

First, the pharmacologic effect in vivo would be dependent on the

endogenous excitatory input (or tone) on these neuronal elements.

That is, if there is very little excitatory input to the dopaminergic terminals relative to the cholinergic interneurons, then

the blockade of excitation by PCP would significantly reduce cholinergic output. However, the relative excitatory tone on these

nerves is unknown. Second, the two- to sixfold greater potency of

PCP-like drugs on ACh release may relegate the effects on DA

release to secondary importance. If this were not the case, one

might expect to observe an increase in ACh release following

blockade of an excitatory input onto the inhibitory dopaminergic

neurons. We never observed this at concentrations as high as

1x10-6 M PCP. It would appear that the inhibition of ACh release

is most important. This indirect anticholinergic effect could be

the basis for PCP-induced turning in this model.

The global nature of glutamate/aspartate distribution and function

suggests the tremendous potential of this mechanism in other PCPinduced behaviors. To determine something of the universality of

this phenomenon, we have conducted preliminary studies in several

brain areas. We have found that PCP inhibits NMDA-induced ACh release from the nucleus accumbens and dendritic DA release from the

substantia nicra. It would be easy to imagine that PCP modulates

excitatory transmission in numerous CNS pathways in addition. How

this occurs at a molecular level is open to speculation. Since

PCP is known to block both Na+ and K+ conductances, and since NMDA

is thought to activate a channel possibly conducting both Na+ and

K

+

, our working hypothesis is that PCP and glutamate (or aspartate) modulate the same conductance channel. At very high concentrations of NMDA, the configuration of the channel and the nearby

PCP/sigma site may be sufficiently altered to account for the

apparent decreased affinity that we observed for 3H-PCP in the

presence of NMDA. At this point, this hypothesis is very tentative, but it will be actively investigated by our laboratory in

the future.

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Leventer, S.M., and Johnson, K.M. Effects of phencyclidine on

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ACKNOWLEDGEMENTS

Thomas Vickroy and Steven Leventer were involved in establishing

the effects of PCP on DA and ACh release that were reviewed in

this paper. This work was supported by the National Institute on

Drug Abuse (DA-02073).

AUTHORS

Kenneth M. Johnson, Ph.D.

Associate Professor

Lawrence D. Snell, B.S.

Research Associate

Department of Pharmacology

and Toxicology

The University of Texas

Medical Branch

Galveston, TX 77550

66
Anticonvulsant Properties of

Phencyclidine and Ketamine

Gary G. Buterbaugh and Hillary B. Michelson

INTRODUCTION

Phencyclidine (1-(1-phenylcyclohexyl)piperidine (PCP)) was the

first in a series of arylcycloalkylamines synthesized in an attempt to develop an intravenous general anesthetic agent. The

compound was subsequently found to produce a complex profile of

acute and chronic effects on overt behavior in animals and humans

(Balster and Chait 1976; Domino 1964; Luby et al. 1958) and central nervous system function, including convulsions (Chen et al.

1959; Matsuzaki and Dowling 1984; Snyder et al. 1981; Winters

1976). In humans, the acute effects of PCP overdosage implicated

in fatalities include seizures and cardiovascular collapse (Burns

and Lerner 1981)) although the most probable cause of death in

humans (Burns and Lerner 1978) and in animals (Chen et al. 1959;

Hackett et al. 1981) is respiratory depression. The production of

end-state convulsive-like activity at lethal doses is common to

many analogs of PCP, with the possible exception of ketamine

(Mattia et al., this volume). Animals administered PCP or PCP

analogs do not move through a dose-related progression of clonic

followed by tonic-clonic convulsions, as is typical of classical

convulsant compounds. The convulsive-like behavior associated

with high doses of PCP-like agents is superimposed upon a background of severe overt behavioral disruption, and is probably a

reflection of a more generalized toxic insult to the central nervous system (CNS) caused by high doses of the compounds.

In contrast to the convulsive-like effects of high doses of PCP

compounds, several models of convulsions have been used to demonstrate anticonvulsant properties of PCP in a variety of species.

In mice, PCP is effective in antagonizing electroshock- or pentylenetetrazol (PTZ)-induced tonic extensor convulsions and audiogenic seizures (Chen et al. 1959; Chen and Bohner 1961). In dogs,

PCP raises the threshold and decreases the duration of the afterdischarge produced by electrical stimulation of the suprasylvian

gyrus (Domino 1964). In rats, the latency for seizures produced

by fluorothyl is prolonged by PCP (Geller et al. 1981). The doses

67
of PCP required to demonstrate anticonvulsant effects are sufficient to cause mild to severe impairment of behavior, but are well

below lethal levels.

The effects of PCP on the amygdala-kindled seizure model have been

reported by Freeman et al. (1982). A 5 mg/kg dose IP results in a

slightly greater than twofold elevation of the threshold for producing amygdala-kindled seizures, but has little effect on the

duration of the EEG afterdischarge or motor seizure. This profile

of effects on the amygdala-kindled seizure does not resemble that

of the convulsant compound pentylenetetrazol, which has no effect

on the threshold but prolongs the duration of the EEG and motor

seizure (Bowyer and Albertson 1982). In addition, PCP and ketamine are effective in antagonizing seizures kindled by repeated

stimulation of the cerebral cortex (Bowyer et al. 1983).

This laboratory has utilized two approaches to define further the

anticonvulsant properties of PCP. One approach involved a relatively simple convulsant model, pentylenetetrazol-induced convulsions. In this model, the administration of ketamine alone, or in

combination with several known anticonvulsants, was tested. Ketamine, as a structural analog of PCP, shares many of the pharmacological properties associated with PCP. The second approach

involved a more complex model, hippocampal-kindled seizures.

Using this model, the ability of PCP, ketamine, and several anticonvulsants to antagonize hippocampal seizures and elevate seizure

thresholds was tested both before and after kindling.

ANTIPENTYLENETETRAZOL ACTIVITY

Male Dublin-ICR white mice were administered pentylenetetrazol

(dissolved in normal saline) by tail vein infusion. This slow

intravenous infusion of PTZ to mice provided three consistent and

easily measured endpoints for assessing anticonvulsant effects:

(a) an initial clonic body jerk followed by (b) tonic limb extension, and (c) lethality. Mice were pretreated with ketamine 15

minutes, and anticonvulsants 30 minutes, prior to PTZ infusion.

All drugs were administered by IP injection.

Figure 1 illustrates the dose-dependent effects of ketamine on

these three endpoints. A dose of 20 mg/kg significantly delayed

tonic limb extension but did not protect against the lethality

associated with this severe convulsive response. Higher doses

significantly delayed the initial clonic convulsive response and

prevented tonic limb extension. At these doses, the tonic extension response was replaced-with the abrupt onset of continuous

clonic limb convulsions, which persisted until death from apparent

respiratory depression. The onset of the continuous clonic convulsions and lethality was also delayed in a dose-dependent

manner, at the higher doses of ketamine.

The profiles of anticonvulsant effects for phenobarbital, phenytoin, and trimethadione were also determined in the PTZ model.

68
Phenobarbital closely resembled ketamine, but was more effective

in delaying clonic and tonic convulsions (figure 1). In contrast,

phenytoin was effective only in preventing tonic extension convulsions and delaying lethality (figure 2). Trimethadione delayed

the clonic and tonic endpoints but did not prevent tonic extension

convulsions or the lethal effect of the tonic convulsion

(figure 2).

FIGURE 1. Effect of phenobarbital and ketamine on pentylenetetrazol convulsions

NOTE: Solid lines = clonic convulsions, dashed Iines = tonic extensor convulsions

and dotted lines = lethality. Open circles represent doses preventing

extension and delaying lethality (see text). Data are expressed as mean +

s.e.m., n=6-7 mice per point. *indicates significant difference from control,

The interaction of ketamine with each of the three anticonvulsant

compounds was also tested. Ketamine, 15 mg/kg, a dose showing no

anti-PTZ effect and causing no overt behavioral changes, potentiated the effect of phenobarbital (20 mg/kg) in delaying the clonic

and tonic convulsive responses and lethality (figure 3). Ketamine

also potentiated the ability of phenytoin (20 mg/kg) to delay

69
FIGURE 2. Effects of Phenytoin and Trimethadione on Pentytenetetrazol convulsions (see legend for figure 1 for

details)

lethality (not shown). No interaction was found between ketamine

and trimethadione (2OO mg/kg).

KINDLED SEIZURES

A model of seizures that many consider to resemble human epileptogenesis closely is the kindling model of epilepsy. Kindling

involves the administration of low intensity stimulation to a

specific brain region (e.g., the amygdala) at regular intervals.

Initially, the stimulation produces a synchronous electrical

afterdischarge with no behavioral correlates; however, as kindling

progresses, a stable clonic convulsive response, which is retained

for long periods of stimulation-free time, gradually results

(Goddard et al. 1969). The kindling model provides the unique

opportunity to assess the effect of a compound on the threshold

for initiating a seizure, the initial prekindled seizure, and the

fully kindled seizure. Many anticonvulsant compounds that are

ineffective against the prekindling afterdischarge are very active

in antagonizing some component of the fully kindled seizure.

70
FIGURE 3. Interaction between ketamine and phenobarbital against

pentylenetetrazol convulsions

NOTE: Ketamine, 17.5 mg/kg and phenobarbital, 20 mg/kg, were Injected 15 and 30

min., respectively, prior to pentylenetetrarol Infusion. Data are

expressed as mean ± s.e.m., n=5-6 mice per point. *indicates significant

difference from control, P< .05.

We have evaluated the dose-related effects of PCP, ketamine, and

selected anticonvulsant drugs on seizure activity in the hippocampal model of kindled seizures. The hippocampal model is particularly well suited for the study of the anticonvulsant effects of

drugs because of the slow rate of acquisition of the fully kindled

seizure. Electrical stimulation of the dorsal hippocampus initially evokes a stereotyped sequence of behavior, accompanied by a

characteristic EEG pattern. Repeated electrical stimulation eventually results in generalized kindled seizures. This allows the

testing of drugs on the unkindled hippocampal seizure (afterdischarge) to be compared to effects on the fully kindled seizure

in the same rats.

Male, Sprague-Dawley rats were implanted under pentobarbital anesthesia with a bipolar electrode in the right dorsal hippocampus

for hippocampal stimulation and recording. Stainless steel screws

were also placed over the contralateral frontal and parietal cortices for recording cortical seizure activity. The electrodes

71
were connected to an Ampherol headpiece and the assembly affixed

to the skull with dental acrylic. Ten days later, the threshold

for eliciting hippocampal afterdischarge (AD) was determined with

an ascending series of stimulations (1 second of 60 Hz, biphasic

square-wave pulses of 1 millisecond duration) at 5-minute intervals. At 7-day intervals, the rats were administered either vehicle or drug, and the threshold determined as above. EEG was

recorded (Grass Model 7 polygraph) 2 minutes prior to stimulation,

and continued for 2 minutes following termination of the seizure.

Each rat received a maximum of four drug trials.

The rats were next administered twice daily hippocampal stimulation (2xthreshold) until three consecutive stage V convulsive

responses (Racine 1972) were obtained, indicating that the rats

were fully kindled. The average number of stimulations to achieve

the kindled state was 41.4 ± 2.3 stimulations. Drug effects on

seizure threshold and the kindled seizure were assessed as described above for the prekindled seizure.

Effect on Hippocampal Seizures (Prekindling)

The control EEG records in figure 4 illustrate the typical EEG

response produced by hippocampal stimulation in unkindled rats.

An initial afterdischarge is followed by a period of postictal

depression, which is interrupted by a brief episode of rebound

spiking. The effects of PCP and ketamine on the hippocampal seizure are also illustrated in figure 4. Doses of PCP and ketamine

(IP administration, 15 minutes prior to stimulation) causing

equivalent overt behavioral effects were chosen, and produced

nearly identical effects on the hippocampal response. The initial

AD was slightly prolonged, and the period of postictal depression

was shortened, allowing the rebound spiking to appear earlier,

thus decreasing the total seizure duration. Ketamine, at an anesthetic dose of 80 mg/kg, resulted in suppression of the rebound

spiking.

Anticonvulsant drugs such as carbamazepine, diazepam, valproic

acid, and phenobarbital also slightly increased the duration of

the initial AD. However, the effects of these drugs on the other

associated seizure events were quite different from PCP and ketamine. The effects of carbamazepine and diazepam, typical of the

four compounds, are illustrated in figure 4. These compounds

either suppressed the rebound spiking (diazepam, valproic acid,

and phenobarbital) or lengthened the total seizure duration with

no rebound suppression (carbamazepine).

Effects on Kindled Hippocampal Seizures

The fully kindled hippocampal seizure is quite different from the

prekindled seizure described above. The hippocampal response typically appears as a continuous AD, with a duration similar to the

total duration of the unkindled response. In other words, the unkindled EEG response of initial AD, postictal depression, and

72
FIGURE 4. Effect of phencyclidine (PCP) and ketamine (KET) on the

prekindling hippocampal seizure (afterdischarge)

NOTE: The effects of carbamarepine (CBZ) and diazepam (DZP) are Included as

representative of antlconvulsant drugs. Total seizure duration (control)

averaged 110 seconds. See text for details of seizure response.

73
rebound spiking is replaced by continuous AD activity. Moreover,

prominent spiking activity is also continuously recorded from the

cerebral cortex, and the characteristic motor seizure responses

occur. Drug effects on the fully kindled hippocampal seizure were

much different from those seen on the prekindled seizure. Moreover, in marked contrast to the effects on the unkindled seizure,

the effects of PCP, ketamine, and the four anticonvulsants on the

kindled seizure were quite similar. PCP, ketamine, and the four

anticonvulsants all significantly decreased the duration of the

hippocampal EEG seizure and reduced the severity of the motor seizures (table 1). However, none of the six compounds, even in

doses resulting in loss of righting reflex, completely prevented

the kindled seizure response. The EEG seizure response was less

sensitive to the drug effects than was the motor convulsive

response.

TABLE 1. Effect of PCP, ketamine and selected anticonvulsants on

the duration and severity of hippocampal kindled seizures

Compound

Dose

(Mg/Kg)

Seizure Convulsive

Duration Response

(Seconds) (Stage)

PCP

Ketamine

Phenobarbital

Valproic acid

Carbamazepine

Diazepam

0

5

15

0

20

40

0

25

50

0

125

225

0

25

121 ± 8

84 ± 9 *

76 ± 11*

119 ± 7

79 ± 4 *

71 ± 6 *

124 ± 9

79 ± 19*

42 ± 7*

123 ± 7

69 ± 14*

24 ± 10*

130 ± 8

107 ± 24

128 ± 7

31 ± 4 *

17 ± 6 *

5.0

4.0

1.8

5.0

3.0

2.4

5.0

1.8

0.5

5.0

1.0

0.8

5.0

1.3

0

2

8

5.0

0.0

0.0

*Indicates significant difference from control, P<.05.

NOTE: Data expressed as mean ± s.e.m., n=4-6 rats per dose.

74
Effects on After discharge and Seizure Threshold

PCP, 15 mg/kg, and ketamine, 40 mg/kg, elevated the threshold for

eliciting hippocampal afterdischarge (prekindling) by 61 percent

and 267 percent, respectively (table 2). Valproic acid and carbamazepine also elevated the threshold. In contrast, phenobarbital

and diazepam had no effect on the prekindling afterdischarge

threshold, even at doses capable of altering the AD.

TABLE 2. Increased sensitivity of hippocampal seizure threshold

to drug effects following kindling

Percent Increase in Threshold

Compound

Dose Before

(Mg/Kg)

Following

Kindling Kindling

PCP 5

15

Ketamine 20

40

Phenobarbital 25

50

Valproic acid 150

225

Carbamazepine 25

Diazepam 2

8

11 ± 11

267 ± 90*

15 ± 7

61 ± 21*

10 ± 7

7 ± 7

75 ± 29 *

180 ± 26 *

16 ± 13

631 ± 89 **

381 ± 83 **

786 ± 98 **

214 ±

389 ±

66 **

120 **

90 **

50 **

272 ±

272 ±

657 ± 150 **

5 ± 3

1 8 ± 12

10 ±

24 ±

4

14

*Indicates significant difference from vehicle control before kindling, P<.05.

**Indicates significant difference from prekindling threshold, P<.05.

NOTE: Data expressed as mean ± s.e.m., n=4-6 per dose.

Following the completion of kindling, the seizure threshold was

not significantly different from the prekindling threshold. However, there was a marked increase in the sensitivity of the

kindled seizure threshold to all drugs except diazepam and the

lower dose of PCP (table 2). The most dramatic increase in

threshold sensitivity was with ketamine, 40 mg/kg. Before kindling, this dose of ketamine elevated the AD threshold by 61 percent; following kindling, this dose elevated the AD and seizure

threshold by 786 percent. In contrast, diazepam, even at a dose

75
(8 mg/kg) resulting in marked sedation and akinesia, had no effect

on the kindled seizure threshold.

DISCUSSION

The results demonstrate anticonvulsant properties of PCP and ketamine in two quite different seizure models. On the one hand,

ketamine was effective in antagonizing several components of PTZ

activity. Others have previously reported anti-PTZ effects of

ketamine. However, the present results demonstrate that the anticonvulsant effects of ketamine against PTZ seizures closely resembled the effects of phenobarbital in that both compounds delayed

clonic convulsions and prevented tonic extension. Moreover, a low

dose of ketamine, which alone showed no anticonvulsant effect or

overt behavioral changes, potentiated the anti-PTZ effects of

phenobarbital. These findings suggest that ketamine possesses

selective anticonvulsant properties. The anticonvulsant mechanism

of action for phenobarbital is not known. However, the similarities between ketamine and phenobarbital, and the interaction between the two compounds, suggest a common mechanism or site of

action.

Although PCP was not included in these experiments using the PTZ

model, PCP has been shown previously to antagonize PTZ convulsions

(see above). Since ketamine and PCP share many common pharmacological properties, it is reasonable to expect that PCP would show

effects similar to those seen with ketamine. In fact, since these

experiments were done, others have compared the anticonvulsant

effects of structural analogs of PCP. For example, all compounds

tested thus far are active against electroshock-induced convulsions, with some analogs more active than PCP or ketamine at behaviorally equivalent doses (Mattia et al., this volume). Further

study of the anticonvulsant properties of PCP derivatives may thus

provide clues to anticonvulsant drug mechanisms of action.

On the other hand, the results using the hippocampal seizure model

revealed an interesting profile of anticonvulsant effects for PCP

and ketamine, compared to several classical anticonvulsant compounds. When tested against the unkindled hippocampal seizure,

the effects of behaviorally equivalent doses of PCP and ketamine

were remarkably similar, but differed substantially from the effects of the anticonvulsant drugs. The compression of the entire

EEG seizure episode to a shorter duration was unique to PCP and

ketamine, and suggests an anticonvulsant effect. Conversely, the

small prolongation of the initial AD episode, and the decreased

duration of the postictal depression, could be reflective of proconvulsive influences. There were, however, no other indications

of enhanced seizure activity , such as the appearance of motor convulsions or spread of seizure activity to the cerebral cortex.

76
The four anticonvulsant compounds, like PCP and ketamine, prolonged the initial AD of the prekindled hippocampal seizure. However, diazepam, valprok acid, and phenobarbital, unlike PCP or

ketamine, also suppressed the rebound spiking. Carbamazepine

showed an even different profile of effects, causing a marked

prolongation of the initial AD, rebound spiking, and the total

seizure duration. Thus, although the seizure discharge evoked by

hippocampal stimulation was altered in a similar manner by both

PCP and ketamine, the seizure activity responded differently to

the anticonvulsant compounds. Moreover, unlike the results with

the PTZ model, ketamine did not resemble phenobarbital in the

hippocampal model. These differences may be a reflection of the

focal character of the prekindled hippocampal seizure, in contrast to the more widespread CNS stimulatlon following PTZ

administration.

During the acquisition of kindled seizures, a progressive recruitment of structures into a network of neuronal circuits capable of

supporting seizures has been described (Engel et al. 1978).

During this process, the changes in seizure discharge and motor

convulsions characteristic of kindling appear. Therefore, the

kindled seizure reflects altered CNS function, and may more

closely approximate the underlying conditions of epileptogenesis.

When the compounds were tested against the fully kindled hippocampal seizure, a different pattern emerged. PCP and ketamine now

exerted anticonvulsant effects similar to the four anticonvulsant

compounds. All six agents caused a dose-related reduction of the

duration of the kindled seizure, and decreased the severity of the

motor convulsions. This similarity suggests that kindled epileptogenesis is associated with altered substrates or the formation

of additional substrates necessary for the support of seizure

activity. It is possible that it is against these altered or

new substrates that drugs with anticonvulsant properties are

effective.

This speculation is supported by the marked increase in the sensitivity of the seizure threshold to drug-induced elevation

following kindling. Clearly, the process of kindling produces

alterations in the manner in which the existing neuronal circuitry

responds to drug administration. Interestingly, diazepam, at

doses capable of altering both the prekindled and kindled seizure,

had no effect on either the prekindling or kindled seizure threshold. Therefore, the change in sensitivity of the seizure threshold following kindling, while related to other kindling-induced

alterations in brain function, is nonetheless distinct from them.

Further studies of the mechanisms of action by which PCP and ketamine alter seizures and thresholds, particularly involving comparisons before and after kindling , and with classical anticonvulsant

drugs, may provide clues to mechanisms of epileptogenesis.

77
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phencyclidine. J Toxicol Clin Toxicol 9:512-528, 1976.

Bowyer, J.F., and Albertson, T.E. The effects of pentylenetetrazol, bicuculline and strychnine on the development of kindled

seizures. Neuropharmacology 21:985-990, 1982.

Bowyer, J.F.; Albertson, T.E.; and Winters, W.W. Cortical kindled

seizures: Modification by excitant and depressant drugs.

Epilepsia 24:356-367, 1983.

Burns, R.S., and Lerner, S.E. Phencyclidine deaths. J Am Coll

Emerg Physicians 7:135-141, 1978.

Burns, R.S., and Lerner, S.E. The effects of phencyclidine in

man: A review. In: Dominmo, E.F., ed. PCP (Phencyclidine):

Historical and Current Perspectives. Ann Arbor: NPP Books,

1981. pp. 449-469.

Chen, G., 'and Bohner, B. Anticonvulsant properties of 1-(1-phenylcyclohexyl)piperidine HCl and certain other drugs. Proc Soc

Exp Biol Med 106:632-635, 1961.

Chen, G.; Ensor. C.; Russell, D.; and Bohner, B. The pharmacology

of 1-(1-phenylcyclohexyl)piperidine HCl. J Pharmacol Exp Ther

127:241-250, 1959.

Domino, E.F. Neurobiology of phencyclidine (Sernyl), a drug with

an unusual spectrum of pharmacological activity. Int Rev Neurobiol 6:303-347, 1964.

Engel, J.; Wolfson, L.; and Brown, L. Anatomical correlates of

electrical and behavioral events related to amygdala kindling.

Ann Neurol 3:538-544, 1978.

Freeman, F.G.; Jarvis, M.F.; and Duncan, P.M. Phencyclidine

raises kindled seizure thresholds. Pharmacol Biochem Behav

16:1009-1011, 1982.

Geller, E.B.; Adler, L.H.; Wojino, C.; and Adler, M.W. The anticonvulsant effect-of phencyclidine in rats. Psychopharmacology

(Berlin) 74:97-98, 1981.

Goddard, G.V.; McIntyre, D.; and Leech, C. A permanent change in

brain function resulting from daily electrical stimulation. Exp

Neurol 25:295-330, 1969.

Hackett, R.B.; Obrosky, K.W.; Borne, R.F.; and Water, I.W. Acute

phencyclidine poisoning in the unanesthetized dog: Pathophysioionic profile of acute lethality.

Luby, E.D.; Cohen, B.D.; Rosenbaum, G.;

R,

Toxicology 19:11-20, 1981.

Study of a new schizophrenomimetic drug--Sernyl. AMA Arch

Neurobiol Psychiatry 81:113-119, 1958.

Matsuzaki. M.. and Dowlina. K.C. Phencyclidine (PCP): Effects on

auditory evoked potentiais in the rhesus monkey. Brain Res Bull

13:155-161, 1984.

Racine, R. Modification of seizure activity by electrical stimulation: II. Motor seizure. Electroenceph Clin Neurophysiol

32:280-294, 1972.

Snyder, E.W.; Schleuhuber, C.; Dustman, R.E.; and Shearer, D.E.

Phencyclidine-induced alterations of rat electrophysiology.

Brain Res Bull 7:249-253, 1981.

78
Winters, W.D. Effects of drugs on electrical activity of the

brain: Anesthetics. Annu Rev Pharmacol Toxicol 16:413-426,

1976.

AUTHORS

Gary G. Buterbaugh, Ph.D.

Associate Professor

Department of Pharmacology and Toxicology

University of Maryland School of Pharmacy

20 North Pine Street

Baltimore, MD 21201

Hillary B. Michelson, NIMH predoctoral fellow

Department of Pharmacology and Toxicology

University of Maryland School of Pharmacy

20 North Pine Street

Baltimore, MD 21201

79
Agonistic and Antagonistic Effects

of PCP-Derivatives and Sigma

Opioids in PCP Behavioral and

Receptor Assays

Patricia C. Contreras, Remi Quirion, and Thomas L. O’Donohue

Phencyclidine (PCP, 1-(1-phenylcyclohexyl)piperidine, angel dust)

was first synthesized in 1957 as an anesthetic by the Parke Davis

pharmaceutical company. PCP is a "dissociative" anesthetic with

minimal respiratory and cardiovascular depression. However, clinical use of PCP was discontinued because it produced post-anesthetic hallucinations often lasting more than 12 hours in about 30

percent of patients (Greifenstein et al. 1958). Today, PCP is one

of the most abused drugs, due in part to its ability to elicit

hallucinations, excitation, and feelings of tranquility. PCP can

also produce very violent aggressive behavior and a psychosis that

resembles the acute symptoms of schizophrenia. Thus, it has been

suggested that PCP may be a better drug model for schizophrenia

than amphetamine (Allen and Young 1978). So far, there is no

specific treatment for PCP intoxication or the schizophrenia-like

psychosis because the mechanisms responsible for the effects of

PCP are not known.

It is believed that many of the behavioral effects of PCP are due

to interactions with specific PCP receptors, which were first

characterized by Vincent et al. (1979) and Zukin and Zukin (1979).

These binding sites appear to satisfy many of the criteria for a

PCP receptor because the binding of 3H-PCP to brain homogenates is

reversible, saturable, stereoselective, occurs with a relatively

high affinity (Vincent et al. 1979; Zukin and Zukin 1979; Quirion

et al. 1981a), and has a selective regional distribution (Quirion

et al. 1981b). Furthermore, the binding of 3H-PCP was rapidly inactivated by heat and destroyed by proteases, indicating that the

PCP receptor is a protein (Vignon et al. 1982). In addition,

serotonin, LSD, benzodiazepines, cholinergic, dopaminergic, and

adrenergic agonists and antagonists did not inhibit the binding

of 3H-PCP. Only drugs that produced PCP-like psychotomimetic

effects--PCP analogs, dexoxadrol, and sigma opioids--were able to

displace the binding of 3H-PCP at low concentrations, which has

led to the suggestion that the PCP receptor is also the sigma

opioid receptor (Quirion et al. 1981b). This possibility is supported by the Finding that PCP analogs inhibit the binding of

80
3

H-cyclazocine (Zukin and Zukin 1981), sigma opioids generalize to

PCP stimulus (Shannon 1981; Brady et al. 1982) and conversely PCP

generalizes to many sigma opioids in drug discrimination paradigms

(Teal and Holtzman 1980; Shannon 1983). But these are repasts

showing that differences between the binding of 3H-PCP and 3H-SKF10,047 are significant (Tam 1983; Martin et al. 1985).

The relevance of PCP receptors is supported by reports that the

ability of PCP-like drugs to produce PCP-like stimulus in drug

discrimination paradigms (Shannon 1981; Holtzman 1980; Brad and

Balster 1981), produce vasoconstriction (Altura et al. 1983) and

produce ataxia (Vincent et al. 1979; Vignon et al. 1982; Vaupel

et al. 1984) correlates well with their ability to bind to PCP

receptors.

In rodents, PCP produces not only ataxia, but also stereotyped

behavior and hyperactivity. The PCP-induced stereotyped behavior

is thought to be due to changes in serotonergic and dopaminergic

systems (Nabeshima et al. 1983; Martin et al. 1979; Sturgeon et

al. 1981). It is not known whether PCP receptors mediate PCPinduced hyperactivity or stereotyped behavior or even the effect

on neurotransmitter systems. It is also possible that mu, kappa,

or sigma opioid receptors are involved (Castellani et al. 1982).

The purpose of these studies was to determine whether stereotyped

behavior and ataxia induced by PCP-like drugs and sigma opioids is

mediated by PCP receptors. Also, we wanted to investigate whether

sigma opioid and PCP receptors are the same receptors using behavioral and radioreceptor assays.

COMPARISON BETWEEN INDUCTION OF PCP-LIKE STEREOTYPED BEHAVIOR AND

ATAXIA TO INTERACTIONS WITH PCP RECEPTORS

Using the PCP rating scale for stereotyped behavior and ataxia as

described by Sturgeon et al. (1979), the central effects of PCP

analogs, dexoxadrol, and its levo-isomer, levoxadrol, were determined. As shown in figure 1, all drugs except the (-) isomers

produced dose-dependent stereotyped behavior. In contrast,

(-)PCMP was equipotent with (+)PCMP in induction of ataxia (figure

2). Furthermore, TCM, which was one-fifth as potent as PCP in the

induction of stereotyped behavior, was as potent as PCP in induction of ataxia. The ability of PCP-like drugs to bind to PCP receptors, as measured by their ability to inhibit the binding of

3

H-PCP, was determined as described by Contreras et al. (in preparation). The order of relative potencies of drugs as compared to

PCP was TCP > PCE > PCP = NIPCA > dexoxadrol > (+) PCMP > TCM =

(-) PCMP >> levoxadrol. A comparison of the ability of drugs to

bind to PCP receptors and induce stereotyped behavior (figure 3A)

resulted in a straight line (r=0.98), that intersected the origin.

However, the correlation between a drug's ability to bind to PCP

receptors and to induce ataxia (figure 3B) did result in a good

fit to a straight line (r=0.80) but did not intersect the origin.

81
FIGURE 1. Dose-response curves for induction of stereotyped behavior. Ratings for each animal were determined 5

minutes after ICY administration of each drug. At

least 21 rats were used to determine each doseresponse curve.

Thus, stereotyped behavior appears to be mediated by PCP receptors, but ataxia appears to be mediated by more than just an

interaction with PCP receptors.

Only the (+) isomer of SKF-10,047, which very weakly inhibited the

binding of 3H-PCP, induced stereotyped behavior. This finding is

consistent with the results of the PCP receptor assay showing that

(+)SKF-10,047 is one-tenth as potent as PCP, but is fivefold more

potent than (-)SKF-10,047 (table 1). However, it was not possible

to determine whether SKF-10,047 was a full agonist because of its

poor solubility in saline. Also, SKF-10,047 produced weaving and

circling behavior that was much less pronounced than that induced

by PCP. In contrast to the results of the assays for stereotyped

82
FIGURE 2. Dose-response curves for induction of atazia. Behavioral ratings were determined 5 minutes after drug

administration ICV. At least 21 rate were used to

determine each dose-response curve.

behavior and binding to PCP receptors, the (-) isomer of SKF-0,047

was more potent than the (+) isomer in induction of ataxia.

Stereoselectivity was evident in the assays for stereotyped behavior and PCP receptor interaction, but not in the assay for ataxia

as the (+) isomers of the PCP-like drugs and SKF-10,047 were more

potent than the (-) isomers in induction of stereotyped behavior

and inhibition of binding of 3

H-PCP. However, one exception to

this trend is that the (-) isomer of cyclazocine was more potent

than the (+) isomer in industion of stereotyped behavior and inhibition of the binding of 3

H-PCP.

Since large doses of naloxone (10 and 50 m/kg) did not antagonize

the ability of PCP or cyclazocine to induce stereotyped behavior

83
FIGURE 3. Comparison of the relative potency (ED50 of PCP/ED50 of

drug) for induction of (A) stereotyped behavior or

(B) ataxia to the relative potency (IC50 of PCP/IC50

of drug) for inhibition of the binding of 3H-PCP

or ataxia, it is unlikely that mu, kappa, or sigma opioid receptors play a role in mediating these PCP-like behavioral effects.

In addition, naloxone pretreatment did not antagonize the ability

of (-)SKF-10,047 to induce ataxia.

EFFECT OF METAPHIT ON PCP-INDUCED BEHAVIORAL EFFECTS AND PCP

RECEPTORS

Metaphit, (1-(1-(3-isothiocyanatophenyl)cyclohexyl)piperidine), is

a PCP analog that specifically acylates PCP receptors in vitro

(Rafferty et al. 1985). Additional experiments were performed to

determine whether metaphit could acylate PCP receptors in vivo and

84
antagonize PCP induction of stereotyped behavior and ataxia. Pretreatment of rats with 1 or 2 μmol/rat of metaphit intracerebroventricular (ICV) 24 hours prior to sacrifice, resulted in a 25

percent and 40 percent decrease in the Bmax, but no change in the

Kd of binding of 3H-PCP.

binding of 3H-etorphine or

Metaphit pretreatment did not alter the

3

H-spiroperidol. Since the preparation

of the brain homogenates for the binding assays consisted of two

washes and was prepared 24 hours after metaphit pretreatment,

these results demonstrated that metaphit specifically binds irreversibly to PCP receptors after in vivo administration.

Metaphit administered alone at doses up to 1 μmol/rat did not produce any significant behavioral effects. However at doses of 2

μmol/rat and larger, metaphit produced PCP-like stereotyped behavior and ataxia. Thus, metaphit is a very weak PCP agonist. In

addition to acute effects, metaphit produced convulsions, which

were evident between 5 and 24 hours after ICV administration of

2 μmol/rat.

Metaphit administered ICV prior to PCP administered ICV antagonized PCP induction of stereotyped behavior and ataxia up to 5

days after metaphit pretreatment. The antagonism of the behavioral effects of PCP by metaphit was dose dependent as is shown in

figure 4. Furthermore, this antagonism by metaphit is specific as

metaphit pretreatment ICV did not antagonize amphetamine-induced

stereotyped behavior and could be prevented by pretreating rats

with PCP just prior to metaphit administration. These results

indicate that acylation of PCP receptors results in decreased

ability of PCP to induce stereotyped behavior.

Since metaphit appears to specifically acylate PCP receptors,

metaphit is a useful tool with which to study the physiological

role of PCP receptors. When metaphit was administered ICV prior

to IP administration of PCP, metaphit antagonized the ability of

PCP to induce stereotyped behavior, but not its ability to induce

ataxia. Thus, it appears that ataxia is mediated by both central

and peripheral mechanisms. It is unlikely that the peripheral

effect of PCP in induction of ataxia is mediated by PCP receptors

as 20 mg/kg of metaphit administered IV only antagonized PCPinduced stereotyped behavior when PCP was also administered

peripherally.

Cyclazocine and PCP probably do not induce stereotyped behavior

and ataxia through an interaction with the same receptor, as metaphit did not antagonize the behavioral effects of cyclazocine.

Yet, cyclazocine was able to displace the binding of 3H-PCP. These

findings are consistent with the finding that metaphit can only

bind irreversibly to about 50 percent of the receptors labeled by

3

H-PCP (Rafferty et al. 1985), which indicates that 3H-PCP binds

to more than one type of receptor. Thus, PCP and cyclazocine

probably exert their effects through different receptors.

85

185-466 0 - 87 - 4
FIGURE 4. PCP (ICV) dose-response curves for induction of

(A) stereotyped behavior and (B) ataxia in control

animals ( ) or 24 hours after ICV administration of

1 μmoZ/rat ( ) or 2 μmol/rat ( ) of metaphit

COMPARISON OF THE BINDING OF 3H-PCP, 3H-TCP, 3H-DEXOXADROL AND

3

H-(+)SKF 10,047

The question whether PCP and sigma opioids bind to more than one

receptor was studied by comparing the binding and regional distribution of binding sites labeled by 3

H-PCP, 3H-TCP, 3

H-dexoxadrol,

86
and 3

H-(+)SKF-10,047. 3H-dexoxadrol, 3H-TCP, 3H-PCP, and 3H-

(+)SKF-10,047 did not bind to mu, kappa, or sigma opioid receptors

or to alpha or beta adrenergic, serotonin, benzodiazepine, or GABA

receptors. Only very large concentrations of cholinergic drugs

displaced the binding of 3H-PCP. Also dopamine, apomorphine,

(+)butaclamol did not inhibit the binding of 3H-PCP. However, the

rank orders of potency for inhibition of binding of 3H-PCP, 3Hdexoxadrol and 3

H-(+)SKF-10,047 by PCP analogs and sigma opioids

were different (table 1). Although the PCP analogs appeared to

bind to the tritiated ligands with about the same degree of potency, dexoxadrol, levoxadrol, and the sigma opioids varied greatly

in their ability to displace the tritiated ligands. Also, the

difference in potency of the isomers varied depending upon the

tritiated ligand. These results indicate that PCP, (+)SKF-10,047

and dexoxadrol do not interact with a homogenous population of

binding sites.

TABLE 1. Relative potency of drugs for inhibition of binding of

3H-PCP, 3H-(+)SKF-10,047 and 3H-dexoxadrol

Relative potency* for

inhibition of the binding of

Drug 3

H-PCP 3H-(+)SKF-10,047 3

H-dexoxadrol

PCP

TCP

PCE

NIPCA

TCM

PHP

THP

PCDEA

1.0

4.8

1.0

4.9

-

-

-

-

-

Dexoxadrol 0.9

Levoxadrol <0.1

0.3

0.4 -

(±)SKF-10,047 <0.1

(+)SKF-10,047 0.1

(-)SKF-10,047 <0.1

(+)cyclazocine 0.1

(-)cyclazocine 0.5

Dextrorphan 0.6

1.6

1.0

<0.1

1.4

0.8

0.3

1.7

0.6

4.0

11.8

0.5

1.7

1.4

1.6

1.0

1.8

0.6

0.2

1.4

0.9

0.2

50.9

0.2

0.3

0.2

0.8

0.9

-

*Relative potency = IC50 of PCP/IC50 of drug for dlsplaclng 8 nM of 3H-PCP,

6 nM of 3H-(+)SKF-10,047, or 7 nH of 3H-deroxadrol.

Another method used to study whether these tritiated ligands bind

to different groups of binding sites was to determine the regional

distribution of binding sites labeled by 3H-TCP and 3H-dexoxadrol.

3

H-TCP was used to label PCP receptors because PCP receptors have

87
a higher affinity for TCP than for PCP and the degree of nonspecific binding is lower for 3

H-TCP than for 3H-PCP. Thus, the

distributiog of binding sites was more clearly defined when

labeled by 3H-TCP than when labeled with 3H-PCP. 3H-TCP appeared

to bind to the same receptors as 3H-PCP because the

potencies for inhibition of binding of 3H-TCP and

order of

3

H-PCP by PCP

analogs and sigma opioids were the same. The areas of the rat

brain with the highest density of binding sites labeled by 3H-TCP

were the superficial layers of cerebral cortex, dentate gyrus,

subiculum and hippocampus, with much lower densities of binding

sites in the olfactory bulb, olfactory tubercle, caudate nucleus,

nucleus accumbens, interpeduncular nucleus, periaqueductal gray,

superior colliculus, and cerebellum. Very low densities of binding sites were found in most of brainstem, spinal cord, and hypothalamus. 3

H-dexoxadrol labeled many more areas of the rat brain

than 3H-TCP (Pilapil et al., in press), For example, in the hypothalamus, which was poorly labeled by 3

H-TCP, there was a large

density of binding sites labeled by 3

H-dexoadrol (figure 5).

Analysis of the binding sites labeled by H-dexoxadrol in the

hypothalamus and cortex, as measured by displacement curves of 3Hdexoxadrol by a variety of ligands, indicated that the binding

sites in the cortex and hypothalamus were different (table 2).

The order of drug potencies of the PCP analogs for inhibition of

binding of 3H-dexoxadrol were similar in the cortex and hypothalamus, but the order of potency for the isomers of SKF-10,047 were

reversed in the hypothalamus as compared to binding in

This is the same order of potency for the isomers of

the cortex.

3

H-SKF-10,047

for induction of ataxia and analgesia (Aceto and May 1983), but

3

H-dexoxadrol does not bind to mu, kappa, or sigma opioid receptors as mu, kappa, or sigma opioid ligands did not displace the

binding of 3H-dexoxadrol in the hypothalamus. Haloperidol only

displaced binding of 3H-dexoxadrol in the hypothalamus. Thus, 3Hdexoxadrol labels more than one kind of binding site.

CONCLUSIONS

These results clearly demonstrate that PCP-like drugs administered

centrally produce stereotyped behavior that is mediated by PCP

receptors. A causal relationship between binding to PCP receptors

and induction of stereotyped behavior is also supported by the

ability of metaphit, which specifically acylates PCP receptors in

vivo, to antagonize induction of stereotyped behavior. The order

of drug potency of PCP analogs and dexoxadrol to induce stereotyped behavior is similar to that seen in other studies on the

binding of 3H-PCP (Hampton et al. 1982; Murray and Leid 1984) and

in drug discrimination assays (Shannon 1981; Shannon 1982). Also,

the finding that the (+)SFK-10,047 and (-)cyclazocine were the

more potent isomers in inducing stereotyped behavior and inhibiting the binding of 3

H-PCP is consistent with results from drug

discrimination paradigms (Herling et al. 1983; Shannon 1983;

Shearman and Herz 1982). Thus, stereotyped behavior, like drug

discrimination paradigms, is a good behavioral assay for studying

PCP receptor interaction.

88
FIGURE 5. Automdiograms of binding sites labeled by (A) 3H-TCP

and (B) 3H-dexoxadrol in coronal sections of rat

brain

89
TABLE 2. Inhibition of binding of 3H-dexoxadrol in cortex and

hypothalamus

Relative Potency*

Drug Cortex Hypothalamus

PCP

PCE

TCP

PHP

THP

TCM

PCC

Dexoxadrol

(+) cyclazocine

(-) cyclazocine

(+) SKF-10,047

(-) SKF-10,047

Haloperidol

1.0

0.6

1.8

1.4

0.9

0.2

<O.1

51

0.8

0.9

0.3

0.2

<0.1

1.0

0.5

1.3

0.7

1.1

<0.4

<0.4

137

1.0

3.8

0.9

3.4

10

*Relative potency = IC50 of PCP/IC50 of drug for displacing 7 nM of 3H-dexoxadrol.

The results of the assays for ataxia indicate that ataxia is

induced by more than just an interaction with PCP receptors. The

inability of metaphit to antagonize PCP-induced ataxia after

peripheral administration is another indication that interactions

other than with PCP receptors also mediate ataxia.

It is unlikely that mu, kappa, or sigma opioid receptors mediate

ataxia or stereotyped behavior as naloxone did not antagonize the

behavioral effects of PCP or cyclazocine. Also, mu, kappa, or

sigma ligands did not inhibit the binding of 3H-PCP. These results are consistent with reports that large doses of naloxone or

naltrexone had no effect or minimal effect on the actions of PCP

or SKF-10,047 in drug discrimination paradigms (Teal and Holtzman

1980; Vaupel 1983; Shannon 1982; Shearman and Herz 1982; Herling

et al. 1983). Since most of the studies indicate that mu, kappa,

or sigma opioid receptors do not mediate the behavioral effects of

PCP, it is unclear why Castellani et al. (1982) found naloxone to

antagonize PCP-induced stereotyped behavior and ataxia.

The finding that metaphit did not antagonize (-)cyclazocine

induction of stereotyped behavior or ataxia is evidence that PCP

receptors and sigma opioid receptors are different receptors.

Also, it is clear that 3H-PCP labels more than one binding site

because metaphit can only bind irreversibly to about 50 percent of

90
the binding sites labeled by 3

H-PCP. It is also evident that 3Hdexoxadrol, and probably 3

H-SKF-10,047, do not bind to a homogenous population of binding sites. The binding sites labeled by

3

H-dexoxadrol in the hypothalamus appear to be similar to the

sigma opioid binding sites describ

peridol displaced the binding of

ed by Tam (1983) because halo3

H-dexoxadrol in this region.

In summary, induction of stereotyped behavior appears to be mediated by PCP receptors, whereas induction of ataxia is due to more

than one mechanism. Metaphit is a useful tool for studying the

role of PCP receptors, as it specifically acylates PCP receptors.

The question whether PCP and sigma opioid receptors are the same

receptors is complicated by the fact that none of the tritiated

ligands used to label PCP and sigma opioid receptors studied binds

to a homogenous population of receptors. However, it does not

appear that sigma opioids and PCP analogs exert their behavioral

effects through a common receptor.

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ACKNOWLEDGEMENT

This work was supported in part by the Chemical Research and

Development Center, U.S. Army.

AUTHORS

Patricia C. Contreras

Experimental Therapeutics Branch

National Institute of Neurological and

Communicative Disorders and Stroke

National Institutes of Health

Bethesda, MD 20205

and

Howard University

Department of Medicine

Washington, DC 20059

Remi Quirion

Douglas Hospital Research Centre

and Department of Psychiatry

McGill University

Verdun, Quebec H4H 1R3 Canada

Thomas L. O'Donohue

Experimental Therapeutics Branch

National Institute of Neurological and

Communicative Disorders and Stroke

National Institutes of Health

Bethesda, MD 20205

93
Electroencephalographic (EEG),

Psychopharmacological, and

Receptor-Binding Profiles of

‘Phencyclinoids’

Antonia Mattia, Arthur P. Leccese, Karen L. Marquis,

Esam E. El-Fakahany, and J. Edward Moreton

INTRODUCTION

Phencyclidine (1-(1-phencyclohexyl)piperidine HCl, PCP) is a widely abused (Petersen and Stillman 1978) psychoactive agent with a

broad spectrum of activity. PCP's effects have been assessed in a

number of diverse experimental protocols producing behavioral,

electraphysiological, and biochemical data (Kamenka et al. 1983;

Domino 1981). Unfortunately, despite its potency in many experimental models, it is not known which of PCP's experimental effects

in these animal models (motor incoordination, analgesia, stereotypy, etc.) are most relevant to its pharmacologic and toxic

effects in humans (anesthesia, analgesia, psychosis). This is at

least partially related to the complexity of PCP's actions. For

example, even seemingly simple protocols of gross behavioral observations of PCP effects can be difficult since stereotypy,

ataxia, and locomotion occur simultaneously, tend to be fragmented

in nature, and compete with each other for expression. Fortunately, however, a number of phencyclidine analogues (Kalir et al.

1969) and compounds from other chemical classes that possess

phencyclidine-like activity (benzomorphan, benz(f)isoquinoline,

and dioxolane derivatives) are available and will no doubt be

helpful in elucidating PCP's spectrum of pharmacologic activity

and mechanism of action. We propose that these and other compounds that exhibit significant phencyclidine-like activity be

referred to collectively as "phencyclinoids." In order to obtain

useful information on the basic pharmacology of PCP, which may

help to understand its mechanism of action, comprehensive profiles

are being developed for a series of phencyclinoids in several

assays which progress from simpler to more complex. This report

will describe the results of EEG, behavioral, and receptor binding

studies conducted to date.

94
METHODS

Animals and Surgical Procedures

Throughout these studies, adult female Sprague-Dawley rats weighing about 250 gm were used. During experimentation, they were

housed in individual plastic cages. Purina Rat Chow and water

were available ad libitum, and they were maintained under an

automated light cycle with illumination from 6 a.m. to 10 p.m.

daily.

Rats were implanted with indwelling jugular cannulae for intravenous (IV) administration of drugs (Weeks and Davis 1964). To

monitor cortical EEG and electromyographic (EMG) activity, respectively, they were also prepared with chronic cerebrocortical

electrodes and temporalis muscle electrodes (Khazan 1975). One

week was allowed for recovery from surgery before experimentation.

Drugs and Drug Administration

The phencyclinoids used in this study are listed in table 1. PCP

analogues were chosen with modifications of the piperidine (PCA,

NMPCA, PCE, NsBPCA, PCPY) or phenyl (TCP and TCPY) ring systems.

Ketamine, also an analogue of PCP, has a piperidine ring replacement and additional modifications at the cyclohexyl and phenyl

rings. SKF-10,047 is a benzomorphan opioid derivative. PCP, its

analogues, and the racemate of SKF-10,047 were obtained from the

National Institute on Drug Abuse. 3

H-PCP (49.9 Ci/mmol) was

obtained from New England Nuclear Company for receptor binding

studies. Dextroamphetamine, ketamine, sodium pentobarbital, and

morphine were obtained commercially.

TABLE 1. Chemical names and abbreviations

Abbreviation Chemical Name

PCP 1-(1-phenylcyclohexyl)piperidine HCl

PCA 1-phenylcyclohexylamine HCl

NMPCA N-methyl-1-phenylcyclohexylamine HCl

PCE N-ethyl-1-phenylcyclohexylamine HCl

NsBPCA N-(s-butyl)-1-phenylcyclohexylamine HCl

PCPY 1-(1-phenylcyclohexyl)pyrrolidine HCl

TCP 1-(1-(2-thienyl)cyclohexyl)piperidine HCl

TCPY 1-(1-(2-thienyl)cyclohexyl)pyrrolidine HCl

Ketamine 2-(o-chlorophenyl)-2-methylaminocyclohexamine HCl

SKF-10,047 N-allylnormetazocine HCl

95
Drugs were prepared biweekly in physiological saline and administered via cumulative IV injections. Acute dose-response data were

generated for each drug in one test session by giving each rat a

series of drug injections beginning at 0.1 mg/kg, and then doubling the dose at successive 30-minute intervals. Rats received

bolus injections of 0.5 ml or less saline alone or 0.1 to 0.2 ml

of drug solution flushed with saline through jugular cannulae. In

anticonvulsant studies, intraperitoneal (IP) drug administration

was used. In the EEG studies, a one-quarter logarithmic dilution

was used for ketamine. Doses are expressed as the hydrochloride

salts.

Direct EEG and EEG Power Spectra

Rats were acclimated to the EEG recording cages and connected by

flexible cables through mercury commutators to a Grass Model 7D

Polygraph. The direct EEG was filtered at the polygraph at 35 Hz.

On the day of an experiment, in addition to paper EEG and EMG

recordings, the EEG was collected on FM magnetic tape using a Sony

TC-277-4 quadradial tape recording system in conjunction with a

Model 4 FM recording adaptor. Spectral analysis of the EEG was

performed using the Fast-Fourier-Transformation on digitized data

points from 0 to 25 Hz with the Nicolet Med-80 and Pathfinder I

computers and software. Sampling was performed at the Nyquist

sampling rate of 50 Hz. Sequential spectra were plotted during

saline and cumulative IV drug injections from 0.1 to 12.8 mg/kg.

Utilizing the overt behavioral assessment described below, doses

were chosen that produced behaviorally similar responses. For all

compounds tested, the peak total power and predominant frequency

of 5 or 6 EEG samples of 10- or 12-second duration were averaged

for each dose. To normalize the data, the absolute power values

were converted to root-mean-square (RMS) voltage and expressed

relative to saline quiet awake baseline for each rat; each rat,

therefore, served as its own control.

Overt Behavior

Locomotion, stereotypy, and ataxia were rated via behavioral observations for all compounds, using behavioral rating scales devised specifically for PCP (Sturgeon et al. 1979). Behaviors were

rated by observing each animal for 1 or 2 minutes at the midpoint

of each 30-minute dosing interval during collection of the EEG.

Spontaneous Locomotor Activity

Spontaneous locomotor activity (SLA) was measured in photocell

activity cages isolated in light- and sound-attenuated boxes.

Each cage contained six infrared photocell beams arranged around

the base of a circular tract. Each interruption of a beam registered a count on a total-event counter and on a cumulative

recorder. Cumulative IV doses at 30-minute intervals were administered over dose ranges that included the complete spectrum of

effects on SLA.

96
Analgesic Activity

The hot plate test with a 55 °C platform was used to measure latency to hindlimb lick at 12 or 18 minutes postinjection in rats.

A maximum latency of 60 seconds was allowed to prevent tissue damage and to enable multiple testing. Drugs were given by cumulative IV injections at 42-minute intervals up to a maximum dose one

unit below the dose which produced rotarod failure.

Rotarod Performance, Righting Reflex, Convulsant Activity, and

Lethality

Rotarod performance, righting reflex, convulsant activity, and

lethality were evaluated in the same rats, which were given saline

followed by cumulative IV drug injections from 0.1 to 51.2 mg/kg

at intervals of 30 minutes. Two-minute rotarod trials at 20 revolutions per minute were conducted at 12 and 18 minutes after

injections, to measure motor coordination. After completion of

rotarod testing, subsequent drug doses were administered to determine the doses at which loss of righting reflex, motor signs of

convulsant activity, and lethality occurred. The doses producing

the maximal effects on each parameter were recorded.

Pro- and Anticonvulsant Activity

The pro- and anticonvulsant effects of the phencyclinoids were

studied by assessing their ability to increase or decrease the

intensity of electrically-induced convulsions. A 32 mA, 0.2-

second stimulus was delivered via cornea1 electrodes with a

constant-current electroshock apparatus. The shock parameters

were chosen to produce a convulsion intensity of "3" on a fivepoint rating scale as follows: 0 = stunned only, 1 = facial and

vibrissae tremor, 2 = clonic forepaw treading, 3 = tonic forelimb

extension, 4 = tonic forelimb and hindlimb extension, and 5 =

death. Thus, both increases and decreases in the convulsion intensity subsequent to drug administration could be observed.

Drugs were given IP in selected doses based on rotarod test

results. The rats received saline and shock on day one, drug and

shock on day three, and saline and shock again on day five. Data

are presented as difference scores in convulsant intensity for

saline versus drug within animals.

Receptor Binding

Displacement binding experiments with 3H-PCP were conducted with

minor modifications of the filtration method described in the literature (Zukin and Zukin 1979; Vincent et al. 1979; Hampton et al.

1982) in crude tissue preparations of rat whole brain homogenates

in 5 mM Tris-HCl (pH 7.4).

97
RESULTS

Direct EEC and EEC Power Spectra

Representations of the direct cortical EEG effects and sequential

l-minute power spectra after cumulative IV doses of 0.4. 0.8, 1.6,

and 3.2 mg/kg PCP are provided in figure 1 (A, B). The direct EEG

and EEG power spectra correlated in a dose-related manner with

PCP's behavioral effects. At 0.4 mg/kg, PCP produced increased

locomotor activity and stereotypy associated with predominant

spectral power in the 5- to 10-Hz range. At 0.8 mg/kg, locomotor

activity and stereotypy intensified and ataxia emerged. In conjunction with ataxia, high-amplitude slower waves were present and

more power was contained in the 0- to 5-HZ band. At the higher

doses of 1.6 and 3.2 mg/kg, the EEG activity consisted primarily

of high-amplitude, slow-frequency waves superimposed upon background theta activity. At the highest doses, severe ataxia and

dyskinetic head and forepaw movements occurred in association with

spectral power concentrated in the 0- to 5-HZ band.

Spectral analysis of the EEG effects of PCP and related compoundson peak RMS voltage revealed similarities and differences between

the compounds tested. In general, moderate increases in peak RMS

voltage occurred as a function of dose, producing relatively flat

dose-response curves, as shown in figure 2, for 6 of the 10 compounds tested. The N-piperidine derivatives were qualitatively

similar to PCP and differed primarily in that they were less

potent. NMPCA, about one-fourth as potent as PCP, and ketamine,

about one-eighth as potent as PCP, also differed in that the

slopes of their increase in RMS voltages were steeper, and greater

maximal increases were obtained. TCP (data not shown) was most

potent and SKF-10,047 was least potent with respect to effects on

RMS voltage. Despite its PCP-like effects on the EEG, PCA produced less intense behavioral effects.

Dose-related shifts in predominant EEG frequency for PCP and several phencyclinoids are shown in figure 3. For all 10 compounds

tested, there was a shift in predominant EEG frequency into the

theta range across the lower doses , associated primarily with increased locomotor activity and stereotyped behaviors. With further increases in dose, PCP and all of its analogues produced

shifts to lower predominant frequencies, which typically fell

between 2 and 4 Hz. As the dose was incremented geometrically,

the lower frequency EEG waves were associated first with ataxia,

then with dyskinetic movements , catalepsy, and possibly seizure

activity. SKF-10,047 also produced ataxia, but was unique in that

it did not cause a shift to a lower predominant frequency and produced only EEG theta activity at all subconvulsant doses.

98
FIGURE 1. The effects of cumulative intravenous PCP on (A) the direct cortical EEG recorded in freely

moving rats, and (B) the associated sequential l-minute EEG power spectra
FIGURE 2. Peak EEG root-mean-square (RMS) voltage from 0-20 hertz

(Hz) as a function of dose for phencyclinoids

PCP produced electrical seizure activity at 12.8 mg/kg IV, EEG

spectra were clearly different from those produced by lower doses

in that fast-frequency, high-amplitude EEG waves occurred and

resulted in a spectral peak at about 15 Hz. EEG activity from 0

to 35 Hz occurred during seizures in contrast to subseizure doses,

which produced EEG with little activity beyond 10 Hz. Generally,

these seizures occurred immediately after IV injections and lasted

1 to 3 minutes. Similar spectra were obtained with NsBPCA (12.8

mg/kg), SKF-10,047 (25.6 mg/kg), and even with ketamine despite

the absence of overt convulsant activity. Motor manifestations of

EEG seizure activity included whole body tremors and vigorous

twitches of the face and vibrissae.

100
FIGURE 3. Predominant EEG frequency as a function of dose for

phencyclinoids

Overt Behavior

Dose-response curves for the effects of PCP and several compounds

on locomotion, stereotypy, and ataxia are shown in figure 4 (A, B,

C). PCP increased behavioral rating scores for stereotypy and

ataxia as a function of increasing dose, from 0.2 to 3.2 mg/kg

cumulative IV. For PCP-induced locomotion, behavioral rating

scores increased up to 1.6 mg/kg, and declined at 3.2 mg/kg.

Similar scores were generated for the other compounds over doses

ranging from 0.1 to 12.8 mg/kg. When scores for one behavior

increased, concomitant increases in the scores for each of the

behaviors resulted, making only quantitative differences between

these phencyclinoids observable. Consequently, similar relative

potencies were obtained from consideration of any one of these

three behaviors. The rank order of potency for locomotion,

stereotypy, and ataxia was TCP > PCP = PCPY = TCPY > PCE = NsBPCA

> NMPCA > ketamine = PCA = SKF-10,047. PCE was unusual in that

its potency for ataxia was nearly equal to PCP's, yet it was only

about one-third as potent in inducing locomotion and about twothirds as potent for producing stereotypy. TCP was more potent,

TCPY and PCPY were about equipotent, and PCA was less potent than

PCP (data not shown).

101
FIGURE 4. Dose-response-curves for the effects of phencyclinoids

on: (A) locomotion; (B) stereotypy; and (C) ataxia.

Overt behaviors were scored using the behavioral

rating scales of Sturgeon et al. (1979).

Spontaneous Locomotor Activity

The relationship between dose and SLA was characterized by an

inverted U-shaped curve for the phencyclinoids tested and dextroamphetamine. Geometric increases in cumulative IV doses produced

nearly linear increases followed by decreases in SLA for each

102
compound, while repeated saline injections resulted only in diminished motor activity. Dose-response curves for the rate-increasing effects of the phencyclinoids were similar and are shown in

figure 5. The psychomotor stimulant dextroamphetamine was nearly

equipotent with PCP. All the drugs tested were significantly less

efficacious than PCP (ANOVA, Dunnett's comparison of means, p <

0.05) with respect to peak increases in SLA, regardless of their

potency. For example, PCE was the least efficacious, yet produced

its maximal effect at 0.8 mg/kg, as did PCP. The doses of phencyclinoids producing peak SLA and maximal disruption of rotarod

performance are strongly correlated (r=0.99). Furthermore, a good

correlation (r=0.77) exists between the doses of phencyclinoids

producing peak SLA and maximum EEG theta activity.

FIGURE 5. Dose-response curves for the rate-increasing effects of

phencyclinoids and dextroamphetamine on spontaneous

locomotor activity.

Analgesic Activity

Analgesic data, expressed as ED50 values and their confidence

limits, are summarized in table 2. All 10 compounds possessed

analgesic activity at doses below those inducing severe ataxia.

Ataxia at higher doses prevented accurate measurement of the response, resulting in a ceiling effect. The rank order of analgesic potency for the phencyclinoids was TCP > PCE > PCP > PCPY =

TCPY > NsBPCA > ketamine > SKF-10,047 > NMPCA > PCA, which varied

103
somewhat from their rank order of potency for disruption of

rotarod performance (figure 6A) and effects on SLA (figure 5).

More important, as was also true in the case of SLA, analgesic

potency was distinguished from analgesic efficacy. But, none of

the phencyclinoids was as efficacious as morphine in producing

analgesia.

TABLE 2. Analgesic effects of phencyclinoide and morphine

Drug

Time

(Min Postdrug) ED5 0

Max Analgesia

(Percent)

PCP 18 0.19 (0.10-0.36) 80.9

NMPCA 12 1.69 (0.44-6.50) 68.8

Ketamine 18 0.48 (0.17-1.36) 54.8

NsBPCA

PCE

18 0.23 (0.13-0.38) 50.7

18 0.10 (0.05-0.22) 48.8

PCPY 12 0.20 (0.12-0.31) 32.8

TCP

TCPY

18 0.02 (0.01-0.07) 31.9

12 0.20 (0.12-0.31) 29.8

SKF-10,047 18 1.49 (0.69-3.31) 27.4

PCA 18 3.94 (0.70-22.2) 15.0

Morphine 12 0.48 (0.11-2.07) 98.4

NOTE: ED50 values determined by the method of Litchfield and Wilcoxon (1949).

Rotarod, Righting Reflex, Convulsant Activity, and Lethality

Figure 6 (A, B, C, D) summarizes the data for 10 phencyclinoids

for disruption of rotarod performance, loss of righting reflex,

convulsant activity, and lethality. The rotarod test proved most

useful in differentiating compounds. The rank order of potency

for the disruption of rotarod performance was TCP > TCPY = PCPY =

PCE > PCP = NsBPCA > PCA = NMPCA > ketamine = SKF-10,047. When

the doses producing disruption of rotarod performance were cornpared to lethal doses, none of the compounds demonstrated an

exceptional margin of safety. Distinctions between the drugs were

also made via behavioral observations of convulsant effects. Except for ketamine, overt motor manifestations of convulsant activity, including full body extensions and vigorous twitches of the

face and vibrissae, were noted for each compound at high doses.

Since ketamine lacked convulsant activity and was not very potent

in disrupting rotarod performance, it had the largest margin of

safety when these drug properties were considered relative to

lethality. Loss of righting reflex and lethality were less useful

parameters for discriminating between drugs, at least with the

dosing schedule used in this assay.

104
FIGURE 6. Histograms depicting doses of PCP and related compounds

which produced: (A) maximal disruption of rotarod

performance; (B) loss of righting reflex; (C) clonic

and/or toxic convulsions; and (D) lethality in rats

(n=6) given cumulative intravenous doses

Pro- and Anticonvulsant Activity

A complete dose-response analysis was generated for PCP for doses

from 0.625 to 20 mg/kg IP (data not shown). PCP exhibited doserelated anticonvulsant action when day one minus day three difference scores were compared for all doses tested. When retested

with saline only on day five, no reduction in convulsant severit

or super-sensitive response was observed (day one minus day five),

indicating no carryover drug effect 48 hours after dosing. At

behaviorally equivalent doses, all compounds assayed were clearly

anticonvulsant (table 3). TCP was most potent at the doses

tested. PCA was the most efficacious, and reduced convulsant severity by 2.58 points. As with PCP, none of the other phencyclinoids had any carryover effects 48 hours after dosing (day one

minus day five).

105
TABLE 3. The effects of phencyclinoids on electrically induced

convulsions

Drug

Dose

(mg/kg IP)

Mean Difference Score

Days 1-3 Days 1-5

Saline - 0.42 0.13

PCP 2.500 -0.83* 0.17

10.000 -0.92** 0.17

PCE 1.250 -0.66* 0.83

5.000 -0.75* 0.17

NsBPCA 2.500 -0.75* 0.33

10.000 -0.83* -0.33

PCA 10.000 -0.75* 0.00

40.000 -2.58** 0.17

NMPCA 5.000 -0.83* 0.50

20.000 -1.40* 0.33

PCPY 1.250 -0.75* -0.17

5.000 -0.83* 0.00

TCP 0.625 -0.33* 0.17

2.500 -0.33* 0.33

TCPY 1.250 -0.33* 0.50

5.000 -0.83* 0.50

Ketamine 5.000 -0.50* 0.00

20.000 -0.50* 0.83

SKF-10,047 5.000 -0.50* -0.17

20.000 -0.50* -0.33

*p<0.05

**p<0.01

NOTE: A mean difference score of zero lndicates no change; a negative score

denotes ant convulsant action; a positive score denotes a proconvulsant

action of the drug. n=6.

Receptor Binding

The binding of 3H-PCP to whole brain homogenates was saturable

and completely displaced by unlabeled PCP at a concentration

1O-5

 M. PCP-related compounds displaced 3H-PCP and varied in

of

potency. Although this work is still in progress, preliminary

results indicate a rank order of potency for the displacement of

3

H-PCP from its receptor similar to those reported for effects on

EEG, rotarod performance, and SLA.

DISCUSSION

These studies provide pharmacologic profiles of PCP and related

compounds ("phencyclinoids") derived from in vivo and in vitro

106
assays relevant to the general pharmacology of this class of

psychoactive agents. While a comprehensive discussion of all the

data is not possible here, several important points can be made

regarding the data and approach employed to study PCP.

Although some EEG data for PCP and/or related compounds can be

found in the literature (Vanderwolf and Leung 1983; Domino et al.

1983a; Domino et al. 1983b; Young et al. 1981; Gerhmann and Killam

1979), no comprehensive EEG studies systematically associated with

behavioral effects of PCP have been reported. In this study,

characteristic EEG effects, produced by PCP, that are dose related

have been described using computer-assisted EEG analysis. At low

doses of PCP, the predominant EEG effect was theta activity (5 to

10 Hz). At moderate doses, the predominant EEG activity consisted

of high-amplitude slow waves (0 to 5 Hz). At high doses, there

was activity over a wider range of frequencies, which was associated with seizure-like activity. There were dose-related

behavioral effects that correlated well with the EEG changes.

Characterization of these EEG and behavioral effects enabled replication and extension of previous descriptions of qualitative and

quantitative differences between PCP and a more limited sample of

related compounds (Mattia and Moreton 1981). The behavioral rating scales of Sturgeon et al. (1979) were very useful in conjunction with EEG recordings, since behaviorally equivalent doses

could be selected for EEG comparisons. However, when used alone,

these behavioral rating scales did not permit qualitative differences in compounds to be observed.

Summarizing the results of the other pharmacologic assays, our

data for the analgesic effects of phencyclinoids are in agreement

with other published data (Itzhak et al. 1981; Itzhak and Simon

1984; Kalir et al. 1978), but extensive analgesic studies of the

analogues have not previously been reported. On the whole, our

results also support existing data for the effects of phencyclinoids on spontaneous locomotor activity (Lozovsky et al. 1983;

Castellani and Adams 1981), and for their pro- and anticonvulsant

effects (Chen et al. 1959; Snyder et al. 1981; Hayes and Balster

1985; Zimmerman et al. 1985). The rotarod test of motor coordination, in agreement with other published data (Vaupel et al. 1984;

Vignon et al. 1982; Cone et al. 1984), proved reliable in separating the compounds with respect to potency. Both quantitative and

qualitative differences were discernible via observations of convulsant activity occurring at higher doses. Measurements of

righting reflex and lethality, however, were less discriminating,

probably because of the narrow range of potencies of the compounds

tested and the use of dose doublings at successive dosing intervals. Given a broader range of potencies, these parameters might

have been more useful. Furthermore, changing the dosing increments or time interval between doses might enhance the utility of

measuring these parameters during cumulative dosing.

Although still in progress, correlations of PCP receptor binding

with the results of the other assays should prove valuable in

107
completing the pharmacologic profiles of the phencyclinoids studied thus far. Such correlations have already been obtained by

others for rotarod performance (Vaupel et al. 1984; Vignon et al.

1982; Cone et al. 1984), drug discriminations (Shannon 1981). and

catalepsy (Mendelsohn et al. 1984). It may also be possible to

relate various pharmacologic effects of phencyclinoids to PCP

receptor subtypes recently described in the literature (Mendelsohn

et al. 1984; Sethy and McCall 1984).

Although generally similar pharmacologic profiles were obtained

for the phencyclinoids, subtle but perhaps important differences

in these compounds were discernible depending upon the individual

assay employed. For example, ketamine never produced behavioral

convulsions and was least potent with respect to SLA and disruption of rotarod performance, but was more potent than PCPY, TCPY,

TCP, and PCA in the assessment of analgesic activity. PCA, which

was very effective in decreasing the severity of electroshock convulsions, was not particularly efficacious or potent in other

assays. While PCE was equipotent with PCP in stimulating SLA, it

was least efficacious of all compounds with respect to peak SLA

achieved.

Cumulative dosing schedules are useful and have practical application in psychopharmacology (Wenger 1980). The use of the cumulative IV dosing schedule in these studies permitted the full range

of activities for each compound to be observed in a group of

animals in one test session.

In conclusion, these data emphasize the need for multiple assays

to discern differences among compounds otherwise regarded as pharmacologically more similar than different. Measurements of EEG

and convulsant activity are useful because each permits qualitative and quantitative differences in the compounds to be observed.

SLA and analgesia are also useful tests which provide information

regarding potency and efficacy. Rotarod performance is helpful in

determining potency but this paradigm does not permit differences

in efficacy to be observed. The binding studies should be of use

in relating diverse pharmacologic effects to specific drug receptor interactions. This integrated approach utilizing multiple

assays to develop pharmacologic profiles, as first accomplished by

Chen et al. (1959) for PCP, should help to better define the agonist properties and mechanism of action of the phencyclinoids.

This would facilitate investigations regarding the physiological

consequences and determinants of drug abuse, and contribute to the

search for antagonists, potentially useful research tools, and

therapeutic agents.

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110
ACKNOWLEDGEMENTS

Supported by National Institute on Drug Abuse Grant DA-03173 and

U.S. Army Contract DAAK-11-84-K-0001.

AUTHORS

Antonia Mattia, Ph.D.

Arthur P. Leccese, Ph.D.

Karen L. Marquis, Ph.D.

Esam E. El-Fakahany, Ph.D.

Associate Professor J. Edward Moreton, Ph.D.

Department of Pharmacology and Toxicology

University of Maryland School of Pharmacy

20 N. Pine Street

Baltimore, MD 21201

111
Modulation of Phencyclidine (PCP)

Pharmacokinetics With PCPSpecific Fab Fragments

S. Michael Owens and Michael Mayersohn

At high doses, phencyclidine (PCP) abuse sometimes leads to a

schizophrenic-like condition as well as violent and destructive

behavior (Lerner and Burns 1978; Fauman and Fauman 1979). As with

most drugs, there is no specific antagonist for reversing effects

from PCP. Therefore, conventional therapy, such as urine acidification and forced diuresis. have been the only available treatments (Domino and Wilson 1977; Aronow et al. 1978). Although

these techniques may aid in the elimination of PCP, there are

several criteria which must be met before these approaches can be

considered clinically effective. First, the degree of ionization

of the drug should be alterable within the physiological urine pH

range. Second, the drug needs to have a fairly small volume of

distribution. Finally, the therapy should cause renal excretion

to become a major route of elimination. PCP meets only the first

of these criteria. In both humans and animals, PCP has been shown

to have a very large volume of distribution (i.e., very little of

the drug is present in the blood stream), and to be primarily

eliminated through metabolism (Cook et al. 1982a; Cook et al.

1982b; Woodworth et al., in press). Therefore, a more effective

detoxification procedure is needed.

A promising technique for detoxification of certain drugs is the

use of drug-specific antibody fragments (Fab, the antigen-binding

fragment of IgG). This type of treatment has been shown to reverse digoxin and digitoxin toxicity rapidly in both animals and

humans (Lloyd and Smith 1978; Smith et al. 1982). The purpose of

this paper is to discuss the important factors in the use of immunotherapy for treating PCP toxicity and to present preliminary

data on the effects of anti-PCP Fab fragments on PCP pharmacokinetics in dogs.

PHARMACOKINETIC CONSIDERATIONS FOR DETOXIFICATION OF PCP BY

IMMUNOTHERAPY

Immunotherapy for drug overdose is a fairly recent medical development (Lloyd and Smith 1978; Smith et al. 1979; Smith et al.

112
1982). The advantages and disadvantages of choosing immunotherapy

as a treatment for drug toxicity have been reviewed by Colburn

(1980). The reasons for choosing immunotherapy for PCP are based

on two important characteristics of the drug: an extremely large

volume of distribution, and pharmacological effects that are

mediated through reversible binding to a drug/receptor complex.

The large volume of distribution of PCP precludes effective detoxification by passive procedures, which are dependent on access to

the drug in the blood stream. For instance, Allen et al. (1985)

have shown that charcoal hemoperfusion of the blood of dogs after

a 5 mg/kg dose of PCP does not affect the pharmacokinetics of PCP,

nor does it alter the pharmacological response to the drug. To

demonstrate the point regarding the large volume of distribution

of PCP, figure 1 illustrates the change in the apparent volume of

distribution of PCP with time, after an intravenous bolus dose of

3

H-PCP in one of our control animals (i.e., no antibody was administered in this experiment).

Fab fragments (M.W. 50,000) have several advantages over IgG (M.W.

150,000) for use as the immunotherapeutic reagent (Smith et al.

1979). The Fab fragments distribute more rapidly and extensively

than intact IgG. In addition, they are catabolized and excreted

earlier than intact IgG. A final important advantage is that the

Fab fragments are less antigenic than the intact IgG.

Even though the Fab fragments can probably distribute throughout

the plasma and interstitial space (i.e., extracellular water)

(Colburn 1980) after intravenous administration, they most likely

will not penetrate directly to sites of action of PCP in the central nervous system. Therefore, the effectiveness of the Fab

fragments will depend on a number of interrelated factors. These

factors include the affinity constant of the Fab fragments relative to other binding sites in the body (i.e., particularly the

PCP neuroreceptor), the binding capacity of the Fab fragments

(i.e., the amount of antibody administered and its affinity for

the drug), and the accessibility of antibody fragments to PCP in

the peripheral compartment, as judged by the magnitude of clearance from the peripheral to the central compartment (see figure

1). The significance of each point will be discussed separately.

Intravenously administered anti-PCP Fab fragments would be expected to "neutralize" drug effects by decreasing the concentration of

PCP at the site of action (i.e., particularly the PCP neuroreceptor). Since the antibody fragment may not be able to penetrate directly to the sites of action of PCP, it must shift the in

vivo equilibrium of the drug through reversible, high-affinity 

binding. Therefore, the affinity of the Fab fragments for PCP

needs to be much greater than the affinity of in vivo binding

sites for PCP. The highest reported in vivo binding site for PCP

is the PCP neuroreceptor. Vincent et al. (1979) and Quirion et

al. (1981) have reported affinity constants for this binding site

of 4.0x106 M-1 and 2.17x107

 M-1, respectively (i.e. Ka or 1/Kd).

113
The affinity constant of the Fab fragments we produced for these

studies (discussed below) was approximately 3.0x109 M-1. This

means that the Fab fragments would have about 138 to 750 times

greater affinity for PCP than for the receptor.

FIGURE 1. Change in the apparent volume of distribution of PCP as

a function of time following administration of an

intravenous bolus dose of 3H-PCP (6.4 μg) in a male

dog (19.5 kg)

NOTE: These results are the predicted values of a nonlinear regression fit of the

concentration-time data, calculated according the method of Colburn (1983).

Note that 2 hours after administration of PCP, the apparent volume of dlstrlbutlon is greater than 95 percent of its maximum value. Thls dog (dog

C) was also used In the anti-PCP Fab fragment studies discussed below. The

inset figure shoes a schematic representation of PCP in the dog as a twocompartment open model with elimination from the central compartment. The

constants K1 2 and K2 1

constant k10 is the apparent first-order elimination rate constant. The

are the Intercompartmental transfer rate constants.

In addition to having a high affinity, the amount of antibody

administered must be sufficient to reduce the body burden of PCP

below that of toxic levels. Therefore, the effectiveness of a

given dose of Fab fragments depends on its affinity and the amount

of antibody administered relative to the dose of PCP. Since the

affinity of the Fab fragments in the present study was so high

114
relative to other binding sites in the body, we felt that an

amount of Fab fragments that was equimolar to the dose of PCP

administered would be sufficient to bring about a favorable redistribution of PCP. Obviously, to attain the same level of

binding with a lower or higher affinity antibody, one would need

to administer more or less antibody, respectively.

The magnitude of drug clearance from the peripheral to the central

compartment (figure 1) will govern the rate of drug redistribution

from the peripheral compartment and, therefore, the rapidity with

which a toxic response is reversed (assuming that the site of toxicity is within the peripheral compartment and that the effect is

reversible). Unfortunately, there are too few experimental systems upon which to judge the relative importance of the rate of

redistribution of drugs, in the presence of Fab, in terminating a

toxic response. One such example is digoxin, whose peripheral to

central clearance is relatively slow; yet Fab fragments produce a

rapid and dramatic reversal of toxicity. It is difficult to judge

the significance of that finding within the context of this discussion, as the toxic effects are probably mediated by action in

both the central and peripheral compartment. However, intravenous

administration of a sufficient amount of Fab fragments, relative

to the dose of PCP, should produce a favorable shift in the equilibrium between the compartment containing the Fab fragments and

the compartments containing PCP. The pharmacokinetic result of

this shift in equilibrium is a significantly smaller volume of

distribution for PCP. In addition, this should lead to rapid reversal of concentration-dependent, receptor-mediated, pharmacological effects through depletion of drug at the receptor binding

site.

PRODUCTION OF ANTI-PCP ANTIBODY FRAGMENTS

A PCP antigen was produced by coupling the hapten 4-[(1-piperidinyl)cyclohexyl]benzoic acid sulfate 1/4 M hydrate (figure 2) to

bovine serum albumin using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl in aqueous dimethylsulfoxide at pH 4.0 to 4.5. The

antibodies produced against this antigen have been shown to be

fairly specific for PCP versus PCP metabolites (Owens et al.

1982). Two goats were immunized three times during the first 2

weeks with 1 mg of the antigen emulsified in 1 ml of Freund's complete adjuvant at several subcutaneous sites near regional lymph

centers. Booster injections of 3 mg of antigen were administered

at monthly intervals. The animals were bled 7 days after each

boost. After several months of immunization, the titer and affinity of the antibody response was judged sufficient for use.

The immunoglobulin fraction from each bleed was purified by use of

a recirculating isoelectric focusing (RIEF) technique (Bier et al.

1979). The whole serum was diluted 1:3 with urea, to yield a

final urea concentration of 3 M, and then desalted by electrodialysis. The urea was added to prevent precipitation under hypotonic conditions. Ampholine (1 percent w/v, pH 3.5 to 10, LKB

115
Instruments, Inc., Rockville, MD) was added, and the proteins were

fractionated using a 10-channel RIEF apparatus. The proteins in

each of the 10 fractions were then dialyzed against large volumes

of phosphate-buffered saline (PBS, pH 7.4). Immunoelectrophoresis

and a radioimmunoassay (RIA) for PCP were used to determine the

RIEF fractions with the greatest purity and anti-PCP activity.

FIGURE 2. Structures of PCP, the hapten used for antigen

production, and come important PCP metabolites

NOTE: The carboxylic acid group of the hapten was coupled to bovine serum albumin

by using a water-soluble carbodiimide reaction.

The active imnunoglobulin fractions from the RIEF separation were

affinity purified using a column containing the hapten covalently

bound to a sepharose bead. After isolation on the affinity

column, the antibody was eluted using glycine HCl and 6 M guanidine HCl. The antibody was concentrated and again tested for

activity and purity using the RIA and immunoelectrophoresis. The

IgG-containing samples were then digested with papain by the

method of Porter (1959)) and the Fab fragments were purified by

anion exchange chromatography using DEAE-sephacel (Pharmacia Inc.,

Piscataway, NJ). Based on the results from immunoelectrophoresis,

only Fab fragments were found in the final product.

The affinity and cross-reactivity of the whole serum and Fab

fragments were determined using equilibrium dialysis for the

affinity determination and RIA for the cross-reactivity studies.

The average intrinsic affinity constant (Ko) of the antibody

(Nisonoff and Pressman 1958) changed very little throughout the

116
entire purification procedure, The average value was about

3x109 M-1. The cross-reactivity of the whole serum and the Fab

fragments was tested against three important PCP metabolites:

1-(1-phenylcyclohexyl)-4-hydroxypiperidine (PCHP), 1-(1-phenyl-4-

hydroxycyclohexyl)piperidine (PPC, a cis/trans mixture), and 5-[N-

(1'-phenylcyclohexyl)amino]pentanoic acid (PCAPA) (figure 2). The

aminopentanoic acid metabolite PCAPA showed no cross-reactivity

with the antibody. The two monohydroxylated PCP metabolites PCHP

and PPC showed approximately 1 to 7 percent cross-reactivity

(depending on the bleed) before purification and about 13 percent

cross-reactivity after digestion and purification to Fab

fragments. This meant that the highest affinity binding of the

Fab fragments was directed at the PCP molecule, which is known to

be the most toxic form of the drug. However, the binding affinity

for the two metabolites was still fairly high. Since both PCHP

and PPC have been shown to have some pharmacological activity in

animal models (Shannon 1981), this cross-reactivity was not

considered a problem.

ADMINISTRATION OF ANTI-PCP FAB FRAGMENTS TO DOGS

Three male mongrel dogs were used for the Fab experiments. Each

dog was administered a trace dose of 3H-PCP (from 2.42 to 4.86

μg), and 2 hours later they were given a dose of Fab fragments

(0.5 to 1.0 mg), equimolar to the dose of 3H-PCP. The 2-hour

delay period was chosen to allow for the distribution phase of PCP

to be essentially complete (figure 2). We believe that this

procedure provided the most critical test of the ability of the

antibody fragments to modulate the disposition kinetics of PCP.

Earlier or concurrent administration of Fab would not have provided as useful an indication of the real-life situation in which

a patient comes to the emergency room after taking the drug.

Blood and urine samples were collected from each dog for about 100

hours. Several analytical assays for PCP and total drug were performed to allow a thorough characterization of the pharmacokinetic

profile in each animal. Serum samples were extracted for PCP with

hexane, after adjusting the pH of each sample to greater than 11.5

with 2 N NaOH. The radioactivity in the hexane extract was then

measured by liquid scintillation spectrometry. Each value was

corrected for extraction efficiency and converted to PCP concentration in serum based on the specific activity of the 3

H-PCP

(specific activity was approximately 7 Ci/mM). These PCP concentrations were used to determine the pharmacokinetics of the parent

drug. An aliquot of serum was analyzed directly for total radioactivity (PCP plus metabolites) to determine the pharmacokinetics

of the total drug administered. An aliquot of serum was also used

for determination of the change in free fraction before and after

administration of the antibody. This value was determined by

equilibrium dialysis, followed by extraction of each sample after

dialysis (bound and free fractions) with hexane, for determination

of the unchanged PCP concentration. The blood to plasma ratio of

selected samples before and after Fab administration was also

117

185-466 0 - 87 - 5
determined by the method of Owens et al. (1983). The amount of

PCP present in the urine was determined after hexane extraction of

each sample. The amount of total drug (parent plus metabolites)

was determined by direct counting of an aliquot of urine. From

these determinations we were able to calculate numerous pharmacokinetic parameters.

EFFECT OF FAB FRAGMENTS ON PCP DISPOSITION IN DOGS

Immediately after administering the anti-PCP Fab fragments, the

PCP concentration in serum increased approximately 17- to 56-fold

within a period of a few minutes (figure 3). The percent unbound

FIGURE 3. Total unchanged PCP concentration (closed symbols and

unbound PCP concentration (open symbols) before and

after anti-PCP Fab fragment administration

NOTE: The dotted Iines at-e used to connect sequential time points. The solid line

is a ilnear regression fit of the log-linear terminal elimination phase.

The unbound PCP concentration was calculated by multiplylng the total unchanged PCP concentration In serum by the unbound fraction in serum at each

time point. The harmonic means for the terminal elimination half-life for

unchanged total PCP and unbound PCP were virtually the same (3.5 and 3.3

hours, respectively). The arrows indicate the time of Fab administration.

PCP changed from about 50 percent before administration of the

Fab, to less than 1 percent unbound PCP immediately after administration of the antibody fragments. By about 10 to 11 hours

after administration of the Fab fragments, the unbound PCP was

37.7 percent, 1.4 percent, and 5.8 percent in dogs A, B,and C,

118
respectively. Based upon the sensitivity of the analytical methods and the relatively short half-life of PCP, the unbound fraction could not be measured accurately beyond those times. The

higher than predicted unbound fraction in dog A at the late time

point was not consistent with the blood to plasma ratio at the

same time point. The blood to plasma ratio indicated that the

drug was still highly bound to the antibody. We suspected that

this might be due to a low molecular-weight breakdown product from

the anti-PCP Fab fragments. Therefore, in subsequent experiments,

we used a 3,500 molecular-weight cutoff (MWCO) membrane, instead

of the 12,000-14,000 MWCO membrane.

We did not measure the terminal elimination half-life of the goat

Fab fragments. However, the terminal half-life of sheep Fab fragments in dogs is 16.4 hours (Lloyd and Smith 1978) (recalculated

as the harmonic mean). Assuming the same half-life for the goat

Fab fragments in this study, after 10 hours, 66 percent of the

intact Fab fragments should have remained in the body. By comparison, after 10 hours, only about 14 percent of intact PCP would

remain in the body, based on the average half-life of PCP in the

three dogs (i.e., 3.5 hours). Therefore, the binding capacity of

the Fab fragments should have been in excess of the amount of PCP.

The total radioactivity in serum (PCP and metabolites) increased

significantly after Fab administration (figure 4). This increase

was mostly due to the dramatic increase in unchanged PCP concentration and not due to an increase in metabolite concentration.

FIGURE 4. Total PCP equivalents in serum (PCP plus metabolites)

before and after Fab administration in three dogs

NOTE: The dotted line connects sequential time points. The solid line is a

linear regression fit of the log-linear terminal elimination phase.

119
In fact, the PCP metabolite concentration actually decreased for

1 to 2 hours after Fab administration. The PCP metabolite concentrations were determined by subtracting the total PCP equivalents

in serum (PCP plus metabolites) from the PCP concentration in

serum at each time point. The most likely explanation for the

temporary decrease in metabolite concentration was that the high

affinity binding of PCP to the Fab fragments temporarily reduced

metabolism, and/or some of the metabolites also bound to the antibody and were prevented from further metabolic changes. The

terminal elimination half-life for the total metabolites in the

three dogs was very long (harmonic mean = 62.4 hours). Since the

serum concentration of PCP was near or below our detection limit

by 24 hours after the administration of PCP, this very long terminal half-life was undoubtedly due to one or more PCP metabolites.

Another interesting and important change in the disposition of PCP

was the blood to plasma ratio. This ratio in the dog is normally

about 1.25, and in man is about 0.94 (Owens et al. 1983). This

indicates that there is an approximately equal distribution of PCP

between plasma and red blood cells. From preliminary experiments,

we knew that the Fab fragments were not found in the red blood

cells. Therefore, the degree of success in modifying the

pharmacokinetics of a drug should also be predictable from the

change in the blood to plasma ratio before and after antibody

administration. The blood to plasma ratio after Fab administration was approximately equal to one minus the hematocrit. This

indicated that the PCP in the vascular compartment was confined to

the plasma space and was prevented from distributing into red

blood cells as it does in the absence of antibody.

The major route of PCP elimination in dogs is through metabolism

(greater than 95 percent) (Woodworth et al., in press). Because

Fab fragments have been shown to be eliminated primarily by the

kidney (Wochner et al. 1967), and since PCP was highly bound to

the Fab in plasma, we expected that the percentage of the dose

eliminated as PCP might increase after Fab administration. This

was not the case. The amount of PCP eliminated in the urine was

1.91 ± 0.45 percent of the total dose, whereas in control studies

the amount was 4.8 ± 3.3 percent (Woodworth et al., in press).

However, the PCP excretion rate did show a temporal increase for a

period of time after the administration of Fab (figure 5). Ochs

and Smith (1977) also found an increase in the percentage of

digitoxin excreted in urine during the first 96 hours after administration of Fab fragments. They concluded that the antibody

fragments increased the amount of digitoxin appearing in the

urine. Since they collected urine for less than one half-life of

the drug (half-life of digitoxin > 140 hours), they cannot reach

that conclusion. A more complete urine collection (of at least

four half-lives of the drug) might have revealed a similar finding

to ours (we collected urine for greater than seven half-lives).

Our finding is also verified by Butler et al. (1977). Their

initial premise was that, since Fab fragments are cleared primarily by the kidney, and antibody binding to digoxin can be detected

120
in urine, the Fab should increase the amount of drug eliminated by

the kidney. However, their data show that the percentage of the

dose appearing in the urine is not different from control values.

Apparently, digoxin and PCP cannot be eliminated bound to the Fab

fragments. Future studies are planned to clarify this aspect of

the influence of Fab on elimination.

FIGURE 5. PCP urinary excretion rate versus the midpoint of the

urine collection time in three dogs

NOTE: Anti-PCP Fab fragments were administered 2 hours after the start of the

experiment.

RELATIVE CHANGES IN PCP PHARMACOKINETICS IN THE PRESENCE OF FAB

Figure 6 summarizes the relative changes in the disposition parameters of PCP after administration of anti-PCP Fab fragments.

These data were calculated by the model-independent methods described in the text by Gibaldi and Perrier (1982). Since we were

interested in calculating the effect of anti-PCP Fab fragments on

121
FIGURE 6. Relative change in PCP pharmacokinetic parameters

NOTE: The control values (dotted line) are from the data of Woodworth et al. (in

press). Both studies were conducted in our laboratory. The * indicates

that the values are significantly different (p<0.05) from control animals

(n=4). NS indicates that the values were not significantly different

(p>0.05). Even though the unbound Cl for the Fab-treated group was over

twice the control value. It was not significantly different due to a large

variability in this parameter, especially in one dog.

PCP pharmacokinetics, we calculated the changes in the pharmacokinetic parameters based on concentration-time data occurring

after the administration of the antibody fragment. For these

calculations, we had to estimate the amount of PCP remaining at

the time of antibody administration (i.e., 2 hours after PCP

administration). The amount of PCP remaining at 2 hours was

estimated by calculating first the total area under the concentration-time curve in the absence of PCP and then the volume of

distribution in the absence of PCP. The volume of distribution

times the serum concentration just before antibody administration

provided an estimate of the amount of PCP remaining at 2 hours.

When we tested the validity of this calculation with data from the

control animals (Woodworth et al., in press), the pharmacokinetic

values for both clearance and volume of distribution were within 5

percent of the values calculated using the complete set of data.

122
The area under the PCP concentration-time curve (AUC) from the

time of antibody administration to the last measured concentration

(Cn) was determined by the trapezoidal rule. The remaining area

from Cn to time infinity was calculated by dividing Cn by the terminal elimination rate constant. By using dose, AUC, and the terminal elimination rate constant, we were able to calculate the

terminal elimination half-life, systemic clearance, and the volume

of distribution. Renal clearance was determined from the total

amount of PCP appearing in the urine, divided by AUC. Unbound

clearances were calculated based on unbound concentrations of

PCP. The control values are from studies performed in our laboratory on dogs administered similar radioactive doses (i.e., 2.4 to

6.5 μg of PCP) (Woodworth et al., in press). Only one of the dogs

(dog C) was used in both studies.

The terminal half-life of PCP did not change significantly, relative to control studies. This reflects the fact that half-life

depends on systemic clearance (Cls) and volume of distribution

(half-life=0.693xV/Cls), and these two independent parameters

changed approximately by the same order of magnitude, thereby producing no net change in half-life. The apparent volume of distribution, systemic clearance, and renal clearance (Clr) decreased to

about one-tenth that of controls. This means that PCP was confined to a much smaller compartment after Fab administration, but

was also cleared at a much slower rate. Both changes can be explained by the high-affinity binding of PCP to the antibody

fragments.

When we calculated systemic and renal clearance based on the area

under the unbound PCP concentration-time curve, we found essentially no change in these parameters compared to the control studies without antibody (Woodworth et al., in press) (figure 6).

Since the values for PCP clearance in the presence of Fab were

consistent with restrictive clearance, a change in free fraction

at steady-state would be expected to result in a change in total

drug concentration, without a change in free concentration.

Nevertheless, we cannot predict from these data what is happening

to total and free concentrations at the PCP site of action. The

most accurate conclusions about drug disposition data are based on

the system following first-order kinetic processes when an equilibrium is achieved. How the introduction of a high-affinity

binding site into the body will affect the amount of drug at the

site of action will have to be determined by physiological modeling, and ultimately by its effect on the pharmacological response.

CONCLUSIONS AND FUTURE DIRECTIONS

Based on the dramatic changes in volume of distribution and the

free fraction of PCP found in serum, we predict that this form of

therapy has the potential to rapidly reverse the toxicity of PCP,

if sufficient Fab can be administered relative to the dose of

PCP. The most practical method for making large quantities of

antibodies with reproducible properties is through monoclonal

123
antibody production (Kohler and Milstein 1975). We are currently

producing large quantities of high-affinity anti-PCP monoclonal

antibody in mouse ascites fluid. In future studies, we plan to

examine the reversal of PCP toxicity in dogs using anti-PCP monoclonal antibodies. A major limitation for this kind of therapy is

the amount of antibody needed for treatment. As a starting point,

we plan to use 2 to 4 grams of anti-PCP Fab to reverse the toxicity of a 1 mg/kg dose of PCP in dogs. This total dose of about 15

to 20 mg of PCP is also a fairly high dose for humans; therefore,

the dog should be a realistic model to demonstrate the feasibility

of this method. The major limitations to this procedure are the

cost of the antibody and the possible antigenicity of mouse monoclonal antibodies in humans. Outside of the applied nature of

this research, this approach should provide an important tool for

studying fundamental concepts in the area of pharmacokinetics and

pharmacology.

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and Demartini, P. Effects of sheep digoxin-specific antibodies

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Clin Invest 59:345-359, 1977.

Colburn, W.A. Specific antibodies and Fab fragments to alter the

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for phencyclidine (PCP) in serum. Clin Chem 28:1509-1513, 1982.

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ACKNOWLEDGEMENTS

This work was supported by grant DA02680 from the National

Institute on Drug Abuse. Roche Diagnostics provided the PCHBA

hapten. Dr. Ned Egen and Mrs. Rebecca B. Owens helped in

purification of the antibody.

AUTHORS

S. Michael Owens, Ph.D.

Assistant Professor

Department of Pharmacology

School of Medicine

University of Arkansas

for Medical Sciences

Little Rock, AR 72205

Michael Mayersohn, Ph.D.

Professor

Department of Pharmaceutical Sciences

College of Pharmacy

University of Arizona

Tucson, AZ 85721

126
Psychopharmacology of

Phencyclidine

Joe Marwah and David K. Pitts

Phencyclidine, 1-(1-phenylcyclohexyl) piperidine hydrochloride

(PCP) was introduced in 1957 as a dissociative anesthetic with a

large margin of safety in humans (Domino 1964). Although limited

respiratory depression was a major asset of this compound, certain

side effects, including emergence psychosis and prolonged excitation, made PCP unsuitable for clinical use. Phencyclidine has now

become a major drug of abuse in the United States (Snyder 1980)

and phencyclidine-related deaths are being reported with increasing frequency (Noguchi and Nakamura 1978). Its continued availability as an animal tranquilizer and its increasing clandestine

production, distribution, and use have contributed to phencyclidine's becoming a major public health concern.

PCP can cause CNS stimulation and depression, which vary markedly

depending upon the dose and species employed. The response of

rodents to PCP appears markedly more sympathomimetic than that of

primates (Balster and Chait 1978). Intoxication in humans with

low doses (5 to 20 mg) of PCP resembles an acute confusional state

lasting several hours. Higher doses (greater than 20 mg) can

elicit serious neurological (nystagmus, gait ataxia, muscle rigidity, EEG changes, and stereotypy), cardiovascular (hypertension),

and psychotic (agitation, disorientation, delirium, auditory hallucinations, thought disorders , and paranoid delusions) reactions.

Current treatment of PCP intoxication involves supportive psychological and medical measures. Similar clinical features between

PCP-induced psychoses and schizophrenia have led investigators to

view PCP intoxication in humans as a heuristic pharmacological

model for schizophrenia. The most compelling evidence that PCP

psychosis resembles schizophrenia is the fact that experienced

psychiatrists have mistaken drug users for schizophrenics, before

the psychiatrists obtained the history of drug use (Snyder 1980).

PCP can both mimic and reactivate schizophrenic psychoses. Some

PCP users have developed classic schizophrenia subsequent to experiencing PCP psychoses. This phenomenon suggests a relationship

127
between the pharmacology of PCP and the neurobiology of schizophrenia. PCP has diverse effects on behavior in rodents, depending on the dose administered. At low doses, PCP has a stimulant

action; at high doses, it has a sedative effect (Chen et al.

1959).

Although the precise mechanism of action of PCP remains obscure,

virtually all known neurotransmitters have been implicated in its

action. Cholinergic (Alburquerque et al. 1980; Maayani et al.

1974), serotonergic (Martin et al. 1979), dopaminergic (Johnson

and Oeffinger 1981; Fessler et al. 1979; Doherty et al 1980;

Sturgeon et al. 1979), and noradrenergic (Marwah 1982; Bayorh et

al. 1983) mechanisms have been implicated as predominant mediators

of PCP effects. Of these, the dopaminergic and noradrenergic

mechanisms have received the greatest attention.

The administration of low doses of PCP to rodents induces hyperactivity and stereotypy (Chen et al. 1959). The observation that

neuroleptics such as chlorpromazine, haloperidol, and pimozide,

and adrenolytics such as alpha-methyl paratyrosine antagonize

these behavioral effects of PCP suggests that they are mediated by

facilitation of central dopaminergic neurotransmission (Murray and

Horita 1979). The actions of PCP on central dopaminergic neurotransmission may be similar to amphetamine. A dose of PCP (2.5

mg/kg) in rats, which has no effects when given alone, enhances

the behavioral effects of 1 and 3 mg/kg of d-amphetamine (Balster

and Chait 1978). PCP, like dopamine, has also been shown to suppress plasma prolactin (Bayorh et al. 1983). However, the firm

establishment of an exclusive relationship between dopamine neurotransmission and PCP effects is difficult because of the prominent

interactions of this drug with other neurotransmitter systems.

For example, in regions densely innervated by noradrenergic

fibers, PCP is a very potent inhibitor of norepinephrine uptake.

In rats, cocaine, PCP, and ketamine have been shown to enhance the

spontaneous and electrically stimulated overflow of tritium from

occipital cortex slices preincubated with 3H-norepinephrine (Taube

et al. 1975). Ary and Komiskey (1980) showed that PCP blocks the

reuptake of 3H-norepinephrine into synaptosomes. Consroe et al.

(1982) reported that, in rodents, propranolol blocks the stereotypy and hyperactivity elicited by PCP. Clonidine and prazosin

have also been reported to block a number of effects of PCP in

various behavioral states. PCP and (+) PCMP, but not (-) PCMP,

increase blood pressure and heart rate and suppress plasma prolactin (Bayorh et al. 1983). These investigators have suggested

that, because of similar stereospecific effects of PCP derivatives

on the cardiovascular system (noradrenergic system) and plasma

prolactin (dopaminergic system), the actions of PCP on both the

dopaminergic and adrenergic systems may be attributed to the same

active conformation of the PCP molecule. In single unit electrophysiological studies with the noradrenergic locus coeruleusPurkinje neuron synapse, PCP has been shown to have prominent

sympathomimetic effects (Marwah, 1982). Use of lesion techniques

128
and receptor antagonists revealed that at this synapse PCP acts as

an indirect sympathomimetic in that it causes release and/or

blocks reuptake of norepinephrine. Marked noradrenergic actions

of PCP have also been observed in the cat spleen (Marwah et al.

unpublished)--a noradrenergically innervated tissue. In the cat

spleen, PCP significantly potentiates the effects of nerve

stimulation and exogenous norepinephrine on the contractile

responses of smooth muscle. This potentiation to exogenous norepinephrine, although attenuated, is also observed in denervated

cat spleens, suggesting that PCP in this system exerts both presynaptic and postsynaptic actions.

PCP has also been reported to possess properties that overlap

with the opioid narcotics. These "opiatergic" effects of PCP are

currently attributed to actions of PCP on the sigma "opiate"

receptor. Activation of the sigma receptor by compounds such as

PCP, SKF-10,047 and cyclazocine elicits dysphoria and other

effects. PCP and SKF-10,047, like amphetamine, elicit locomotor

activity through presynaptic dopaminergic mechanisms within the

mesolimbic system (French and Vantini 1984). SKF-10,047 and PCP

have also been shown to produce a biphasic (initial activation

followed by inhibition) action on single dopaminergic neurons in

the substantia nigra (Freeman and Bunney 1984). The actions of

PCP and SKF-10,047 on sigma receptors are poorly antagonized by mu

opiate receptor antagonists such as naloxone. Geller et al.

(1981) showed that PCP, SKF-10,047, and cyclazocine block flurothyl seizures. These effects are not antagonized by naloxone.

However, Glick and Guido (1982) recently reported that PCP can

interact at mu opiate receptors in brain areas controlling

thermoregulatory processes.

It appears that mechanisms contributing to the psychopharmacology

of PCP are indeed complex. Despite numerous studies, it is not

yet apparent which, if any, of the above actions are responsible

for the behavioral effects of PCP in humans. An increasing number

of reports (Quirion et al. 1983; Vincent et al. 1979; Zukin and

Zukin, 1978) point to the existence of an endogenous "PCP-like"

(probably peptides) ligand. This ligand (angeldustin!) has been

proposed to interact with sigma or "PCP" receptors (Quirion et al.

1981). Since PCP has been demonstrated to interact with numerous

transmitter systems, it is conceivable that the PCP (sigma)

receptor is located at critical (transmitter release modulating)

sites on susceptible neurons. PCP, by virtue of its interaction

with such a receptor, may subsequently affect steps necessary for

transmitter release (or stimulus-secretion coupling). A candidate

for such a step is the calcium channel. This may explain the

rationale for the use of calcium antagonists during PCP intoxication. The modulation by PCP of calcium channel properties could

be expressed as increased muscular strength (Marwah, 1980, 1982).

Stimulation of the PCP "receptor" may alter fundamental excitability processes such as gk+

, which in turn could modulate calcium

mobilization (Aguayo et al. 1984).

129
If PCP produces its multitude of effects by activating PCP (sigma)

receptors, then chronic exposure to agonists should elicit the

development of tolerance. Tolerance to plasma prolactin suppression by PCP is observed in rats following daily administration for

28 days (Quirion et al. 1982). Chronic PCP treatment has been

also shown to reduce the number of PCP sites (receptors) in rodent

brains (Quiriun et al. 1983). Behavioral studies have documented

the development of tolerance to and dependence on PCP (Balster and

Woolverton 1980; Flint and Ho 1980). A tolerance syndrome develops in humans, in which the user is compelled to increase his

intake of drug (Jain et al. 1977).

Despite this wealth of information, numerous questions regarding

the action of PCP still remain unanswered. These are:

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

What is the endocrine status of chronic PCP users?

Are the analgesic effects of PCP due to its local anesthetic

properties or actions at sigma or perhaps mu receptors?

Is the development of ultrashort-acting (less abused) PCP

derivatives that are good anesthetics and analgesics with

very little respiratory depression possible?

Can a PCP receptor antagonist be developed?

What is the action of PCC (a PCP analog without psychotomimetic effects) on the numerous synapses that PCP affects?

What are the effects of PCP, SKF-10,047, and PCC on other

central noradrenergically innervated synapses?

How does PCP compare with cocaine and amphetamine at the

various neuronal test systems , where PCP has been documented

to have prominent actions?

What could be the reasons for the existence of endogenous

PCP reactive ligands and receptors? Do they produce a

dissociated mental state following severe trauma or stress?

What causes "flashback" psychosis in some individuals who

abstain from further PCP consumption following the initial

dose? Is it residual drug, slow metabolism to a new stable

metabolite, or a "permanent" change in a defined portion of

the CNS?

What are the effects on the developing nervous system after

chronic in utero exposure? Neurophysiological, neuropharmacological, and neuroanatomical studies should be useful.

130
(11) Is the development of tolerance to PCP pharmacokinetic or

pharmacodynamic? Since PCP psychosis may be the result of a

mixed tolerance and/or altered receptor plasticity, this

phenomenon should be investigated at single monoaminergic

neuron test systems.

Management of PCP intoxication would be significantly enhanced if

the physiologic mechanisms of the drug's effects were better

understood. Such knowledge, which could be derived from basic

science studies in animals, might pave the way to the development

of specific pharmacotherapeutic agents in treating acutely and

chronically intoxicated patients. Additionally, such research

might suggest the development of newer anesthetics and analgesics.

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ACKNOWLEDGEMENTS

Studies in Dr. Marwah's laboratory were supported in part by

grants NIDA R01-DA-03519; American Heart Association Grant-in-Aid,

83-757; and an Established Investigatorship, 85-118.

AUTHORS

Joe Marwah, Ph.D.

David K. Pitts, Ph.D.

Department of Pathology

University of Medicine and Dentistry

of New Jersey

Camden, NJ 08103

133
Discriminative Stimulus Properties

of PCP Mimetics

Ronald G. Browne

Phencyclidine (PCP), a dissociative anesthetic agent, which is

subject to abuse, produces behavioral effects in man that frequently resemble schizophrenia (Luisada 1978). Manifestations of

persistent psychopathology frequently remain after the acute

effects of PCP have diminished. With PCP, subjects may display

autistic and delusional thinking typical of schizophrenics (Luby

et al. 1959). A more striking link between schizophrenia and PCP

comes from observations of cases in which PCP was given to hospitalized schizophrenics (Luisada 1978). After receiving PCP, these

patients showed extreme exacerbation of their psychoses; the reaction persisted for up to 6 weeks. By contrast, LSD produced no

more severe effects in schizophrenics than in normal subjects.

The close resemblance between schizophrenia and PCP-induced psychosis suggests that the behavioral effects produced by PCP might

be useful as a model of psychosis. On this basis, most animal

studies have examined the ability of various agents to modify PCPinduced hyperactivity and stereotypy. While some studies suggest

that neuroleptics such as haloperidol (Castellani and Adams 1981;

Garey et al. 1980), chlorpromazine, or clozapine (Freed et al.

1980) antagonize the alterations in locomotor activity produced by

PCP, Sturgeon et al. (1981) could find no consistent effects of

neuroleptics on PCP-induced hyperactivity. In man, phenothiazines, butyrophenones, benzodiazepines, and cholinesterase inhibitors have been claimed to be partially effective in treating PCPinduced effects (Burns and Lerner 1976; Showalter and Thornton

1977; Stockard et al. 1976; Luisada and Brown 1976; Dorand 1977;

Castellani et al. 1982). Thus, the fact that antipsychotic agents

do not completely antagonize the actions produced by PCP in man or

animals suggests that the psychotomimetic effects of PCP are probably mediated by as yet unelucidated neurochemical mechanisms.

In searching for an animal model specific to PCP and PCP-like

agents, the drug discrimination procedure historically has been

used. The use of drugs as discriminative stimuli provides a

sensitive technique for establishing the similarities among

134
various agents, and the method is useful for elucidating the mechanism of action of psychoactive drugs (Lal 1977; Ho et al. 1978;

Colpaert and Rosecrans 1978; Thompson and Pickens 1971). The

paradigm requires animals to emit different behavioral responses

depending upon differential drug states. For example, following

injections of PCP, rats, pigeons, or monkeys have been required to

press one of two manipulanda in operant conditioning chambers to

receive a food reward. Following injection of the drug vehicle,

the animals are required to press a different lever or button to

receive reinforcement. After a varying number of sessions where

reinforcement is associated with differential responding dependent

upon drug state, animals learn to identify correctly the appropriate response, based on interoceptive stimuli produced by the

drug. The dependent measure in such paradigms is the number of

responses or number of animals "choosing" the "correct" lever in

the absence of reinforcement feedback. If a drug fails to produce

discriminative stimuli, then no evidence of learning is obtained,

and animals respond at chance levels (50 percent of responses on

both levers or 50 percent of animals choosing the correct

lever). By contrast, drugs that readily produce subjective effects in man--PCP, for example--engender stimulus control in

animals such that nearly 100 percent discrimination accuracy is

often obtained.

The unique aspect of the drug discrimination paradigm is that the

discriminative stimulus properties produced in animals by drugs

tend to show a great deal of pharmacological specificity. Animals

trained to discriminate one type of drug readily identify pharmacologically similar agents as producing similar interoceptive

stimuli, while agents from different classifications do not result

in stimulus generalization. For example, in rats trained to discriminate morphine from vehicle, other opiates and opioid peptides

mimic morphine's effects, and narcotic antagonists such as naloxone block the discriminative stimulus properties of these agents

(Browne and Fondren 1978). By contrast, stimulants, depressants,

and anesthetics are not perceived as opiates in the discrimination

paradigm.

A number of investigators have examined PCP in drug discrimination

paradigms. Such studies have revealed a number of PCP analogs

that mimic PCP's discriminative stimulus properties (Shannon 1981,

Brady and Balster 1981). In addition, the sigma opiate agonist

SKF-10,047 has been shown to produce stereoselective PCP-like discriminative effects (Holtzman 1980; Brady et al. 1982). While

some studies have suggested generalization to the PCP cue by opiates such as cyclazocine and dextrorphan (Holtzman 1980, Herling

et al. 1981), the PCP cue does not appear to be mediated via mu

opiate receptors, since it was not blocked by narcotic antagonists

(Holtzman 1980). Other attempts to block PCP's discriminative

properties have not been successful, consistent with the fact

that, to date, there is no established PCP antidote. This paper

135
will therefore review the data obtained in discrimination paradigms that have characterized compounds as PCP-mimetics or have

attempted to antagonize PCP's discriminative properties.

AN EXAMPLE OF DISCRIMINATION METHODOLOGY

Adult, male, Sprague-Dawley rats obtained from Charles River Labs

and weighing 200-250 gm on arrival were used. Throughout the

study, the rats were housed individually, with water freely available. Purina Rat Chow was fed after each experimental session and

on weekends, in quantities adjusted to maintain the rats between

270 and 350 gm throughout the experiment.

Training and testing sessions were conducted in 10 identical isolated Colbourn operant chambers equipped with two levers mounted

on either side of a motor-driven dipper. Reinforcement consisted

of 3-second presentations of 0.2 ml Carnation Slender, a commercial liquid diet food, diluted 1:1 with water. Reinforcement

contingencies and data recording were performed using a Rockwell

AIM 65 microcomputer.

The procedure used was based on the two-lever fixed ratio 10

(FR-10) drug-discrimination protocol, first described by Colpaert

et al. (1975). At 30 minutes prior to the 15-minute session,

phencyclidine HCl (1.0, 1.78, or 3.2 mg/kg, depending upon experimental group) or vehicle (5 percent ETOH: 95 percent water) was

administered SC in a volume of 1.0 ml/kg. Each animal was

required to discriminate the effects of only one dose of PCP from

vehicle. Depending on whether the rat received drug or vehicle,

reinforcement was programmed exclusively on either the left or

right lever. Only responses on the left lever were reinforced

after drug administration, and responses on the right lever were

reinforced after vehicle administration. Sessions were conducted

Monday through Friday under the alternating drug sequence used by

Colpaert et al, 1975): drug-vehicle-vehicle-drug-drug and

vehicle-drug-drug-vehicle-vehicle. To avoid the possibility that

the correct lever for rats previously tested in the chambers could

serve as an olfactory cue, the sequence of treatments on training

days was alternated for successive groups (i.e., half the animals

received vehicle and half received PCP).

For each session, the number of responses emitted before the first

reinforcement was the measure of discrimination accuracy. For example, following PCP administration, if a rat made 10 responses on

the left lever before making 10 or more responses on the opposite,

unreinforced lever, then the animal correctly identified the

training condition for that day. Most rats were clearly discriminating the effects of PCP from vehicle within about 30 training

sessions, as demonstrated by the animals emitting their first 10

responses on the appropriate lever in 9 out of 10 consecutive

sessions.

136
In order to determine stimulus generalization profiles for different doses of PCP, various other drugs, and drug interactions with

PCP, twice weekly (Wednesdays and Fridays) experimental tests were

interposed between PCP and vehicle maintenance sessions. Experimental treatments were given in the same ETOH:water vehicle

described above in a volume of 1 ml/kg. Unless noted otherwise,

all treatments were given SC 30 minutes prior to a 15-minute

session. The reinforcement scheduling procedure was changed on

experimental test days as follows: the first reinforcement was

programmed after 10 responses were emitted on either lever. The

lever on which 10 responses were first accumulated defined the

animal's "choice" for that test treatment. If it was the left

lever, the animal was said to have selected the drug side, indicating generalization of the treatment to the PCP training condition; if it was the right lever, the animal was said to have

selected the vehicle side, indicating nongeneralization of the

treatment to the training condition. Following the first reinforcement on experimental treatment days, subsequent reinforcements were given on an FR-10 schedule on either lever.

The degree of generalization of the various treatments to the PCP

cue during the experimental sessions is reflected in the percentage of animals choosing the lever previously paired with PCP.

Assuming 100 percent discrimination accuracy for both training

conditions, probability estimates for selection of the drug or

vehicle lever can be ascertained from the binomial theorem with an

underlying probability of 50 percent. For example, using the most

frequent test sample size of n=10, if fewer than four rats (40

percent) chose the PCP lever, then the treatment was considered to

be identical with the vehicle condition. If eight or more rats

selected the drug lever, then the treatment was considered identical to the training dose of PCP with p<.05. Drug choice in the 40

to 70 percent range was assumed to be different from both training

conditions (i.e., not significantly different from 50 percent).

Response rate data were evaluated using paired t-tests. Calculations of ED50 values for compounds mimicking PCP were obtained by

linear regression analysis.

RESULTS WITH PCP-MIMETICS

After about 30 training sessions, most animals had acquired the

PCP vs. vehicle discrimination, as evidenced by at least 9 out of

10 consecutive sessions during which the rats emitted fewer than

20 responses before the first reinforcement. Following this

acquisition of the discrimination, the animals were tested in a

random order with different doses of PCP. Figure 1 shows the

dose-response profile for PCP discrimination in different groups

of rats trained to discriminate 1.0, 1.78 or 3.2 mg/kg of PCP from

vehicle. At low doses of PCP few, if any, rats chose the lever

previously paired with PCP (i.e., most rats chose the vehicleassociated lever).

137
FIGURE 1. Dose-response curve for rates trained to discriminate

various doses of PCP from vehicle administered 30

minutes before the test. N=10/dos.

As the dose of PCP was increased, more rats generalized the treatment to that produced by the training dose, so that, when tested

with doses comparable to the training condition, essentially all

animals completed their first 10 responses on the PCP-appropriate

lever. At higher doses of PCP, a significant reduction in the

number of responses emitted during the 15-minute session was

observed. The rate of responding in animals trained at the lowest

dose (1.0 mg/kg) appeared to be more sensitive to disruption by

PCP than in those animals trained at higher doses (figure 2).

However, no tolerance to this rate-disrupting effect of PCP was

seen over the course of the experiments.

138
FIGURE 2. Dose-response curve for the effects of PCP on response

rates in rats trained to discriminate various doses

of PCP from vehicle. N=10/dose.

Generalization tests indicated that a number of compounds were

able to substitute for PCP (table 1). Ketamine and tiletamine,

which are structurally similar to PCP, produced dose-dependent

effects mimicking PCP. These compounds are interesting examples

of the structural requirements of molecules for PCP-mimetic activity, demonstrating that neither the piperidine nor the phenyl

moieties are absolutely necessary for activity.

139
TABLE 1. Compounds generalizing to the PCP cue

Compound Structure

PCP

ED50

PCP Cueing

0.55

(±)Ketamine

Tiletamine

2.20

0.46

Dexoxadrol

Levoxadrol

(-)2-MDP

(+)2-MDP

± SKF 10047

1.68

>100

2.13

>10

2.74

NOTE: All compounds were administered SC 30 minutes prior to a 15-minute test.

ED50 values for compounds to mimic the effects produced by 1.78 mg/kg of

PCP.

When the animals were tested with dexoxadrol, PCP-mimetic activity

was found to be about one-third that of PCP. This compound is of

interest because its stereoisomer, levoxadrol, was found to be

completely devoid of PCP-mimetic activity at doses as high as 100

mg/kg (table 1). Another example of the stereoselectivity of the

PCP cue is seen with 2-methyl-3,3-diphenyl-3-propanolamine isomers

(2-MDP). Consistent with the original findings by Tang et al.

(1984), the (-) isomer of 2-MDP is a stereoselective PCP mimetic,

with a potency about one-fourth that of PCP (table 1). SKF10,047, the prototypical sigma opiate receptor agonist, also

engenders a dose-dependent generalization to the PCP cue. This

compound has been extensively investigated for its discriminative

properties (Shearman and Herz 1982; Teal and Holtzman 1980;

Shannon 1983). and PCP-mimetic activity is exhibited stereospecifically by the dextro isomer (Brady et al. 1982).

140
TABLE 2. Structure-activity relationship for piperidine analogs

mimicking the discriminative stimulus properties of

PCP 1.78 mg/kg

ED50 Compound R Cueing

PCP

CP-63,713-1

CP-63,986-1

CP-63,404-1

CP-63,631-1

CP-63,402

CP-63,774-1

CP-63,579-1

0.55

0.38

<<3.2

5.37

1.65 racemlc

0.33 R(+)

>10 S(-)

11.5

0.30

1.04

In addition to the structurally diverse compounds described above,

which can serve as PCP mimetics, analogs of PCP have also been

examined for their ability to support PCP cueing. The most extensive work reported to date has been done in Harlan Shannon's laboratory (Shannon 1981; Cone et al. 1984; McQuinn et al. 1981) and

has demonstrated (1) that the piperidine moiety is not required

since the free primary amine is active; (2) modifications to the

cyclohexyl ring greatly reduce or abolish activity; and (3) increasing the chain length to the phenyl group or replacement with

naphthyl abolishes activity. In addition, table 2 shows that a

number of piperidine modifications can be made and still retain

PCP-mimetic activity.

141
In contrast to the generalization observed with PCP-like compounds, a large number of agents that share similar pharmacological activities with PCP failed to mimic PCP's discriminative

effects (table 3). Psychomotor stimulants, hallucinogens like THC

and LSD, opiates, cholinergic and anticholinergic agents, as well

as a diverse group of miscellaneous drugs, consistently produced

vehicle choice.

TABLE 3. PCP discrimination. PCP 3.2 mg/kg vs. vehicle.

Compounds failing to mimic PCP.

Compound Dose Range

Percent PCP Response

Choice Level

Amantadine 10. - 32. 0 518

Methylphenidate 3.2 - 32. 12 530

Cocaine 3.2 - 10. 0 65

d-Amphetamine 1.0 - 1.78 0 140

Apomorphine .32 0 400

THC 3.2 - 10. 12 455

Muscimol 1.0 0 476

LSD .1 0 532

Yohimbine 3.2 0 721

Morphine 3.2 0 145

Ketocyclazoclne 3.2 - 56. 25 144

Cyclazocine 3.2 - 32. 12 357

Mecamylamine 1.0 0 572

QNB 1.0 - 3.2 12 419

Nicotine

Arecoline

Tacrine

Physostigmine

Scopolamine

Ditran

Benrtropine

Pirbuterol

1.0 0 691

- 3.2 12 360

3.2 0 602

.1 - .32 12 136

.32 - 1.0 0 141

10. 0 250

3.2 - 10. 12 321

10. 0 309

Cyproheptadine 3.2 - 10. 33 769

Althesin 10. - 32. 25 233

Veratridine

Methaqualone

Navane

Pentoberbital

Diazepam

.001 - .32

32. -100.

10. - 32.

10.

10.

12

12

8

0

14

8 3

543

544

391

634

NOTE: A number of compounds failed to generalize to PCP when administered 30

minutes prior to testing. N=at least 8 rats/treatment. Values are the

highest generalization and lowest number of responses obtained over the

dose-range tested.

ATTEMPTS TO ANTAGONIZE PCP DISCRIMINATION

A search for compounds that might block the PCP cue found that

many drugs failed to reverse PCP discrimination to the vehicle

level. Table 4 lists alphabetically the results obtained with

such compounds over the dose range tested. A few agents,

142
TABLE 4. PCP discrimination. PCP 3.2 mg/kg vs. vehicle.

Compounds failing to block PCP.

Compound Dose Range

Percent PCP Response

Choice Level

Alprazolam

Amantadine

Apomorphine

Baclofen

Caffeine

Chlorpromazine

Cinanserin

Clonidine

ClozaDine

Cyproheptadine

Diazepam

Diphenhydramine

Dipyridamole

Ditran

Doxapram

Etazolate

Haloperidol

lmipramine

Levamisol

Mecamylamine

Methysergide

Mezilamlne

Morphine

Naloxone

Naltrexone

Nifedipine

Nimodipine

Oxolinicacid

Pentylenetetrazol

Phenltrone

Phenytoin

Prazocine

Propranolol

QNB

Scopolamine

Sulpiride

Traiazolate

TRH

Vasopressin

Yohimbine

32.

10.

.32

1. - 3.2

56.

.32 - 10.

3.2

.032

1. - 3.2

10.

1. - 10.

10.

32.

1.0

32. -178.

10.

-056

;1

,178

.32

10.

10. - 32.

1.0

32.

.1

.178

.178

.32

3.2

10. -178.

10.

10.

3.2

3.2

10;

32.

10. - 32.

3.2

10;

1.0

.1

32.

32.

3.2

.5 - 2.0

10. - 32.

83 322

100 382

75 169

75 256

87 253

50 46

100 326

87 172

100 68

83 198

56 192

75 347

92 457

67 130

50 615

100 381

100 296

57 184

5 6 64

67 20

75 248

91 252

87 318

75 240

50 338

75 187

87 193

62 97

100 74

75 85

62 562

75 78

100 669

100 413

100 324

87 290

100 288

75 336

71 291

60 55

87 441

87

92

478

510

80 270

50 722

50 238

NOTE: Drugs which failed to reduce PCP discriminability below 50 percent. At

least 8 animals/treatment were tested. However, when response level was

suppressed below about 75 responses/15 minutes, a number of animals

frequently failed to complete 10 responses within 15 minutes; their data

were not included.

including doxapram, diazepam, haloperidol, vasopressin, and yohimbine, produced a partial antagonism to approximately the 50 percent PCP-choice level. Frequently, however, testing these agents

at higher doses failed to reduce PCP discrimination further and/or

resulted in complete disruption of responding. In contrast to the

143
absence of antagonism by these agents or by PCP analogs, we observed that potent, metabolically stable, adenosine analogs were

capable of blocking completely the discriminative properties of

PCP (Browne and Welch 1982). However, subsequent findings in our

laboratory (Browne et al. 1983) indicated that the anti-PCP activity of adenosine analogs was most likely attributable to dispositional factors retarding PCP absorption into brain. It is of

interest to note that, in contrast to reported antagonism of PCP's

effects in other endpoints (e.g., locomotor activity), there has

been no definitive report of an agent capable of completely

reversing the discriminative properties produced by PCP. Since

there is no known antidote to PCP intoxication in man, the discriminative stimulus assay may be an appropriate model for

screening for such an agent.

In summary, the results presented here confirm and extend previous

findings that PCP can serve as a discriminative stimulus, and that

pharmacologically similar agents such as ketamine, dexoxadrol, and

SKF-10,047 can mimic the PCP cue (Brady and Balster 1981; Brady et

al. 1982; Herling et al. 1981; Holtzman 1980; Shannon 1981). It

is known that PCP exerts a multiplicity of effects on brain monoaminergic and cholinergic systems (Ary and Kominskey 1980; Arora

and Meltzer 1980; Ward and Trevor 1981). However, compounds that

activate or attenuate activity of CNS noradrenergic, dopaminergic,

serotonergic, cholinergic, GABAergic, opiate, or benzodiazepine

systems all failed to mimic or block completely the discriminative

effects of PCF. These results indicate that PCP-like agents probably exert their effects through unique neurochemical mechanisms

distinctly different from other classes of agents. Indeed, it

appears that PCP-like compounds may be acting on specific "PCP

receptors" in brain (Vincent et al. 1979; Marwaha et al. 1981;

Quirion et al. 1981; Zukin and Zukin 1979). Although good correlations between the ability of agents to support PCP cueing and

their ability to displace labeled PCP from binding sites have been

obtained (Zukin and Zukin 1981; Browne and Kozlowski, in preparation), it remains to be determined whether antagonists of PCP

cueing and receptor binding can be eventually discovered.

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Current Perspectives.

PCP (phencylidine): Historical and

Ann Arbor: NPP Books, 1981.

AUTHOR

Ronald G. Browne, Ph.D.

Pfizer Central Research

Groton, CT 06340

147
Clinical Implications of Behavioral

Pharmacology Research on

Phencyclidine

Robert L. Balster

icipated epidemic of phencyclidine

and ear ly 197Os, biomedical and behavioral research on this drug expanded by the late 1970s (Balster

and Pross 1978). Partly because of the improved public health

response resulting from this research activity, the PCP epidemic

has been stopped. The major credit for this rapid growth of PCP

research should go to the National Institute on Drug Abuse, NIDA

supported most of these research activities, and took an active

role in disseminating information on PCP (Peterson and Stillman

1978). Also exceedingly important has been NIDA's leadership in

providing PCP and many critically important analogs for research

use. For the last 10 years or so, NIDA has provided nearly all

the PCP utilized by researchers throughout the world. NIDA has

also had an active intramural research program on PCP, leading to

a number of important findings.

As a consequence of the unant

(PCP) abuse in the late 1960s

This update of NIDA's 1978 monograph on PCP provides an opportunity to see what we have learned from this enormous expansion of

PCP research over the last decade. This paper will focus on the

results of behavioral studies. Since the development of PCP as an

anesthetic was discontinued in the 196Os, there have been no laboratory studies of the behavioral effects of PCP in humans, presumably because of potential dangers to the subjects and probable

difficulties in obtaining an IND to give behaviorally active

doses. Thus, most of what we have learned about the behavioral

pharmacology of phencyclidine has been from animal research. This

review will highlight some of the major findings of that research.

It will also examine the implications to be drawn from this research for treatment and prevention of PCP abuse. Some of these

predictions for PCP abuse are consistent with clinical reports.

In other cases, clinical information is incomplete. One goal of

this paper is to suggest some areas where clinicians and clinical

researchers might focus their attention to learn more about the

implications of PCP abuse.

148
WHAT IS PCP?

Pharmacologists and epidemiologists have always had trouble classifying PCP. In early writings, it was classified as an anesthetic because this was its intended use; however, differences in the

pharmacology of PCP and typical general anesthetics are significant, as we shall see. Initially, when PCP was abused, it was

often classified as a hallucinogen; early epidemiologic studies

grouped it together with classical hallucinogens such as LSD.

Again, clinical experience and research have demonstrated the

inappropriateness of this classification. Behavioral pharmacologists have also been very interested in classifying PCP's behavioral effects and comparing them to other drugs of abuse.

Depending upon the effects being examined, PCP has many properties

in common with other drugs; but, on some measures, PCP seems to

represent a unique class of CNS-active drugs.

Amphetamine-Like Effects

A pioneer in studies of the pharmacology of PCP, Graham Chen,

often characterized PCP as a "sympathomimetic anesthetic" (Chen

1973), a curious juxtaposition of terms. However, the two drugs

to which PCP has been most often compared in behavioral research

are amphetamine, or other sympathomimetic stimulants, and pentobarbital or other classical CNS depressants. PCP clearly has

effects usually associated with both. PCP has many behavioral

effects characteristic of indirect-acting dopaminergic agonists

(Meltzer et al. 1981; Johnson 1983). Among these effects are the

production of amphetamine-like stereotyped behavior (Sturgeon et

al. 1979) and ipsilateral rotation in substantia nigra-lesioned

rats (Kanner et al. 1975). These amphetamine-like actions are

often blocked by antipsychotic drugs. PCP's effects on schedulecontrolled lever pressing for food reinforcement also often appear

similar to those of amphetamine, with large increases in rates of

responding and rate-dependent effects (Balster and Baird 1979;

Brady et al. 1980; Wenger 1976). Although amphetamine-like

effects on operant behavior have been seen in mice, pigeons, and

monkeys, the amphetamine-like stereotyped behavior and hyperactivity are particularly prominent in rodents. Monkeys exhibit

decreased responsivity, motor incoordination, changes in visual

attention, and, at high doses, a characteristic anesthesia. These

species differences in overt behavioral effects of PCP lead to the

speculation that dopaminergic actions are less prominent in primate species, possibly including humans.

Nonetheless, the amphetamine-like actions of PCP are of considerable interest for the following reasons. Malfunction of the

dopaminergic system has been implicated as having considerable

importance in schizophrenia. PCP's interactions with this system

may be responsible in large measure for its schizophreniform manifestations in humans. Like amphetamines, PCP would be expected to

exacerbate schizophrenia, and users with this or related disorders, or with latent psychiatric diseases, may be at

149

185-466 0 - 87 - 6
considerable risk from taking PCP. This possible connection between the effects of acute or chronic PCP administration and

schizophrenic diseases has motivated much of the research done

with PCP, since it is very possible that a further understanding

of this drug will provide valuable leads for study of this important psychosis (Domino and Luby 1981). Another implication of the

evidence for amphetamine-like effects of PCP is that high-dose PCP

toxicity may have components of amphetamine toxicity. For example, hypertensive crises have been reported in PCP overdose

(Eastman and Cohen 1975), and PCP can cause convulsions at high

doses. It is tempting to suggest treating PCP overdose with antipsychotic drugs; however, there is also considerable evidence for

differences in the acute toxicity of PCP and amphetamine. The

well-known aggregate toxicity seen with amphetamine in mice does

not occur with PCP (Landauer and Balster 1982). Chlorpromazine,

which antagonizes amphetamine lethality in mice, does not have a

similar protective effect against PCP; indeed, it has additive

toxicity (Landauer et al. 1982). Also, considering that many

antipsychotic drugs lower seizure thresholds and may contribute

anticholinergic effects to those of PCP, it is difficult to find a

clear pharmacological rationale to use antipsychotic drugs routinely to treat PCP overdose. A final implication of PCP's stimulant properties is that there may be dangerous interactions in the

combined use of PCP and sympathomimetic stimulants such as amphetamine and cocaine. PCP has been shown to enhance amphetamine

stereotyped behavior in rats (Balster and Chait 1978). Further

research on this possibility is needed.

Barbiturate-Like Effects

Although PCP was developed as an anesthetic, its profile as an

anesthetic is very different from typical general anesthetics of

the CNS-depressant class (Domino 1964). Nonetheless, PCP has a

number of behavioral and pharmacological effects similar to those

of depressants such as the barbiturates (Balster and Wessinger

1983). PCP has profound motor effects, as evidenced by effects on

rotorod performance and similar measures (Kalir et al. 1969;

Balster 1980). In this production of ataxia, PCP differs considerably from both stimulants and classical hallucinogens. Although

further, more detailed study of the motor effects of PCP is needed

(Ando et al. 1983), it is clear that abusers of PCP would be expected to exhibit motor signs of intoxication that might contribute significantly to PCP's behavioral toxicity. Performance of

tasks requiring motor coordination, such as driving an automobile,

would be expected to be significantly disrupted by PCP.

PCP, like barbiturates, also has anticonvulsant effects in various

animal models (Chen et al. 1959; Geller et al. 1981; Hayes and

Balster 1985). Certain convulsants, such as strychnine, are not

antagonized, and PCP has some specificity for tonic rather than

clonic convulsions.

150
Perhaps of most clinical significance, PCP very markedly enhances

the effects of classical depressant drugs, including barbiturates

and ethanol (Balster and Wessinger 1983). We have extensively

studied this interaction. and find that quantitatively the interactions can be as large as the interactions among CNS depressants,

a well-established toxic combination. This interaction has been

shown in pigeons, rodents, and primates using a number of different behavioral measures (Chait and Balster 1978; Thompson and

Moerschbaecher 1982a; Thompson and Moerschbaecher 1982b; Wessinger

et al. 1982; Woolverton and Balster 1981). Since there is a high

likelihood of combined use of PCP and depressants such as alcohol,

there is a high likelihood that some of the behavioral manifestations commonly attributed to PCP may be due to combined effects.

Careful histories on concurrent use of depressants such as alcohol, barbiturates, or benzodiazepines should be helpful in establishing the cause of problems encountered during acute PCP

intoxication.

Classical CNS depressants, such as barbiturates and benzodiazepines, have prominent antianxiety effects. In the animal laboratory, these drugs increase responding that has been suppressed by

punishment in what are often referred to as conflict procedures.

Because this effect on responding-suppressed-by-punishment is

relatively specific for antianxiety drugs, it is believed to be an

animal model for anxiolytic activity. PCP has potent rateincreasing effects on responding-suppressed-by-punishment, at

least in pigeons.(Chait et al. 1981), a widely-used species for

studying these types of effects. Although it requires considerably more study, this benzodiazepine-like antipunishment activity

of PCP suggests that it might have antianxiety effects in humans.

These effects may contribute to PCP's attractiveness to abusers.

An interaction between predisposing anxiety disorders and some

forms of PCP abuse warrants further investigation.

Unique Effects of PCP

In spite of the similarities described in the behavioral effects

of PCP to those of stimulants and depressants, users of PCP

describe an intoxication unlike that reported for other drugs of

abuse. PCP appears to have a unique spectrum of subjective

effects: a spectrum that has been characterized by clinical investigators (Pollard et al. 1965; Siegel 1978). The corresponding

animal behavior model for these effects utilizes a drug discrimination procedure. Animals are trained to detect whether or not

they have been given a PCP injection and to indicate their condition by pressing one of two response levers. Another chapter in

this volume (Browne) will consider the research using this paradigm in detail; however, a few aspects of the findings warrant

mention here.

The discriminative stimulus effects of PCP differ considerably

from those of other drugs of abuse (Poling et al. 1979; Shannon

1981). Animals do not generalize from PCP to other drugs of

151
abuse: neither to stimulants, depressants, nor hallucinogens

(i.e., they do not respond as if they had detected PCP). These

data are consistent with the ability of PCP to produce a unique

intoxication in humans, and with its separate classification as

representative of a distinct class of psychoactive drugs. The

public health implications are that the PCP abuse problem would

need specific treatment and prevention approaches. It would be

expected that some PCP abusers would have this as their drug of

choice, and not mix and match PCP with other drugs, as occurs

routinely within drug classes such as opiates and hallucinogens.

Patterns of PCP use and abuse would be expected to be distinctive;

because of its unique effects, PCP might appeal to certain types

of drug users. It is important to recognize that treatment and

prevention strategies developed for other drugs of abuse may be

inappropriate for problems of PCP abuse.

PCP SELF-ADMINISTRATION

Early evidence that PCP had significant abuse potential was the

finding, from behavioral pharmacology research, that PCP would be

self-administered by rhesus monkeys (Balster et al. 1973). In

that study, monkeys with IV catheters could respond on a lever to

receive injections of PCP. They readily acquired this behavior

and self-administered very large doses. This finding has been

replicated and expanded upon in numerous subsequent studies (e.g.,

Balster and Woolverton 1980; Carroll and Meisch 1980; Lukas et al.

1984; Risner 1982). Strong reinforcing properties are typically

obtained only with drugs having significant potential for human

recreational use. One of the interesting findings from PCP selfadministration research is that, given unlimited access to the

drug, monkeys will maintain nearly continuous intoxication. These

results are unlike the pattern of episodic self-administration

typically obtained for stimulants, and more like the patterns

associated with dependence-producing drugs such as the opiates and

depressants. I will have more to say on the dependence properties

of PCP later. These animal results suggest that at least some

segment of PCP abusers would become chronic heavy users with daily

use patterns. Also, unlike the results of self-administration

studies of opiates, where little overt behavioral toxicity is

observed in the animals at self-administered doses, monkeys selfadminister doses of PCP sufficiently high as to cause marked

behavioral effects. In these respects, PCP may more closely

resemble barbiturates and alcohol, with which self-administration,

by animals and human users, results in severely debilitating

doses. Another interesting recent development in PCP selfadministration research is that the oral route is also effective

(Carroll and Meisch 1980). PCP would be expected to have the

potential for both IV and oral abuse, although smoking appears,

currently, to be the most preferred route.

152
PCP-LIKE DRUGS

Although PCP has certain unique behavioral properties among drugs

of abuse, behavioral pharmacology research has established that

there are a number of drugs with PCP-like effects. The primary

tool for classifying drugs as PCP-like has been the drug discrimination procedure, since this is presumably a model of acute subjective effects, and because this is the one behavioral measure

that clearly establishes PCP's uniqueness. One group of drugs

with PCP-like discriminative stimulus effects are chemical analogs

of PCP, other arylcycloalkylamines. Rats or monkeys trained to

detect PCP will readily respond as if they had been given PCP,

when given any of a large number of PCP analogs (Shannon 1981;

Brady and Balster 1981; Solomon et al. 1982). Shannon and coworkers have made considerable progress toward determining

structure-activity relationships among arylcycloalkylamines and

essential structural requirements for PCP-like effects (Shannon

1983; Cone et al. 1984). A number of these PCP analogs have been

tested for reinforcing properties in IV self-administration studies (Risner 1982; Lukas et al. 1984). Those that are selfadministered are also identified as PCP-like in drug discrimination studies; thus, there is an excellent concordance in these

properties. The PCP molecule is a highly versatile one for making

substantial modifications and retaining activity; therefore, many

potentially abusable PCP analogs could be prepared. As of this

writing, only the N-ethyl analog (TCE), the thienyl analog (TCP),

and the pyrrolidine analog have been subject to much abuse, and

have consequently been scheduled under the Controlled Substances

Act. It would appear that many presently uncontrolled analogs

have PCP-like properties. Since animal behavioral research seems

capable of predicting PCP-like abuse potential, perhaps data from

these procedures will be used to regulate some of these analogs

before they are abused.

Ketamine is an arylcyclohexylamine analog of PCP that warrants

special mention. Ketamine is currently marketed as a parenteral

anesthetic for human use, and has many important clinical indications. In behavioral studies, including drug discrimination and

self-administration studies, ketamine acts very much like PCP. It

is generalized from PCP and is reliably self-administered. It has

also been subject to some abuse, and is presently controlled.

Although it is about one-tenth as potent, and is shorter acting

than PCP, there are little laboratory data showing qualitatively

different effects. Because ketamine is marketed, there has been

more research on it than on other PCP analogs. This research

literature is an important source of information with probable

relevance to PCP.

Among the more important series of discoveries in behavioral

research with PCP are the reports that drugs chemically distinct

from PCP also have PCP-like discriminative stimulus effects.

These drugs are of little immediate clinical significance because

they are all research compounds not easily available to potential

153
abusers. On the other hand, the emergence of various classes of

these PCP "biologs" has proven to be of considerable importance to

basic research on PCP's neural mechanisms of action. For example,

the finding that the opioid derivative, N-allylnormetazocine (also

known as SKF-10,047), which was found to have PCP-like discriminative effects (Shannon 1981), also had affinity for the PCP binding

site (Zukin and Zukin 1979), was very important in establishing a

possible functional significance for this site. Subsequent research has considerably advanced our understanding of the behavioral and biochemical effects of this and other PCP-like opioids

(Brady et al. 1982a; Holtzman 1980; Shannon 1983; Slifer and

Balster 1983; Zukin et al. 1984). Remarkably, a general concordance shows that diverse drugs with PCP-like behavioral effects are

active at the PCP receptor. It would appear that at least one of

the major effects of PCP mediated by this newly-discovered receptor mechanism is its discriminative effect. It is unclear how

many other effects of PCP are mediated through this receptor. One

way to study this is to examine these PCP biologs to determine the

extent of overlap with PCP in their behavioral and pharmacological

properties. It is beyond the scope of this paper to review the

relatively large research literature relating the pharmacology of

certain opioids with unusual "psychotomimetic" effects to the

pharmacology of PCP. Other papers in this volume document the

considerable progress being made in identifying the neural bases

for many of the important behavioral actions of PCP. This basic

research may lead to novel approaches to treatment of PCP abuse

and will contribute substantially to our understanding of brainbehavior relationships.

In addition to opioid derivatives, drugs from other chemical

classes have been found to have PCP-like discriminative stimulus

effects. The best characterized compounds are 1,3-substituted

dioxolane derivatives such as dexoxadrol and etoxadrol (Brady et

al. 1982b). Each has also been given to humans with evidence of

PCP-like effects (Lasagna and Pearson 1965; Wilson et al. 1970).

This class of compounds is of particular research interest because

it shows stereospecificity of action both behaviorally (Cone et

al. 1984; Slifer and Balster, in press) and in binding to the PCP

receptor (Hampton et al. 1982). Stereospecificity further supports the hypothesis that PCP's discriminative stimulus effects

are receptor-mediated. The finding that PCP-like effects occur in

a variety of chemical classes, including the opioid and dioxolane

classes described above, as well as some others (Tang et al. 1984;

Zimmerman et al. 1983), suggests that the potential exists for

arylcyclohexylamines to be only the first of many chemically

heterogeneous classes of PCP-like compounds. New compounds may

emerge with differing potential for abuse. On a more positive

side, there is also the possibility that new therapeutic agents

may be developed that will retain some of PCP's desirable effects

but be devoid of its abuse potential (Domino 1981). The laboratory procedures to study these new compounds are already relatively well developed. This variety of PCP-like drugs also provides

powerful tools for the basic study of PCP's pharmacology.

154
TOLERANCE

There have been a number of laboratory studies of tolerance to the

behavioral effects of PCP. Some of our earlier work on this has

been summarized previously (Balster and Woolverton 1981). The

usual procedure for tolerance studies is to give PCP repeatedly to

subjects trained to perform an operant task. We have given it

daily, or up to four times a day, at behaviorally active doses, in

some cases in escalating doses, to rats and squirrel monkeys. We

routinely find evidence of two- to fourfold shifts in dose-effect

curves, but no more. More recent studies have attempted to determine the important factors in this tolerance development. Most of

it appears to be accountable for by pharmacological mechanisms,

including some evidence for biodispositional changes (Woolverton

and Balster 1979; Woolverton et al. 1980; Johnson and Balster

1981; Freeman et al. 1984), although, in one study (Woolverton and

Balster 1979), there was some evidence that behavioral factors

(learning to respond while intoxicated) play some role. Practically speaking, PCP produces relatively modest tolerance development. It would be predicted that considerable tolerance would not

be a major characteristic of PCP abusers. The only evidence we

have to the contrary comes, not from direct tolerance studies, but

from studies of IV PCP self-administration. In one of these studies (Balster and Woolverton 1980), in which rhesus monkeys had

continuous access to relatively high doses, the monkeys often

self-administered over 10 mg/kg/day. These very high doses were

accompanied by behavioral disruption and decreased food intake,

but were tolerated for periods of weeks: food intake often

recovered. Although we have not systematically studied this, I

believe we could not have administered nearly as high daily doses

to naive animals. It is important to keep in mind that these

monkeys were, generally, keeping themselves continuously intoxicated 24 hours a day. Under conditions of unlimited access, very

large tolerance often develops to other drugs as well (Balster and

Woolverton 1982). Thus, this condition--unlimited access--

probably reflects the extreme circumstances favoring tolerance.

It is difficult to imagine human PCP abusers self-administering

this much drug.

DEPENDENCE

In the study described (Balster and Woolverton 1980), of unlimited-access self-administration of PCP, in which monkeys' very

large daily doses of PCP resulted in blood levels of 100 to 300

ng/ml during periods of over a month, dramatic withdrawal signs

were observed when PCP access was terminated. Signs included

vocalizations, bruxism, oculomotor hyperactivity, diarrhea, piloerection, difficulty remaining awake, tremors, and, in one case,

convulsions. These signs appeared within 8 hours of abstinence

and were most severe at about 24 hours, corresponding to the rapid

decline in plasma PCP levels. To examine this evidence of dependence more fully, high daily doses by continuous IV infusion were

attempted, but, as stated earlier, could not be done without

155
difficulty in maintaining the animals in good health. When lower

doses were infused, the observable withdrawal signs were more

subtle and variable.

To study the possibility of dependence upon lower, more reasonable

doses of PCP, a different approach was used (Slifer et al. 1984).

Again, rhesus monkeys were used, but these subjects were first

trained to lever press for their daily ration of food utilizing an

intermittent schedule of reinforcement (FR100). Behavioral measurements were made during four equally-spaced, 30-minute sessions

each day. After the animals were well trained, continuous IV PCP

infusions began through an implanted catheter. The initial dose

was 0.05 mg/kg/hr (1.2 mg/kg/day). As seen in figure 1, this dose

had little effect upon responding for food. The animals appeared

only very mildly intoxicated. When PCP was withdrawn after 10

days, behavior was markedly affected. By 8 hours after the infusion was terminated (response period A on day 11), some animals

completely ceased responding (see figure 1) and behavior recovered

slowly over the next 7 to 9 days. Some mild withdrawal signs were

occasionally observed during the first 24 hours of abstinence, but

the animals appeared normal by after the second day. When PCP was

given to animals in withdrawal, the animals recovered responding,

but were disrupted again as the acute effects wore off.

FIGURE 1. Effects of continuous PCP infusion and withdrawal on

rates of responding for food reinforcement in a

rhesus monkey

NOTE: Response rates in each of tour daily response periods are shown before

(open circles), during (closed circles), and after (open circles) lnfusion

of 0.05 mg/kg/hr PCP for 10 days. PCP was wlthdrawn at the arrow, 2 hours

before the next session where there was no effect. The first session on

day 11 was 8 hours after PCP was withdrawn. The results with this monkey

are similar to the other tour monkeys studied (modified from Slifer et al.

1984). Copyright 1984 Williams and WiIkins.

156
We have viewed these withdrawal effects on behavior as evidence of

behavioral dependence on PCP. Behavioral signs have also been reported in human users of PCP during withdrawal (Tennant et al.

1981); however, these instances appear to be relatively rare.

Nonetheless, the relative ease with which a dependence phenomenon

can be produced in monkeys suggests that PCP has a potential for

producing dependence in PCP users, particularly those who use the

drug very frequently. Behavioral sequelae seen in chronic PCP

abusers might be examined as possible manifestations of dependence

as well as of cumulative toxicity.

SUMMARY

This discussion has highlighted only some of the areas of behavioral, pharmacology research with PCP, focusing largely on studies

in our laboratories. Some of the areas touched upon lightly have

been much more extensively investigated (e.g., PCP-like properties

of psychotomimetic opioids). Some areas, such as the search for a

PCP antagonist, have been studied with relatively little success

so far. Two other areas, among many that are worthy of mention,

are the extensive series of studies of the effects of PCP on complex learning procedures, starting with the studies by

Moerschbaecher and Thompson (1980a, Moerschbaecher and Thompson

1980b), and an elegant series of studies on the determinants of

oral PCP self-administration, beginning with the study by Carroll

and Meisch (1980).

Much progress has been made on the clinical implications of behavioral research with PCP, and we are in a much better position to

respond effectively to this public health problem than we were

when it emerged, only a little over 10 years ago. The impetus behind PCP research has come from two directions--from the emergence

of PCP as a drug of abuse with the pressing practical questions

raised by this epidemic, and from the potential that PCP research

has for a fuller understanding of the brain and behavior. Although this discussion has focused on the former, progress toward

the latter goal has been equally, if not more, substantial, and

may have long-term health implications far beyond those presented

by problems of PCP abuse.

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161
ACKNOWLEDGEMENTS

My colleagues whose names appear as my co-authors on the papers

cited for this report are due a substantial portion of the credit

for most of the research described herein. The research has been

supported by National Institute on Drug Abuse Grant DA-01442.

AUTHOR

Robert L. Balster, Ph.D.

Department of Pharmacology and Toxicology

Medical College of Virginia

Virginia Commonwealth University

Richmond, VA 23298

162
Phencyclidine: Changing

Abuse Patterns

Raquel Crider

GENERAL TRENDS 1973 TO 1984

Phencyclidine (PCP), one of the arylcyclohexylamines. was developed and originally used as a general anesthetic for humans. Due

to psychotic and hallucinogenic reactions, use of the drug for

humans was discontinued. It is now used legally only in veterinary medicine as an animal immobilizing agent.

Currently, trends in PCP abuse are monitored through emergency

room visits, deaths, initiates entering drug abuse treatment programs, and surveys, as shown in table 1 and figures 1 and 2. The

years between 1973 and 1984 have been divided into three periods:

during the years between 1973 and 1978/1979, the indicators of PCP

use increased; the period 1978/1979 through 1981 marked a decline

in the PCP indicators; 1981 to the present time are years in which

PCP indicators have shown resurgence.

Indicators of PCP abuse, i.e., emergencies, deaths, and the number

of initiates entering treatment, increased between 1973 and 1978/

1979. Between 1973 and 1975, the rate of initiates, based on

treatment year-of-first-use records, increased more rapidly than

the number of emergencies. This phenomenon may be explained, in

part, by a change in the route of administration. Beginning about

1972, PCP users changed from administering the drug orally in tablet or capsule form to smoking the drug on leaf material, such as

marijuana, tobacco, or parsley. By smoking, PCP users were able

to control the dosage more effectively, thus decreasing the chance

of overdose.

By 1978/1979, indicators of PCP abuse leveled off and started to

decline. This trend is thought to be related to a variety of

activities initiated by health and law enforcement officials,

including a nationwide education campaign in which 18,000 letters

163
were mailed to treatment programs, emergency rooms, health agencies, and medical examiner/coroner offices describing the typical

reactions to PCP, and treatment procedures. In addition, PCP was

rescheduled from Schedule III to Schedule II of the Controlled

Substance Act, a highly restrictive category reserved for substances with limited legitimate use and/or significant abuse

potential. The PCP analogues, PCE, PHP, and TCP were placed in

Schedule I. Required reporting of production of the precursor,

piperidine, began in 1979. Penalties for possession of PCP with

intent to sell were increased at about the same time. As a result

of these and other efforts, the number of emergencies, deaths, and

PCP initiates entering treatment began to decline.

TABLE 1. PCP indicators

Number Percent Percent

PCP Emergencies PCP “Ever Use” 30-Day Use Age 12-17

PCP Related

National2

Initiate in "Ever Use"

Deaths In Panel3 Treated4

Households5

In High

School Households7

1973 1.400

1974 1.934

1975 1.768

1976

8.1

2.799

1977 4.993

1970 12.3 9.877

1979 10.5 10.288

1980 8.5 7.154 3.781

1981 9.4 5.840 2.722

1982 16.4 8.067 3.383

1983 23.8 9.782 4.376

1984 21.7 4.526

3.42

4.24

5.49

6.32

7.16

9.13

5.67

2.88

1.27

6.98

7.01

8.28

2.4

1.4

1.4

1.0

1.3

1.0

3.0

5.8

3.9

2.2

1. Number of PCP related deaths x 10-1 reported to DAWN. Newark and New York exeluded after 1981. The 1984 data are preliminary (National lnstitute on Drug

Abuse 1985c).

2. Number of PCP related emergencies x 10-3 reported to DAWN projected to the Nation (Hinkley and Greenwood 1982).

3. Number of imputed PCP related emergencies x 10-3 reported to a consistent panel

of hospitals In DAWN (National lnstitute on Drug Abuse 1985a).

4. Number of PCP lnitiates x 10-2 starting use 1973-1983 admitted to a consistent

panel of 402 treatment programs In 1977 through 1981.

5. Number of persons in households x 10-6 having ever used PCP 1970, 1979, and

1982 (Miller et al. 1983).

6. Percent of high school seniors using PCP In the 30 days prior to the survey

(Johnston et al. 1985).

7. Percent ages 12 to 17 years In households reporting ever having used PCP

(Miller et al. 1983).

164
KEY: = PCP ralated mortalities (NY and Newark excluded) x 10-1

; =PCP

emergencies projected to nation x 10-3; = PCP emergencies reported to consistent panel x 10-3

.

FIGURE 1. The number of PCP-retated emergencies projected to the

Nation, and the number of PCP-related deaths, peaked

in 1978/1979, declined through 1980/1981, then

increased in 1981 through 1984

By 1981, some of the indicators of PCP abuse began to increase

again. The number of PCP-related emergencies projected to the

Nation from the Drug Abuse Warning Network (DAWN) data showed an

increase from 5,840 in 1981 to 9,782 in 1983 (Hinkley and

Greenwood 1984). Data from a consistent panel of reporting hospitals indicate that the number of emergencies continued to increase

through 1983. The number of PCP-related deaths reported to DAWN

increased from 96 in 1981, to 154 in 1983 (National Institute on

Drug Abuse 1984). The estimated number of persons reporting ever

having used PCP increased from 7.01 million in 1979 to 8.28 million in 1982 (Miller et al. 1983).

The recent increase, however, appears to be concentrated primarily

in the metropolitan areas of Los Angeles, Washington, D.C., and

New York City. These three areas accounted for 76.0 percent of

the emergencies reported to DAWN in 1983, while Los Angeles and

Washington, D.C. accounted for 81.8 percent of the PCP-related

deaths2. Rates of PCP emergencies per 100,000 total emergencies

are available for 26 major metropolitan areas in 1983, based on

DAWN data (National Institute on Drug Abuse 1985d). The areas of

Los Angeles, Washington, D.C., and New York City show the highest

rates at 2.52, 2.03 and 0.53 per 100,000 emergencies, respectively, in 1984.

165
KEY: = Percent of household residents ages 12 to 17 years reporting "ever use”

of PCP; = Percent of high school seniors using PCP In past 30 days; = PCP

lnitiates In treatment x 10-2, corrected for lag between first use and treatment.

FIGURE 2. The increase in PCP indicators starting in 1981 does

not reflect an increase for new or young users. The

number of PCP initiates first admitted to treatment,

the percent of high school seniors using the drug in

the 30 days prior to the survey, and the percent of

persons ages 12 to 17 years in households reporting

ever having used PCP declined in the late 1970s and

remained at low levels since the early 1980s.

Table 2 shows the number of PCP-related emergencies for the period

of 1982 to 1984 by quarter for New York, Los Angeles, and

Washington, D.C. For New York and Washington, D.C., the average

number of mentions increased significantly between 1983 and 1984.

The decline in Los Angeles between 1983 and 1984 cannot immediately be interpreted as a decline in PCP use for that city. In 1981,

during an investigation of PCP trends in Los Angeles, it was discovered that many PCP emergencies were diverted to psychiatric

units, better equipped to handle the violent behavior sometimes

accompanying PCP reactions. These psychiatric units were not participating in the DAWN network at that time (Kozel and Husson

1981). It is possible that similar systemic problems may have

occurred in 1984.

166
TABLE 2. Number of PCP-related emergencies from a consistent

panel of emergency rooms in New York, Washington,

D.C., and Los Angeles, 1982-1984

Time Frame New York Washington, D.C. Los Angeles

1982 Q1 93 49 567

Q2 147 68 660

Q3 147 68 660

Q4 125 96 589

1983 Q1 142 104 568

Q2 173

Q3 214 130 910

Q4 303

97 807

179 910

1984 Q1 267 190 641

Q2 217 285 635

Q3 237 285 635

Q4 239 229 493

Mean 1982 121.6 70.0 600.6

Mean 1983 207.9 127.6 751.8

Mean 1984 240.0 241.4 621.0

SOURCE: National institute on Drug Abuse 1985b.

Potential problems in PCP abuse were also reported in New Orleans

and St. Louis (National Institute on Drug Abuse, in preparation),

although the quarterly frequencies of emergency room mentions in

those SMSAs were small compared to New York, Washington, D.C., and

Los Angeles.

NEW OR YOUNG USERS

Based on data from national surveillance systems, the increase

between 1981 and 1983 does not appear to reflect substantial increased use among new or young users, as occurred during the early

and mid-1970s, although there may be regional variations. In general, the number of initiates declined sharply after 1977 and

remained at low levels through 1981. Table 1 and figure 2 show

that there were 913 initiates starting use in 1978, first treated

in a panel of 402 consistently reporting treatment programs. The

167
number of initiates in treatment declined to 127 by 1981. Preliminary data from 1982 and 1983, corrected for the lag time between

first use of the drug and first entry into treatment, do not show

an increase. In addition, the percent of high school seniors

using PCP in the 30 days prior to an annually conducted survey declined from 2.4 percent in 1979 to 1.0 percent in 1984 (Johnston

et al. 1985). There was also a smaller percent of emergency cases

ages 6 to 19 years in 1983 compared to 1979: 34 percent vs. 18

percent (National Institute on Drug Abuse 1984; Drug Enforcement

Administration 1981).

Consistent with the decline in use among youth in these indicators

is the decline in self-reported PCP use among youth and young

adults in the household population. The National Survey on Drug

Abuse showed a significant decline between 1979 and 1982 in the

percent of 12- to 17-year-olds and the percent of 18- to 25-yearolds reporting ever having used PCP, from 3.9 percent to 2.2

percent, and from 14.5 percent to 10.5 percent, respectively

(Miller et al. 1983).

One exception was noted to the declining trend among youthful

users relative to other age groups. The number of 6- to 19-yearold black and Hispanic PCP emergency patients increased in one

Harlem hospital from 14 in 1981, to 297 in 1984. However, since

90 percent of all PCP-related emergencies in that hospital in 1984

were ages 6 to 19 years, indicating a bias or specialized program,

the hospital was eliminated from all subsequent analysis.

CHARACTERISTICS OF USERS

According to data from emergency rooms reporting to the Drug Abuse

Warning Network (table 3), most users were male, black, and

between the ages of 20 and 29. Table 3 shows the distribution by

gender, showing 71.8 percent were male. Table 4, giving the characteristics of emergency room patients over time, shows little

change in the gender of PCP emergency patients between 1976/1977

and 1983.

In contrast to the stable trends in gender, the age of emergency

room patients increased. As table 3 shows, in 1983 18.1 percent

were ages 6 to 19 years, 61.8 percent were ages 20 to 29 years,

and 19.6 percent were ages 30 years and older. Table 4 shows the

decline in the proportion of young users ages 6 to 19 years with

an emergency, from 51 percent in 1976/1977, to 18 percent in 1983.

This change in age can also be seen by SMSA, where New York and

Los Angeles both show significant change in the age distributions

between 1981 and 1984 toward older users (NY X2 =17.35, df=3,

p < .001; LA X2 =44.72, df=3, p < .001). No significant change in

age was noted for Washington, D.C.

168
TABLE 3. Distribution of PCP-related emergency room visits by

age, race and 8ex, 1983

Age (Years) Percent Race Percent Sex Percent

10-19 18.1 Black 53.9 Male 71.8

20-29 61.8 White 29.3 Female 28.1

30 and older 19.6 Hispanic 13.7 Unknown 0.1

Other or

Unknown 0.5 Unknown 3.1

Total 100.0 Total 100.0 Total 100.0

SOURCE: National Institute on Drug Abuse 1984.

TABLE 4. Distribution of PCP-related emergency room visits by

selected characteristics, May 1976 to December 1983

Period

Percent Ages Percent

10-19 Years Black

Percent

Male

May 1976-Apr 1977a

May 1977-Apr 1978b

51 24 70

47 28 72

Jan 1979-Dec 1979c

40

Jan 1980-Dec 198Od

34 71

32 37 71

Jan 1981-Dec 1981e 39 72

Jan 1982-Dec 1982f

28

22 48 71

Jan 1983-Dec 1983g

18 54 72

SOURCES: a

Drug enforcement Administration 1977; b

1978;

Drug Enforcement Administration

Drug Enforcement Administration 1979; Drug

Administration 1981; National Institute on Drug Abuse 1982;

Enforcement

National

lnstitute on Drug Abuse 1983; gNational Institute on Drug Abuse 1984.

The race distribution of emergency patients is also changing over

time in the direction of a larger proportion of black and Hispanic

patients. In 1983 (table 3), 53.9 percent of emergency room patients were black, 29.3 percent were white, and 13.7 percent were

Hispanic. Trends over time (table 4) indicate a change from 24

percent black in 1976/1977, to 54 percent by 1983. Within SMSA,

all three SMSAs showed significant changes between 1981 and 1984

toward a higher proportion of black and Hispanic patients in New

York and Los Angeles, and a higher proportion of black patients in

Washington, D.C. (NY X

2

=33.23, df=2, p < .001; DC X

2

=116.68, df=2,

p < .001; LA X2

 =29.32, df=2, p < .001).

169
While most PCP emergencies involve patients ages 20 years and older, the problem among 6- to 19-year-olds is nonetheless important.

Among young patients ages 6 to 19 years, PCP is more popular than

any other drug of abuse. In New York, 50.7 percent of young black

emergency room patients reported use of PCP, as did 19.9 percent

of the young Hispanic patients. In Washington, D.C., 35.4 percent

of the young black patients reported PCP abuse; in Los Angeles,

22.3 percent of the young black and 30.0 percent of the young

Hispanic patients did so.

PCP-RELATED DEATHS

More than 66 percent of PCP-related deaths reported to DAWN in

1983 involved at least one other drug. Table 5 shows a statistically significant relationship for

heroin combined with PCP (alcohol

alcohol combined with PCP and

X

2

=12.41, df=1, p < .001; heroin

X

2

 =29.13, df=1, p < .001).

The number of deaths associated with alcohol combined with PCP,

and for heroin combined with PCP has been increasing. Nationally,

the number of alcohol:PCP-related deaths was 21, 50, and 59, respectively, for the three years 1981, 1982, and 1983, according to

the DAWN annual reports. The number of heroin:PCP-related deaths

increased from 11 in 1981, to 24 in 1982, and 58 in 1983.

TABLE 5. PCP-related deaths in combination with alcohol or

heroin, 1983

Alcohol

No Alcohol

PCP No PCP PCP No PCP

59 988 Heroin 58 761

144 4,189 No Heroin 145 4,416

SOURCE: National Institute on Drug Abuse 1984.

The higher than expected frequency of alcohol:PCP-, and heroin:PCP-related deaths may be the result of an interaction of

the combined substances. Balster (this volume) anticipated an

interaction of the combined substances when he reported "PCP

very markedly enhances the effects of classical depressant drugs,

including barbiturates and ethanol."

The higher than expected frequencies of alcohol:PCP- and heroin:PCP-related deaths also would have occurred if the combinations were preferred by the users. The motivation may involve the

injection of heroin to moderate the adverse effects of PCP, or the

use of PCP to ease the pain of heroin withdrawal. Another explanation assumes a stimulant effect of PCP. The use of stimulants,

especially cocaine, with heroin is increasingly popular among

heroin users (Kozel et al. 1982).

170
Many of the PCP-related deaths were not the result of overdose or

drug interaction or reaction, but the direct result of some external event. The percent of cases involving a manner of death of

"drug and external event" increased from 31.3 percent in 1976 to

43.4 percent in 1983 (National Institute on Drug Abuse 1984).

According to Kozel and Husson (1981), in a report on a series of

104 PCP-related deaths in Los Angeles, 54 were homicides, 29 were

accidents, and 14 were accidental drug overdoses; the remainder

were reported as suicides. The 54 homicides were not deaths resulting from PCP, but were the result of some event, such as a

gunshot wound or strangling, in which the victim was found to have

been using PCP. Of the 29 accidents, 18 were drownings and 5 were

automobile accidents, while other accidents were the result of

various other causes, such as, a fall or cut. The various manners

of death reported in PCP-related deaths are consistent with observed symptoms of disorientation and violent aggressive behavior.

CONCLUSION

In general, PCP indicators increased between 1973 and 1978/1979,

declined between 1978/1979 and 1981, then increased again through

1984. The increase is predominantly among older, over age 20

years, former users, rather than among young and new users. Nonetheless, PCP is the most popular drug of abuse among 6- to 19-

year-old black and Hispanic youth with an emergency, in some

cities. The age of emergency room patients presenting for PCPrelated problems increased between 1976 and 1983, and there was an

increasing proportion of emergencies occurring among blacks during

the same period. Certain cities, such as Los Angeles, Washington,

D.C., and New York, have more PCP-related emergencies per 100,000

total emergencies than other metropolitan areas of the country.

The number of alcohol:PCP- and heroin:PCP-related deaths was

higher than expected. Users may prefer taking these drugs in

combination, or there may be an interaction in the effect of the

combinations. Many of the PCP-related deaths are the consequence

of some external event rather than a direct consequence of the

drug itself.

FOOTNOTES

1. DAWN is a morbidity and mortality information system, funded

by the National Institute on Drug Abuse, in which data are

collected from a sample of more than 800 hospitals located in

27 major metropolitan areas in the continental United States,

from a National panel of hospitals outside of these areas, and

from medical examiners/coroners located in 26 major metropolitan areas.

2. Medical examiner data from New York City are not included because of incomplete reporting.

171
REFERENCES

Drug Enforcement Administration. Drug Abuse Warning Network

(DAWN) Phase V Report, May 1976-April 1977. Washington, D.C.:

Drug Enforcement Administration, 1977. p. 152.

Drug Enforcement Administration. Drug Abuse Warninq Network

(DAWN) Phase VI Report, May 1977-April 1978. Washington, D.C.:

Drug Enforcement Administration, 1978. p. 158.

Drug Enforcement Administration. Drug Abuse Warning Network

(DAWN) 1979 Annual Report. Washington, D.C.: Drug Enforcement

Administration, 1979. p.130.

Drug Enforcement-Administration. Drug Abuse Warning Network

(DAWN) 1980 Annual Report. Washington, D.C.: Drug Enforcement

Administration, 1981. p. 130.

Hinkley, S., and Greenwood, J. Emergency Room Visits in DAWN

Projected to the Nation. Computer printout. Washington, D.C.:

Drug Enforcement Administration, 1984.

Johnston, L.P.; Bachman, J.G.; and O'Malley, P.M. Use of Licit

and Illicit Drugs by America's High School Students 1975-1984.

DHEW Pub. No. (ADM) 85-1394. Washington, D.C.: Supt. of Docs.,

U.S. Govt. Print. Off., 1985. p. 33.

Kozel, N.J., and Husson, B. An epidemiologic assessment of

selected drug trends. In: National Institute on Drug Abuse.

Drug Abuse Trends and Epidemiologic Issues, Proceedings of

Community Epidemiology Work Group. Vol. I. Rockville, MD:

National Institute on Drug Abuse, 1981. 2:5-19.

Kozel, N.J.; Crider, R.A.; and Adams, E.H. National surveillance

of cocaine use and related health consequences. Morbidity and

Mortality Weekly Report. Atlanta, GA: Centers for Disease

Control, May 28, 1982. 31:20:1-3.

Miller, J.D.; Cisin, I.H.; Gardner-Keaton, H.; Harrell, A.V.; and

Fishburne, P.M. National Surve on Drug Abuse: Main Findings

1982. DHEW Pub. No. (ADM) 83-1263. Washington, D.C.: Supt. of

Docs., U.S. Govt. Print. Off., 1983. p. 48.

National Institute on Drug Abuse. Annual Data 1981, Data from the

Drug Abuse Warning Network (DAWN). Rockville, MD: National

Institute on Drug Abuse, 1982. p. 198.

National Institute on Drug Abuse. Annual Data 1982, Data from the

Drug Abuse Warm Network (DAWN). DHEW Pub. No. (ADM) 83-1263.

Washington, D.C.: Supt. of DOCS., U.S. Govt. Print. Off., 1983.

p. 200.

National Institute on Drug Abuse. Annual Data 1983, Data from the

Drug Abuse Warning Network (DAWN). DHEW Pub. No. (ADM) 84-1353.

Washington, D.C.: Supt. of DOCS., U.S. Govt. Print. Off., 1984.

p. 58.

National Institute on Drug Abuse. DAWN Drug by SMSA: Quarterly

Totals for 60 Months Ending December 1984 Imputed Data.

Computer printout. Rockville, MD: National Institute on Drug

Abuse, 1985a. p. 147.

National Institute on Drug Abuse. DAWN Drug Alert December 1984.

Rockville, MD: National Institute on Drug Abuse, 1985b. p. 39.

172
National Institute on Drug Abuse. DAWN Drug by SMSA: Quarterly

Totals for 60 Months Ending December 1984, Newark and New York

Excluded, All Medical Examiner Data as of March, 1985.

Rockville, MD:

Computer

printout. National Institute on Drug Abuse,

1985c. p. 147.

National Institute on Drug Abuse. Total DAWN System - Rates of

Mentions - Top 50 Drugs by County, DAWN-SMSA, and Nation, 1/84-

12/84. Computer printout. Rockville, MD: National Institute

on Drug Abuse, 1985d. pp. 82, 86, and 99.

National Institute on Drug Abuse. Proceedings of Community

Epidemiology Work Group Meeting XVIII. Rockville, MD: National

Institute on Drug Abuse, in preparation.

ACKNOWLEDGEMENTS

Marc D. Brodsky provided assistance in correcting the year-offirst-use data for the delay between first use of PCP and first

treatment. Nicholas J. Kozel provided assistance in analysis of

death data.

AUTHOR

Raquel A. Crider, Ph.D.

National Institute on Drug Abuse

Division of Epidemiology

and Statistical Analysis

Parklawn Building, Room 11A52

5600 Fishers Lane

Rockville, MD 20857

173
PCP and Crime: Just Another

Illicit Drug?

Eric D. Wish

AVAILABLE LITERATURE

The scientific literature on PCP use and crime is sparse and consists mainly of case studies of persons who have committed violent, often bizarre acts after ingesting the drug (Siegel 1978;

Siegel 1980; Fauman and Fauman 1982). Death from drowning, often

in small amounts of water, has been a frequent cause of PCPrelated death in California, and the media's emphasis on such

extreme events has helped to increase the drug's notoriety.

PCP is easily synthesized and inexpensive. One should therefore

not expect to find the need for funds to purchase PCP to be the

strong motive for committing income-generating crimes that exists

for users of more expensive drugs like heroin and cocaine. A

potential link between PCP use and violent, impulsive crimes

against persons is often hypothesized, because some users appear

to become so disoriented from the drug that they commit extraordinary aggressive acts. One study of drug use and crime, in 112

boys (mean age of 15 years) committed to a training school,

reported that abusers of PCP had a greater number of offenses

against persons (e.g. rape, assault, robbery) than did abusers of

any other drugs (Simonds and Kashani 1980). Level of PCP use was

not significantly related to rates of property offenses. However,

because many of these boys abused multiple drugs, and only 17

percent of the offenses against persons were preceded by use of

any drug within the prior 24 hours, it is not possible to attribute the violent acts directly to the use of any of these drugs,

including PCP.

The potential link between PCP use and violent crime is reflected

in the legal debate regarding the defense of diminished capacity

for crimes committed by persons intoxicated with PCP (Baxley

1980). It is argued that persons who have committed violent

crimes under the influence of PCP are not legally responsible for

their acts because they have an inability to have criminal intent.

One reviewer concluded:

174
The PCP-intoxicated user's orientation toward the immediate present and disregard for long range consequences

of his/her behavior would make it difficult for him/her

to premeditate criminal acts. But the tendency to react strongly to sensory stimuli in the immediate environment, the inclination to refer everything to oneself

that often develops into paranoia, and the need to do

something due to intense psychomotor stimulation can

all produce an aggression-prone individual. Once again

it must be emphasized that emotionally stable people

under the influence of low doses of PCP probably will

not act in a way very differently from their normal

behavior. (Siegel 1978, p. 285, emphasis added)

The percentage of all PCP users who become intoxicated and commit

violent acts is unknown. As the statement above implies, however,

one would suspect that only a small minority of disturbed users

reach such a stage, In a recent review of the literature concerning PCP use and crime, the authors concluded that:

PCP is used by persons who tend to be multiple drug

users. PCP is one of the more common drugs found in

arrestee populations , although its prevalence varies

considerably by jurisdiction. An unknown, but probably

very small percentage of users suffer extreme PCPinduced intoxication and disorientation and commit

bizarre, often violent acts. Much more research is

needed to identify the extent of these problems in

users, and to learn how personality, other drug use,

and the quality and quantity of PCP ingested contribute

to the occurrence of violent behavior. (Wish and

Johnson, in press)

PROBLEMS IN THE STUDY OF PCP AND CRIME

A principal reason for the paucity of rigorous studies of the

association between PCP use and crime is the quantity of methodological problems that must be surmounted. Researchers may not be

able to depend upon the accuracy of self-reported PCP use. First,

PCP is often sold under a variety of names and may be misrepresented as other drugs. Thus, users may be unable to report

accurately whether they have taken the drug. Second, because

marijuana is sometimes laced with PCP, users may be unaware that

they have consumed the drug. Third, users of PCP may concurrently

use other illicit drugs. Disentangling the effects of each drug

on behavior is therefore difficult, if not impossible. Finally,

to assess the impact of the drug on individual criminal behavior,

one must have some idea whether PCP was present (or biologically

active) in the body near the time of the crime. In view of these

methodologic problems, the most basic questions regarding the

prevalence of PCP use in offender populations, the characteristics

of arrestees with the greatest risk of PCP use, and the types of

crimes they are charged with, have gone unanswered.

175
Our current study of drug use and crime in arrestees in Manhattan

overcame some of these measurement problems and enabled us to

address some of these basic questions regarding PCP use and crime.

The recent use of PCP (as well as other drugs) in male arrestees

was measured by a urinalysis of a specimen obtained within hours

after arrest. We therefore did not have to rely on each person's

accurate report that he had taken PCP. We shall use the urinalysis test results, with information from interviews with the

arrestees, and from their criminal records, to describe the prevalence of PCP use in arrestees, the demographic characteristics of

users and the types of offenses for which they are arrested. The

next section describes our study of drug use and crime in arrestees in Manhattan.

STUDY OF ARRESTEES IN NEW YORK CITY

Since 1971, the District of Columbia has routinely used urinalysis

tests to detect recent drug use in all arrestees held in the D.C.

Superior Court lock-up prior to arraignment. This program has

been a valuable source of epidemiologic data regarding drug abuse

trends, and drugs and crime associations (Wish et al. 1980; Forst

and Wish 1983; Toborg 1984). Our current study was designed to

determine whether a similar program of urine testing of arrestees

could be established in New York City, and whether arrestees identified by urine tests to be current users of hard drugs are at

greater risk for pretrial rearrest and/or failure-to-appear (for

scheduled court appearances) than are arrestees not detected to be

using drugs. We approached 6,406 male arrestees processed in the

Manhattan Central Booking facility between March and October,

1984, and asked each to participate in the voluntary research.

All persons arrested anywhere in Manhattan for more than the most

minor crimes are brought to Central Booking for fingerprinting and

processing before they are arraigned in court. We did not have

the resources to approach all persons who appeared in Central

Booking during the study period. Because this research was

intended to focus on serious offenders who would have substantial

pretrial periods, priority was given to approaching persons

charged with Felony offenses. We also excluded persons charged

with offenses that were so minor that they were not detained in

Central Booking prior to their arraignment.

For these reasons, about three-quarters (77 percent) of the persons in our sample were charged with felony offenses. A drugrelated offense (sale or possession) was the top charge at arrest

for 20 percent of the sample. Comparisons of the characteristics

of our sample members with those of all males processed in Central

Booking during the months that we collected data indicates that 58

percent of all males were charged with a felony, and 32 percent

with a drug-related offense. Thus, our findings apply to all male

arrestees processed in the Manhattan Central Booking facility,

overweighted for felony offenses and underweighted for drugrelated offenses.

176
Response rates for this voluntary, confidential research were

high. Approximately 95 percent of the eligible persons approached

answered the interview questions regarding their drug use and

treatment experiences. Of those interviewed, 84 percent agreed to

provide a urine specimen for analysis. The specimens were sent to

the New York State Division of Substance Abuse Services laboratory

in Brooklyn for analysis.

layer chromatography (TLC),

Each specimen was tested using thin

a widely used general screen for about

20 drugs. In addition, each specimen was tested for alcohol by

gas chromatography, and for opiates, PCP, cocaine, and methadone

using the more sensitive EMIT tests. Information regarding criminal history and recent arrests was obtained from criminal justice

records. Additional information regarding the study methodology

and some preliminary findings may be found in Wish and Johnson (in

press).

FINDINGS

In this section we first describe some background and case characteristics of the arrestees, and the types of drugs found in their

urine specimens. We next describe the persons found to have a

urine test positive for PCP and compare them with arrestees having

other urine test results.

Characteristics of the Sample Members

Because our subsequent analyses are based upon the urine test results, we present information here only from the subset of arrestees who provided a urine specimen (n=4,847). Other analyses (not

presented here) indicate that the persons who provided a specimen

were virtually identical on these characteristics to the entire

group of persons approached in Central Booking (n=6,406).

As one might suspect, the modal age range of the arrestees was the

twenties. Almost one-half of the men (47 percent) were age 25 or

less, and only 19 percent were 36 or older. The majority of the

men (54 percent) were black, with a sizable minority (33 percent)

being of Hispanic descent. Ten percent of the sample members were

white. Education was limited in the men. More than one half (56

percent) never completed high school or its equivalent (GED).

Only 15 percent had received some education at the college level.

Larceny and robbery were the most common top arrest charges in the

sample. Each of these charges accounted for 14 percent of the

arrests. (Arrestees are often charged with multiple offenses, and

tend to plead guilty to, or be convicted of, a lesser offense.

The top charge is the crime the police officer thought the arrestee had committed.) Possession of drugs was the top charge for

13 percent of the sample, and the sale of drugs accounted for an

additional 7 percent. As we noted earlier, the percentage of

arrestees charged with a drug-related offense would have been much

higher had we not limited their recruitment into the sample. Nine

percent of the sample were charged with possession of stolen

177
property, 10 percent with assault, and 7 percent with burglary.

The remainder of the sample (about 26 percent) consisted of a

variety of charges, none of which was found in more than 5 percent

of the arrests.

Urinalysis Test Results

Table 1 provides the urinalysis test results for the 4,847 arrestees. While PCP was tested for by an EMIT test only, cocaine, opiates and methadone were tested for by both EMIT and thin layer

chromatography (TLC). (The EMIT test for opiates is not specific

to morphine, the metabolite of heroin, and can detect the recent

use of a variety of opiates. A specimen positive for opiates is

most likely to indicate the use of heroin in this population, however.) Our analyses will use only the results from the EMIT

tests, because we have learned that the TLC general drug screen is

less sensitive for detecting recent use of these illicit street

drugs (Wish et al. 1983; Wish et al. 1984).

TABLE 1. Drugs detected in the specimens of male arrestees

(n=4,847)

Drug Detected by EMIT

Cocaine

Opiates

PCP

Methadone

Percent

42

21

12

8

Number of Drugs Found (of Four)

None

One

Two

Three or more

4 4

3 3

18

5

56

Total 100

A test positive for opiates, cocaine, or methadone probably indicates that the drug was used within the prior 24 to 48 hours.

There is some possibility that PCP, like marijuana, may be detected in the urine days or weeks after the last use (Khajawall and

Simpson 1983). Thus, a test positive for PCP indicates that the

drug was present in the body at the time the specimen was obtained, but does not necessarily mean that the arrestee last used

the drug near the time of the crime or the arrest. This may not

be too important, however, since the presence of the drug in the

body implies a potential effect upon the person.

178
Cocaine was the drug most likely to be found in the arrestees; 42

percent had a test positive for cocaine. The next most frequently

detected drug was an opiate (21 percent), followed by PCP (12 percent). Only 8 percent of the arrestees were positive for methadone. (The urine test could not, of course indicate whether the

methadone was obtained legally, by a prescription, or through

illegal channels.) The prevalence of PCP in the arrestees in

Manhattan contrasts with its prevalence in arrestees in Washington, D.C. In recent years, PCP has been the drug most frequently

detected in arrestees in Washington (found in more than 30 percent), followed by cocaine. As-table 1 indicates, 56 percent of

the tested arrestees were positive for at least one drug. (This

percentage is similar to the statistics currently coming out of

the D.C. testing program, in which 55 to 65 percent of all male

and female arrestees were positive for a drug.) More than one

drug was detected in almost one-fourth (23 percent) of the

specimens.

Specimens containing PCP were somewhat less likely to contain

other drugs than were specimens containing any drugs other than

PCP. Forty-nine percent of the PCP-positive specimens contained

another drug, compared with 52 percent of the cocaine positives,

73 percent of the opiate-positive specimens, and 73 percent of the

methadone positive specimens. The drug found most frequently with

PCP was cocaine; 35 percent of the PCP-positive specimens contained PCP and cocaine. The third most frequent combination found

in specimens containing PCP was PCP, cocaine, and an opiate (8

percent). Opiates and methadone were rarely detected in specimens

containing PCP, probably because PCP was most likely to be detected in younger arrestees, while opiates and methadone were concentrated in older arrestees. As figure 1 shows, PCP was most likely

to be detected in arrestees between the ages of 16 and 25. In

fact, PCP use was the only drug use that peaked for those in their

early twenties. Cocaine, and especially opiates and methadone,

tended to become more prevalent in arrestees above age 20, and to

peak for those in their thirties.

Arrest Charges Associated With a PCP-Positive Specimen

If PCP use were associated with a greater risk of violent, unpremeditated crimes, one would expect persons charged with assault,

murder, or public disorder to be most likely to be positive for

PCP. As table 2 shows, however, persons charged with robbery were

most likely to be detected to be PCP users. Persons charged with

drug-related offenses, larceny, and fare beating were next most

likely to be positive for PCP. Persons charged with assault,

sexual assault, public disorder, and murder actually were below

the average (12 percent) likelihood of a PCP-positive test for the

entire sample. PCP users appeared to be arrested for the more

goal-oriented, income-generating offenses rather than for bizarre,

unpremeditated crimes.

179
FIGURE 1. Percent of male arrestees with a positive urine test,

by age

TABLE 2. Percent of persons charged with each offense vho had a

urine teat positive for PCP (n=4,833)

Offense Charged Frequency

Percent Positive

for PCP

Robbery

Possession of drugs

Sale of drugs

Larceny

Fare beating

Weapons

Poss. of stolen property

Burglary

Sexual assault

Public disorder

Assault

Stolen credit card

Forgery

Murder/manslaughter

Gambling

Fraud

Criminal mischief

Other offenses

676

615

355

667

98

157

474

348

79

108

506

56

56

64

147

54

66

269

18

16

15

14

14

11

11

10

10

10

10

9

6

5

5

4

4

8

180
We found that PCP use is concentrated in the younger arrestees and

that almost one-half of the PCP-positive arrestees were also positive for another drug. It is, therefore, possible that the PCPcrime associations in table 2 could have been partially confounded

by the youthful ages and multiple drug use of PCP users. (For

example, PCP users, being predominantly young, may be more likely

to commit robbery merely because youths tend to specialize in this

crime.) The analyses in the remainder of this paper examine PCP

use and crime, taking into account these possible confounding

variables.

We divided our sample into four groups: (1) persons negative for

all drugs (D- , n=2,153); (2) persons positive for PCP only (PCP

only, n=309); (3) persons positive for PCP and another drug (PCP +

other, n=295); and (4) persons negative for PCP but positive for

another drug (D+, no PCP, n=2,090). As table 3 shows, both groups

of PCP-positive arrestees were younger than the other arrestees.

TABLE 3. Age at arrest in the four groups of arrestees (n=4,821)

Urine Test Results

Age

D-

(n=2,141)

PCP Only PCP + Other D+, No PCP

(n=307) (n=294) (n=2,079)

(In Percent) (In Percent) (In Percent) (In Percent)

16-20

21-25

26-30

31+

Mean age

(years)

27 28 25 13

22 37 42 24

17 17 22 25

34 8 11 38

100 100 100 100

28.4 22.9 24.3 29.2

Even the PCP-positive arrestees who were also positive for another

drug were rarely over age 30 (11 percent). The PCP-positive arrestees had average ages in their early twenties, while the other

arrestees had average ages in their late twenties. Age will

therefore continue to be a possible confounding factor to be allowed for in comparisons of drug use and crime in the four groups

of arrestees. The remaining section of this paper examines the

drug use and crime patterns for these four groups of arrestees.

We will especially be looking at whether the two PCP-positive

groups of arrestees tend to resemble the D- arrestees or the other

hard drug users.

181

185-466 0 - 87 - 7
Self-Reported Drug Use in the Four Groups of Arrestees

During the brief interview at Central Booking, we asked each

arrestee several questions about his prior use of drugs and his

treatment needs. Table 4 presents these results.

TABLE 4. Self-reported drug use and treatment, by urine test

result (n=4,847*)

Urine Test Results

D- PCP Only PCP + Other D+, No PCP

Ever used (percent)**

Marijuana 56 79 80 76

Cocaine 22 34 48 60

PCP 8 36 33 8

Heroin 10 11 24 48

Used PCP within 24 to

48 hours before

arrest (percent) 1 14 18 1

Mean age first felt

dependent on PCP 18.3 19.5 19.1 17.8

(Base N) (18) (26) (27) (9)

Needs any drug abuse

treatment now

(percent) 10 8 24 35

*Group n's vary slightly because of missing information.

**Percentages may add to more than 100 because of multiple drug use.

Lifetime use of illicit drugs varied considerably in the four

groups, but the nature of the differences depended on the drug.

For example, more than three-fourths of the arrestees in the three

drug positive (D+) groups reported having used marijuana, compared

with only about half (56 percent) of the D- arrestees. Cocaine

use was relatively rare in the D- arrestees (22 percent), more

prevalent in the two PCP-positive groups (34 to 48 percent), and

most prevalent (60 percent) in arrestees detected to be using

drugs other than PCP. The high level of reported cocaine use in

the latter group is probably related to our finding that these

persons were older; many had a urine test that was positive for

cocaine.

182
The two groups of PCP-positive arrestees were four times more

likely to admit using PCP at least once than were persons who were

D- or positive for drugs other than PCP. Still, only about onethird of the PCP-positive arrestees admitted to using PCP. One

reason for this discrepancy is intentional underreporting of PCP

use by the arrestees. (Underreporting of illicit drug use and

other deviant behaviors is common in persons interviewed in the

potentially threatening criminal justice environment. In contrast

to research conducted in relatively neutral research settings, it

is difficult to convince apprehended persons to disclose sensitive

information about themselves in Central Booking, even in a confidential and independent research project such as ours.) The fact

that many persons are unaware that they have been given PCP is

another possible reason for this lack of concordance.Selfreported heroin use was rare in the D- and PCP-only groups. Consistent with the urine test results, heroin use was most frequently reported in the other two groups of arrestees.

Both groups of arrestees who were positive for PCP were more likely to report using the drug in the 24 to 48 hours prior to arrest

than were arrestees in the other two groups (14 percent and 18

percent vs. 1 percent). Again, however, only a small minority of

the PCP positives reported recently using the drug. (Arrestees

are even more likely to underreport illicit behaviors that

occurred in the very recent past.) Fewer than 10 percent of the

arrestees in the four groups who reported using PCP at any time in

their lives reported ever feeling dependent on the drug. However,

of those who did report such feelings, it is clear that the average age of onset for feelings of dependency was in the late teens.

Few arrestees said that they currently needed drug abuse treatment. There was a clear difference here between the two PCPpositive groups. The PCP-only arrestees were as unlikely to

indicate a need for treatment as were the D- arrestees. The PCP +

other arrestees were three times more likely to report that they

needed treatment (24 percent vs. 8 percent). This was still less

than we found among the persons positive for drugs other than PCP

(35 percent). These findings are consistent with the fact that

drug dependence and treatment were more common in older persons

abusing cocaine and/or heroin, drugs that were detected in the

urine of the latter two groups of arrestees.

Our findings suggest that the arrestee who is detected by urinalysis to be using only PCP is more involved with drugs than the

arrestee who is negative for all drugs, but is less seriously involved than the arrestee detected to be using PCP and other hard

drugs. The arrestee who is detected by urinalysis to be using

only PCP is typically younger than hard drug use arrestees, and

may be an especially good candidate for interventions that may

prevent his progression to more serious drug abuse.

183
Criminal Behavior in the Four Groups

Table 5 presents the top charge at arrest and other criminal background information (obtained from criminal justice records) for

the four groups of arrestees.

TABLE 5. Arrest charge and criminal history, by urine test result

(n=4,847*)

Urine Test Results (Percent)

D- PCP Only PCP + Other D+, No PCP

Top charge at arrest**

Robbery 14

Larceny 14

Poss. of drugs 7

Assault 15

Stolen property 9

Burglary 7

Drug sale 5

Other 29

100

22

14

13

11

8

6

6

20

100

19

17

20

5

9

5

12

13

100

12

14

18

7

11

8

10

20

100

Prior felony

conviction 15 28 27 29

Prior misdemeanor

conviction 34 47 59 55

Had 2+ arrests within

3 years*** 35 60 70 55

*Group n's vary slightly because of missing information.

**Specifies all charges applied to at least 5 percent of either PCP group.

***Counts arrests In a J-year period that extends before and after the index

arrest: excludes the index arrest at which the person was interviewed.

We found that the group of arrestees who were positive for PCP

only were most likely to be charged with robbery (22 percent).

While assault was the most common charge for D- arrestees, it was

the fourth most frequent charge for the PCP-only arrestees, and

was even less common in the arrestees detected to be using hard

drugs.

184
Table 5 also presents information about PCP-positive arrestees'

involvement with the criminal justice system. The D- arrestees

were least likely to have had a prior felony or misdemeanor conviction, or two or more other arrests within 3 years of their

current arrest. The criminal records of the three drug-positive

groups tended to be quite similar, however, and indicated a greater level of prior criminal justice contacts. More than one-fourth

of these groups of D+ arrestees had a prior felony conviction,

one-half had a prior misdemeanor conviction, and over half had

multiple arrests within 3 years of their current arrest. Most important, the criminal backgrounds of the arrestees positive for

PCP alone were similar to those of persons found positive for the

harder drugs (opiates, cocaine, or methadone).

We were most interested in the PCP-using arrestees' apparent affinity for robbery. It occurred to us that there were two competing hypotheses that could explain this association: (1) our

findings could simply reflect the fact that youths tended to be

charged with robbery and that many of the PCP-positive arrestees

were younger; (2) perhaps many of the persons positive for PCP had

last used the drug weeks before the arrest (or crime). Would

robbery still be the most prevalent crime in persons known to have

used PCP in the day or two prior to arrest? To test for these

possibilities we first looked at the proportion of arrestees, by

age, in each group, who were charged with robbery. Figure 2

presents these findings (n varies from 38 to 790).

FIGURE 2. Percent of arrestees charged with robbery, by urine

test result and age

185
Within each age group, at least one of the groups positive for PCP

was the most likely to be charged with robbery. On the other

hand, the size of the differences depended on age. Arrestees 16

to 17 years of age and positive for PCP only were more likely to

be charged with robbery than any other group of arrestees at any

age level. With increasing age, the PCP-only arrestees' higher

likelihood of robbery decreased. At the higher age levels, the

arrestees positive for PCP plus other hard drugs were those most

likely to be charged with robbery. Thus, although PCP users had

more arrests for robbery at all age levels, in the younger ages,

when PCP is most likely to be found in an arrestee, persons positive for PCP only are the most likely to be charged with robbery.

To examine the possibility that our findings might change if we

knew that the person had taken PCP within hours of the arrest, we

isolated the 96 persons who reported using PCP in the 24 to 48

hours prior to arrest and were positive for PCP by the urine test.

We found that robbery was still the most frequent offense charged.

Twenty-three percent of these persons were charged with robbery;

the percentage was identical for persons positive for PCP only,

and those positive for PCP plus other hard drugs. The next most

frequent offense charged was the possession of drugs (20 percent),

followed by larceny (14 percent). A charge of assault was found

for 12 percent. Thus, even in a group of PCP-positive persons who

admitted to using PCP shortly before arrest, we found that robbery

was the most frequent offense charged.

This information suggests that the PCP-positive arrestee in

Manhattan looks much like other drug-using arrestees. Far from

being charged with assaults or bizarre types of offenses, PCP-positive arrestees are most likely to be charged with robbery, larceny, and other drug offenses.

DISCUSSION

This section presents some of the implications of our findings.

Where possible, we will discuss comparable information from the

urine testing program in Washington, D.C., in order to provide a

larger context for our findings.

Perhaps of most significance, we have found that PCP use is relatively common in an arrestee population. Twelve percent of the

male arrestees in Manhattan and about 30 percent of arrestees in

Washington, D.C. have a urine test positive for PCP. In New York,

this would translate into approximately 12,000 PCP-positive

persons arrested and processed in Manhattan Central booking each

year. Furthermore, these are probably minimum estimates of the

number of users, since the urine tests failed to detect the many

users who had not taken the drug soon before arrest.

The fact that PCP is the drug most frequently detected in the

urines of arrestees in Washington, D.C., but only the third most

frequently detected drug in Manhattan, implies that there may be

186
considerable differences in the use of this drug in different

regions of the country. We cannot say whether these differences

are the result of fads in drug use, accessibility of the drug, or

some other factor.

Another implication of the large numbers of arrestees who use PCP

is that only a small percentage of users probably experience the

bizarre, violent behavior that is often attributed to PCP. If

more than one or two percent of the arrestees in New York City and

Washington, D.C. were to experience violent psychotic-like behavior when they use PCP, the police and treatment resources in these

cities would be overburdened by the problem. Furthermore, these

estimates do not include the many users of PCP who are never

arrested.

PCP use is concentrated in young offenders under age 25. Since

opiates and methadone are largely found in older arrestees, it

would appear that PCP may be an excellent marker for identifying

the drug-involved offender before he progresses to other hard

drugs. Our findings indicate that the PCP-positive arrestee in

New York City is no stranger to the criminal justice system. He

is likely to have a history of prior arrests and convictions. By

identifying the young PCP-using arrestee at entry to the criminal

justice system and by applying suitable constructive interventions, it may be possible to deter him from progressing to the

more serious hard drug habits found in older arrestees.

Far from finding a preponderance of charges for bizarre, violent

offenses in PCP-positive arrestees, we unexpectedly found that

their most frequent offense was robbery. This affinity for robbery remained at all age levels, and was found even when we

selected out the few persons in our sample who were positive for

PCP and admitted taking the drug within hours of arrest. One

possible explanation for this association between robbery and PCP

use is that both behaviors require a willingness of the person to

risk his/her physical and/or mental well-being. If this is the

case, the PCP-using robber may be an especially dangerous

offender. A top charge of robbery accounted for only a minority

of the PCP-positive arrestees. Following the robbery charge,

larceny, drug offenses, and assault were the most frequent charges

for PCP-positive arrestees. Comparable analyses of information

from the testing program in Washington, D.C. confirm these

findings. Drug offenses, robbery, possession of stolen property,

and assault were the most frequent offenses charged for persons

positive for PCP only, in that city.

Our findings indicate that many PCP users are apprehended for

goal-oriented, income-generating crimes. We did not find a preponderance of the types of offenses one might expect from persons

commiting the bizarre, irrational acts ascribed to PCP users. One

possible explanation for these findings is that PCP use in these

offenders is so light that PCP intoxication is rare. It is probably true, as Siegel (1978) suggested, that emotionally stable

187
persons taking low doses of PCP will behave the way they would

normally act. Because the criminal backgrounds and the drug abuse

histories of many PCP-positive arrestees were similar to those of

other drug-positive offenders in our sample, we suspect that the

detection of PCP use in an arrestee is the same indicator of intense criminal activity that the presence of cocaine and heroin is

(Wish and Johnson, in press).

REFERENCES

Baxley, R.C. Voluntary intoxication from phencyclidine: Will it

raise a reasonable doubt of the mental capacity of a person

charged with a crime requiring specific intent or mental state?

J Psychedelic Drugs 12(3-4):330-335, 1980.

Fazman, B.J., and Fauman, M.A. Phencyclidine abuse and crime: A

psychiatric perspective. Bull Am Acad Psychiatry Law 10(3):171-

176, 1982.

Forst, B. and Wish, E. Drug use and crime: Providing a missing

link. In Feinberg, K.R., ed. Violent Crime in America

Washington, D.C.: National Policy Exchange, 1983. pp. 84-95.

Khajawall, A.M., and Simpson, G.M. Peculiarities of phencyclidine

urinary excretion and monitoring. J Toxicol Clin Toxicol

19(8):835-842, 1982-83.

Siegel, R.K. Phencyclidine, criminal behavior, and the defense of

diminished capacity. In: Petersen, R.C., and Stillman, R.C.,

eds. Phencyclidine (PCP) Abuse: An Appraisal. National

Institute on Drug Abuse Research Monograph 21. DHEW Pub. No.

(ADM) 78-728. Washington, DC: Supt. of Docs., U.S. Govt.

Print. Off., 1978. pp. 272-288.

Siegel, R.K. PCP and violent crime: The people vs. peace. J

Psychedelic Drugs 12(3-4):317-330, 1980.

Simonds, J.F., and Kashani, J. Specific drug use and violence in

delinquent boys. Am J Drug Alcohol Abuse 7(3&4):305-322, 1980.

Toborg, M. Preliminary findings on the D.C. urine testing experiment. Paper presented at the annual meeting of the American

Society of Criminology, Cincinnati, November 1984.

Wish, E.D.; Klumpp, K.A.; Moorer, A.H.; and Brady, E. An Analysis of Drugs and Crime Among Arrestees in the District of

Columbia. Springfield, VA: National Technical Information Service, 1980.

Wish, E.D.; Strug, D.; Anderson, K.; Miller, T.; and Johnson, B.

Are urine tests good indicators of the validity of self-reports

of drug use? It depends on the test. Paper presented at the

annual meeting of the American Society of Criminology, Denver,

1983.

Wish, E.D.; Brady, E.; Cuadrado, M.; and Sears, A. Preliminary

findings from the "Drug use as a predictor of pretrial behavior

in arrestees" project. Paper presented at the annual meeting of

the American Society of Criminology, Cincinnati, November, 1984.

Wish, E.D., and Johnson, B.D. The impact of substance abuse upon

criminal careers. In: The National Research Council Panel on

Research on Criminal Careers, in press.

188
ACKNOWLEDGEMENTS

Elizabeth Brady and Mary Cuadrado of Narcotic and Drug Research,

Inc., provided data collection and computer programming. Steven

Belenko of the New York City Criminal Justice Agency provided

criminal record information for sample members. Mary Toborg of

Toborg Associates and John Carver of the D.C. Pretrial Services

Agency provided information from the Washington, D.C., program of

urine testing of arrestees.

Preparation of this manuscript was supported by National Institute

of Justice grant 83-IJ-CX-K048. Points of view or opinions in

this document do not necessarily represent the official position

or policies of the U.S. Government.

AUTHOR

Eric D. Wish, Ph.D.

Senior Research Scientist

Narcotic and Drug Research, Inc.

2 World Trade Center, Room 6754

New York, NY 10047

189
Neuropsychological Assessment of

Phencyclidine Abusers

James E. Lewis and Robert B. Hordan

The behavioral testing of phencyclidine (PCP) abusers by means of

neuropsychological (NP) assessment serves as a bridge between

neuroscience research into brain effects of PCP and the treatment

and rehabilitation of the drug abuser in the community. The systematic individual NP case study includes: (1) a critical review

of historical/developmental antecedents to an individual's drug

use; (2) observations pertaining to a mental status evaluation,

performance on full-scale intelligence, NP, and screening achievement tests; and (3) a diagnostic interview focusing on educational , occupational, and legal implications of the evaluation.

Due to the subtle and gross effects found in brain functioning of

the PCP abuser, assessment information can be critical to developing rehabilitation plans, successful psychotherapy and/or behavioral treatment programs, and total treatment objectives. The

development of briefer screening assessment techniques, in lieu of

the 6- to 8-hour full NP evaluation, has been recommended for particular clinical populations, to provide a cost-effective service

while still obtaining important clinical information. Nevertheless, a significant amount of professional time and effort continues to be spent providing treatment to PCP and other polydrug

abusers: time and effort that prove unsuccessful, possibly due to

the lack of any form of objective assessment.

PURPOSES OF THE REVIEW

The purposes of this review are twofold: (1) to describe the contents and rationale of an abbreviated (2- to 4-hour) NP evaluation

of PCP abusers; and (2) to explain the usefulness of this evaluation in relating critical information concerning an individual's

pattern of higher cortical strengths and weaknesses to the therapist's treatment and rehabilitation decisions. Specifically, we

discuss the nature of NP tests and their value in assessing PCP

abusers, and the relevance of history-taking of certain premorbid

developmental variables or factors pertinent to a drug abuse lifestyle, e.g., toxicity-related transient organic brain syndromes,

190
closed head injuries (CHI), etc. Further, this paper summarizes

patterns and trends in the predrug histories and NP test data

obtained in a pilot sample of PCP-polydrug abusers. Finally, four

case studies are presented to illustrate the diversity of effects

that PCP abuse may have on persons with varied predrug-use characteristics and with varied patterns of drug abuse.

HISTORY OF THE NP EVALUATION IN CHEMICAL DEPENDENCY

In the early stages of clinical neuropsychology, Reitan (1955) and

others demonstrated the utility of NP tests as instruments sensitive to subtle forms of brain dysfunction. Medical specialists,

particularly in neurology, have acknowledged the need to quantify

and elaborate on "soft signs" of brain dysfunction. Despite rapid

advances in radiological (e.g., computed tomography) and EEG technologies, the medical model approach alone has been insufficient

for full evaluation of impairment of higher cortical functions,

especially complex sensory, cognitive, and coordinated motor

behavior. Parsons and Farr (1981), in their review of research on

alcohol and polydrug abuse, illustrated that a careful NP evaluation can provide valuable information on an abuser's verbal and

nonverbal intelligence, complex motor and sensory functions, and

adaptive "everyday functioning" skills (Heaton and Pendleton

1981). From these NP data, both subtle and gross impairment of

higher cortical functions can be inferred.

At this time, the most thorough and widespread use of NP tests, in

the field of chemical dependency, has been to evaluate effects of

alcohol abuse on higher cortical functions. Though similarities

exist between alcohol abusers and other drug abusers, there are

many ways in which these two groups differ. Grant et al. (1979),

Mider and Lewis (1981), and Parsons and Farr (1981) have applied

knowledge gained from research and clinical use of NP test results

obtained from evaluation of alcohol abusers, to the study of more

complex polydrug and PCP abusers.

COMPLICATIONS IN THE EVALUATION OF THE PCP ABUSER

Kolarik and Vayhinger (1983) implied that any neurological investigation into PCP abuse must begin by addressing drug identity and

purity problems inherent in the "street supply" of PCP. Analysis

of street samples of PCP reveal significant chemical differences,

with indications that one-third to one-half of all sampled PCP

illegally distributed is contaminated with chemical agents that

differ significantly from pharmaceutically manufactured PCP. The

issue of the chemical nature of the drug presumably ingested as

PCP is further complicated by street sales of chemicals that often

have little or no chemical resemblance to PCP, but may grossly

mimic PCP's physiological and psychological effects. Thus, NP

deficits identified in individual PCP abusers may be due to other

unknown substances that are toxic to the brain and central nervous

system (CNS). In addition to these pharmacologic issues, the vast

differences in patterns (frequency, amount, and types) of drugs

191
used by PCP abusers further complicates the evaluation of suspected PCP-induced toxic organic brain syndromes.

To date, nearly all published studies of human PCP use have shown

that most PCP abusers are not single-substance abusers. Specifically, PCP abuse is more often part of a larger pattern of polydrug abuse, which may include the abuse of alcohol, marijuana, and

cocaine. Other drugs of abuse, reported less frequently by PCP

abusers, are amphetamines, barbiturates, sedative/hypnotics, opiates, and inhalants. Thus, clinical NP research on the CNS effects of PCP is complicated not only by differing characteristics

of the drug itself, but also by prior and concurrent patterns of

PCP and other drug use. This polydrug abuse produces indeterminable, though suspected, potentiating and addictive effects.

Although many PCP abusers have histories of normal (before-drug

use) physical and psychological development, recognition of relevant historical and developmental antecedents to PCP and polydrug

abuse are especially important in light of NP models that underlie

the interpretation of NP test results. Adolescence, in terms of

NP functioning, represents the "meeting point" of interpretive

models used to understand child versus adult brain dysfunction.

The child NP model presumes a developing, maturing brain in which

complex cognitive and perceptual skills are being acquired and

mastered. Childhood brain dysfunction is hypothesized as delaying

or impairing acquisition of verbal and nonverbal skills as well as

of psychological coping strategies used to deal with normal life

stresses. In contrast, the NP model of adult brain dysfunction

presumes a developed, mature brain, in which most skills have

"peaked" in terms of acquisition and mastery. Insult to the adult

brain may involve loss or impairment of previously acquired and

mastered cognitive and perceptual skills as well as loss or impairment of other psychological mechanisms and coping strategies.

By the onset of puberty, many basic academic (and other) skills

and abilities have been acquired and mastered, but there continues

to be some "fine tuning" of complex psychological functions mediated by the higher cortex.

Recent research (Mider and Lewis 1981) suggests the existence of a

large subsample of PCP abusers who have premorbid histories of

moderate to severe learning disabilities (LD). The genesis of LD

is often associated with prenatal, birth, and early childhood factors that are postulated to have influenced or delayed the development of various higher cortical functions related to the

acquisition and mastery of specific academic skills. The General

Accounting Office Report to the Congress (1977) suggests a further

correlation between developmental LD and juvenile delinquency

(JD), a term often associated with drug abuse. The LD-JD hypothesis derives from the observation that LD is estimated to be present in 50 percent to 80 percent of the JD population, compared to

estimates of LD's presence in 8 percent to 12 percent of the

normal-IQ school-age population at large.

192
The interpretation of NP test results, in adolescents and young

adults suspected of drug-induced brain dysfunction, can be a difficult task, since most NP and psychological evaluations represent

a first testing, or "baseline" situation. Inferences of predruguse levels of brain functioning often must be made using existing

educational data and/or by making a premorbid optimal estimate of

functioning from "best subtest" IQ scores. Thus, it becomes a

complex diagnostic issue to determine (1) whether observed deficits on complex cognitive, sensory, and motor tasks represent a

pattern of loss or impairment of previously acquired functions due

to PCP and other associated drug abuse effects, or (2) whether the

observed deficits represent poorly developed learning and performance skills that were impaired prior to PCP and other drug abuse.

These complex diagnostic issues have important prognostic and

treatment implications. For example, an individual PCP abuser may

have no history of developmental learning or performance disorders; however, the toxic effects of PCP on higher cortical functions may contribute to the onset of learning disabilities

"acquired" as part of a toxic organic brain syndrome. Thus, PCPinduced brain toxicity will impair skills involved in new learning

and directly influence academic and vocational success.

The examination of individual NP case studies by other investigators, as well as summary results of our pilot research, suggest

at least two clinically distinct populations. One subsample of

PCP abusers has a developmental history of prenatal and birth

complications, e.g., prematurity, anoxia at birth, or low APGAR

scores, and of early childhood factors, e.g., CHI with loss of

consciousness, febrile illnesses with or without convulsions, or

chronic ear infections. These histories contribute to developmental learning and performance disorders. In this group, LD

causes academic failure and frustrations, which in turn contribute

to the development of psychological and interpersonal problems.

The second subsample has little or no evidence of LD or impairment

of cognitive skills necessary for academic success, prior to PCP

abuse. However, this group does show evidence of impairment in

skills involved in new learning, following PCP and other drug

abuse. Socially, these adolescents have little or no history of

associating with a JD peer group but engage in experimental or

"recreational" drug use only. PCP-induced changes in personality

and behavior in these adolescents are anathema to their parents

and families, and sometimes even to the individual abuser.

RECOVERY OF FUNCTION

In working with PCP and polydrug abusers who have impaired everyday functioning, counselors must be ultimately concerned with the

individual's ability to recover. Objective prediction of recovery

of function, using NP tests, involves a baseline evaluation and at

least one repeated assessment. Patterns of NP strengths and deficits in the two or more assessments may then be compared. Clinical inferences can be made, describing skills that show relative

permanence of deficit (with no change on repeated measurement), or

193
skills that show relative recovery of function (with NP test score

improvement).

After drug abstinence has been established, the subgroup of PCP

abusers with no premorbid history of brain dysfunction or LD would

be expected to show the least impairment on NP tests and have the

best prognosis for recovery of lost or impaired functions. However, case study reports utilizing NP assessment in evaluating PCP

abusers find highly idiosyncratic effects of PCP, as measured on

higher cortical functions. Specifically, NP case studies have

shown moderate to severe impairment on NP tests in individuals

with histories of minimal use. Conversely, there is another group

of PCP abusers who show only borderline to mildly impaired NP

functioning subsequent to 1 or more years of chronic, moderate to

heavy PCP abuse.

Similar findings have been noted in NP case studies of PCP abusers

after 6 months or more of abstinence from all drugs of abuse. The

less frequent the PCP use, the better the prognosis usually is for

lost or impaired higher cortical functions to recover, following a

period of drug abstinence. However, there are instances of individual PCP abusers who show moderately to severely impaired performances on NP tasks after months of abstinence, following light

or "experimental" PCP use. As indicated above, these mixed findings may be due to the actual chemical nature of what is presumed

to be PCP, as well as to additive and potentiating effects from

using PCP and other drugs. Other idiosyncratic differences in the

body's ability to metabolize PCP and related chemical contaminants

occur among individual PCP abusers. Human and animal neuroscience

research of PCP effects on neurotransmission may enhance the

understanding and interpretation of NP test results.

An analogue to drug-induced CNS dysfunction suggested by Parsons

and Farr (1981) is the dysfunction seen in aging. Reitan (1973)

first conceptualized the "brain age quotient" (BAQ), a combination

of Wechsler Adult Intelligence Scale-Revised (WAIS-R) and

Halstead-Reitan Battery (HRB) subtests as representing behavioral

manifestations of impaired brain functioning that occur as a normal consequence of aging. The BAQ pattern appears surprisingly

similar to deficits resulting from alcohol and polydrug abuse.

Because they reflect impairment in adaptive abilities necessary to

cope successfully with everyday functioning, BAQ test deficits may

be good prognostic indicators of diminished potential for completing treatment and/or of drug and alcohol recidivism. Serious

clinical and research consideration of this hypothesis may lead to

more revealing NP interpretations, especially since PCP abuse may

be far more devastating to NP functions than are alcohol and other

polydrug abuse.

RATIONALE FOR BRIEF NP ASSESSMENT WITH PCP ABUSERS

Due to drug treatment program budgetary constraints and the relative unavailability of clinicians having expertise in the use of

194
NP assessment techniques, little or no psychological or NP evaluation is currently employed. It is believed that the lack of

knowledge of the PCP abuser's pattern of higher cortical strengths

and deficits is responsible for a vast majority of current treatment and program failures. This supposition is in marked contrast

to blaming the individual abuser or drug counselor for treatment

failures and recidivism. For an individualized treatment and

rehabilitation plan to be effective, both the PCP abuser and the

counselor should have a thorough understanding of that individual's pattern of higher cortical strengths and deficits. The

following sequence of events is not uncommon. First, many counselors and therapists are predominantly trained in counseling

techniques that rely heavily on use of verbal concept formation.

However, results of NP case studies, as well as research into

"group" differences among PCP abusers, suggest that it is not uncommon for verbal abstraction skills to be moderately to severely

impaired as a result of PCP abuse. Regardless, the PCP abuser is

unwittingly placed into a treatment program where success in the

therapy or counseling session depends implicitly on reliance on an

impaired or defective skill. The subsequent treatment failure and

return of the PCP user to a drug-use lifestyle, away from achieving and maintaining abstinence, is frequently attributed to client

"resistance" or the therapist's lack of skills.

Historically, the HRB NP test, the most widely used and wellvalidated of all NP test batteries, takes from 6 to 8 hours for

complete administration. Reducing an established test battery to

a 2- to 3-hour structured assessment procedure requires the use of

selected subtests: those most sensitive to PCP-induced brain dysfunction. The development and validation of briefer screening

batteries, which represent a reduction in the total number of subtests used, professional time, and expense is an emergent trend

(Hartlage and Mains 1982, Reynolds et al. 1983). Based on our

literature review and results of a pilot sample study of 30 PCP

and polydrug abusers, the following subtests are recommended for

inclusion in a brief NP assessment battery.

Wechsler Intelligence Scales

Depending on the drug abuser's age, either the Wechsler Intelligence Scale for Children-Revised (WISC-R) or WAIS-R should be used

to assess Verbal and Performance (nonverbal) IQ. These intelliaence scales contain subtests that have been documented. over a

20- to 30-year history of research, as being sensitive to discrete

types of brain dysfunction. The NP research with adults suggests

that WAIS-R Verbal IQ may estimate the efficiency of functioning

of the left cerebral hemisphere. Among the Verbal portions of the

WAIS-R, the Similarities subtest gives important information

regarding the client's ability for verbal abstract reasoning, an

important skill that underlies success in most forms of counseling

and psychotherapy. The Comprehension subtest estimates the individual's knowledge of social conventions and expectations. This

subtest has specific treatment implications, and relates to an

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individual's capacity for understanding relationships between the

components and consequences of socially acceptable behavior.

Revised Wechsler Memory Scale (RWMS)

The RWMS is included to assess the PCP abuser when specific evidence regarding verbal and nonverbal memory functions are necessary for treatment and rehabilitation planning, or when other HRB

and WAIS-R performances suggest impairment of discrete memory

functions. Originally, age norms for this test were generally

inadequate, but Russell (1975, 1984) has developed scoring techniques and criteria that improve the clinical utility of this

test.

Category Test

The Category Test involves nonverbal problem solving with complex

and novel stimuli where the skills of flexibility of thinking,

incidental memory, and nonverbal concept formation are implicit.

Since adequate performance on this test requires the brain to

function efficiently as a unified whole, the test tends to be

sensitive to any impairment of higher cortical functioning. The

research history of this subtest established it as the single best

indicator of comprehensive brain dysfunction when compared to all

other psychological and NP tests. Specific damage or impairment

to frontal lobe functions is inferred when performance on the

Category Test is impaired, but performances on other HRB subtests

are in the average range.

Speech-Sounds Perception (SSP) and Seashore Rhythm Test (SRT)

Presented in a recorded tape format, these HRB subtests give evidence of efficiency of left and right temporal lobe functioning,

respectively. Individuals with specific LD impairment in acquiring language-related academic skills, such as reading and spelling, often perform poorly on SSP. Notably, SSP deficits among PCP

abusers may be due to developmentally-related as well as to PCPinduced impairments. The SRT shows impairment when there is

damage or dysfunction associated with the right anterior temporal

lobe. Also, this subtest contains rather significant attention

and concentration components, skills often impaired as a result of

PCP-induced brain toxicity, especially when the NP assessment test

results are obtained with fewer than 30 days of PCP abstinence.

Trail-Making Test

Trails A is a timed task which requires graphomotor performance

with a random visual presentation of a numerical sequence. Trails

B, also a timed task, requires the individual to perform a similar

visual-motor task, but with an additional cognitive component of

alternating between a numerical and alphabetical sequence. The

presence of above-average times as well as number of errors gives

important information about the brain's capacity to function as a

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unified whole. Left, rather than right, hemisphere dysfunction is

suggested when performance on Trails B (alphabetic sequence) is

much more impaired than Trails A.

Hand Dynamometer and Finger Oscillation Tasks

These tasks provide reliable information and measurement of gross

and fine motor functions, respectively. It is important to realize that psychomotor functions are the basis, and therein the

foundation, of all behavior. The measurement of intensity of

gross voluntary motor activity (grip strength in kilograms) has

been associated with the total functional efficiency of cerebral

hemisphere activity. Skills of finger oscillation have been associated more specifically with the functional efficiency of the

primary motor cortex. In addition to comparing functional efficiency of both sides of the body, the presence of below-average

performances on these tasks may indicate gross CNS disturbances

rather than specific and/or subtle functional deficits.

Test of Finger Agnosia

This subtest was included because it indicates the relative functional efficiency of somatosensory-mediated brain functions.

Furthermore, difficulty with either the left or right hand on this

tactile finger recognition task has been associated with disturbances of the angular gyrus, and associated with developmental

dyslexia. Significant differences between the preferred and nonpreferred hand also gives important lateralizing information

regarding differential PCP-induced toxic effects on left versus

right hemisphere parietal functions.

Wide Range Achievement Test (WRAT)

The WRAT (Jastak and Jastak 1978) provides grade equivalents and

standard scores on subtests of reading (word recognition), written

spelling, and written arithmetic calculations, and is included in

this brief assessment battery for several reasons. An objective

screening measure of academic achievement is needed to compare

with an individual's self-report of highest grade completed and

average report card grades. Further, functional illiteracy may

suggest evidence of either developmental or "acquired" LD. And,

finally, specific information on academic achievement in reading,

spelling, and arithmetic are critical for rehabilitation plans for

adolescent and young adult abusers, prior to recommending tutorial

(remedial) academic assistance and/or enrollment in General

Education Diploma (GED) classes.

SUMMARY OF PILOT FINDINGS

The above-described subtests were administered in part or in whole

to 30 adolescents and young adults referred either on a voluntary

or court-ordered basis for drug abuse counseling. Psychodiagnostic and developmental histories were taken--additional information

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was obtained through family members when needed. These individuals ranged in age from 18 to 32 with a mean age of 24.3 years.

Males outnumbered females in this sample by 3 to 1 (24 to 6).

Highest grade completed in school ranged from seventh grade to

college level work with a mean of 10.9 grades completed. Approximately 25 percent of this sample reported having been identified

within the school system as LD and having been placed in special

education classes. Nearly 90 percent of the sample reported

predrug-use histories of one or more of the following: prematurity either by weight or by term, anoxia or low APGAR scores at

birth, febrile illnesses, early childhood seizures or convulsions

with no subsequent adolescent or adult seizure occurrences, chronic ear infections, and CHI with or without loss of consciousness.

Subsequent to drug use, nearly 80 percent of the sample reported

histories of at least one of the following: CHI with or without

loss of consciousness, episodes of fainting and/or dizziness,

blackouts, seizures, and complaints of headaches or memory

difficulties.

Verbal, Performance, and Full-Scale IQ scores ranged from 67 (mentally deficient range) to 111 (bright normal range) with a mean

Full-Scale IQ score of 92.5, a mean Verbal IQ of 91.7, and a mean

Performance IQ of 96.2. On the whole, these results are similar

to past research findings (Mider and Lewis 1981), which suggest

that adolescents and young adults with histories of JD have

slightly higher Performance (nonverbal) IQ than Verbal IQ. The

extreme variation from individual to individual, in light of the

obtained prenatal and early childhood histories, suggests that

there have been impaired intellectual functions prior to drug use,

as well as loss of previously acquired intellectual capacity, subsequent to PCP and other drug abuse. Furthermore, about 30 percent of the sample showed above brain-damage cutoff scores on

Trails B while fewer than 10 percent showed above brain-damage

cutoff scores on Trails A. This may be due either to the fact

that Trails B is a much more sensitive indicator than Trails A to

impairment of the brain's functioning as a unified whole, or that

left hemisphere-mediated language dysfunction may occur somewhat

more among PCP abusers, a finding consistent with the lower Verbal

IQ than Performance IQ scores reported above.

Among the HRB subtests, the Category Test showed the most impairment in terms of total number of individuals in the sample who

scored above the brain-damage cutoff score (50 errors) as recommended by Reitan (1973). More than 70 percent of the sample were

in the mild, moderate, or severe impaired range on the Category

Test, a finding that suggests that PCP predominantly affects the

brain's capacity to function as an intact unified whole. These

findings suggest significant difficulty with flexibility of thinking, incidental memory, and the ability to formulate simple and

complex abstractions. These observed difficulties with changing

mental set and perseverating errors despite constructive feedback

form a pattern typically found with organic brain syndromes.

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Compared to the Category Test, SSP and SRT results show a relatively mixed performance profile. This profile is indicative of

temporal lobe impairment and may explain the idiosyncratic character of PCP-induced brain dysfunction. Other HRB subtest data

suggest that parietal lobe-mediated functions are less influenced

by PCP abuse, since approximately 30 percent of this sample had

error-free performances on a test sensitive to finger agnosia.

When finger agnosia was present, there were more errors with the

nonpreferred hand (2.05 mean errors) than with the preferred hand

(1.88 mean errors). Fewer than 10 percent of the sample showed

performances on the hand dynamometer below the normative

standards. Conversely, nearly 60 percent of the sample showed

below normal performances on the finger oscillation test, a finding that suggests that fine motor dysfunction is more prevalent as

a result of PCP and other drug abuse than gross motor dysfunction.

The net results of our pilot study suggest that PCP-induced brain

dysfunction cannot be understood solely on the basis of the pharmacological characteristics of PCP itself. There appear to be as

many individuals with histories of intermittent, light use as

there are chronic, moderate to heavy abusers of PCP who show significant impairment on the NP tests.

CASE STUDIES

Case Study #1

This was a 31-year-old white married male with a 14-year history

of chronic, light to heavy PCP abuse and a late adolescent history

of heroin, cocaine, LSD, and marijuana abuse. Also, he drank beer

in moderate to heavy amounts, at times, to enhance the effects of

PCP. His wife also had a significant PCP abuse problem. Originally, both were self-referred with presenting concerns about the

obsessive-compulsive nature of their involvement with PCP, financial problems, an unproductive lifestyle, and a general deterioration of physical and mental health. The couple had recently had a

baby and were concerned for the child's welfare. Little progress

was made in reducing the amount of PCP abuse, and, after 2 weeks

and four marital counseling sessions, they did not return for

additional treatment. However, due to a criminal drug-related

charge, the court ordered him to obtain treatment. Child custody

and other marital/familial problems were additional reasons for

his compliance with drug counseling requirements and his rehabilitation plan.

The NP assessment was completed after 6 months of drug abstinence. Assessment of developmental (predrug-use history),

orientation, lateral preference , and sensory-perceptual examination provided significant evidence of mixed dominance. For

example, since age 5, he had played the guitar and was ambidextrous on many tasks requiring the coordination of fine motor

movements. This strongly suggested that, prior to drug abuse,

higher cortical functions were bilaterally mediated. Though he

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reported having great difficulty with mathematics in high school,

he graduated, and continued to be an avid reader. His history of

employment was primarily as an adept tradesman. He was a socially

uninhibited person and at times a very assertive communicator.

Diagnostic interview information revealed an inherent high energy

level with strong libido interests. He remembered sustaining two

CHI at age 17 and 24. Further, 1 month prior to our examination,

he sustained a broken jaw in a barroom altercation. Although

there was no indication of concussion-like symptoms, the shear/

strain effects of the injury may have caused an additional CHI.

Measures of intellectual functioning were in the average range and

showed little variability, except for poor performance on a test

designed to measure visual and inductive reasoning skills. However, this exception was incidental , as other Performance subtest

measures of visual-motor and perceptual skills requiring nonverbal

abstract reasoning were at or above his age group mean. The NP

tests designed to assess the brain's ability to discriminate auditory speech and rhythmic-sound information were also in the average to above-average range. Actually, these latter test scores

may reflect in part avocational interests and practice in reading

and music. Scores on the memory and intelligence subtest as well

as a subtest of the Category Test (measuring incidental memory)

indicated a full range of at least average memory functions. In

contrast, his poorer performances on other NP tests and WAIS-R

visual-spatial tasks, considered the most sensitive general indicators of brain impairment, suggested a mild diffuse organic brain

syndrome, probably transient in nature.

Though a recent facial impact injury may have caused additional

diffuse cerebral damage, the total performance seemed more indicative of chronic PCP and alcohol abuse. Specifically, the NP

profile was characteristic of deficits in frontal lobe-mediated

adaptive abilities. While the severity of these deficits seemed

slight as compared with the mental status of others of similar

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histories of abuse, many higher cortical functions may have been

spared due to the premorbid bilateral representation of higher

cortical functions.

Case Study 12

This was a 23-year-old black male with a 5-year history of chronic, moderate marijuana use and a 5-month history of moderate PCP

abuse ending 1 month prior to the NP assessment, as certified by

urinalysis reports. Further, he reported multiple personal and

legal problems as a result of PCP abuse, and complained of chronic

bilateral headaches, several times weekly during the last 5 years.

He described these headaches as caused by an undiagnosed "brain

tumor or brain cancer." Birth and prenatal history suggested that

he was the victim of Fetal Alcohol Syndrome (FAS). He was reared

by relatives and had minimal contact with his parents through

adolescence. He withdrew from vocational high school in the 12th

grade, then worked for 5 years as an attendant cashier in fast

food franchises, with dependable performance, until he began to

use PCP. His ambitions were to reestablish permanent employment

or to join the military to receive job skill training. Further,

he was ordered by the court to be on a 3-year probation with special requirements to obtain a GED and to maintain full-time

employment, as contingencies in lieu of incarceration.

All NP and intelligence testing was accomplished in 1 day. The

client sustained good attention throughout the examination, but

was anxious about his failure to complete the more difficult

sections of particular subtests. He showed a strong preference

for lefthanded and ocular activity and mixed preference foot-leg

coordinated motor movement. His aggregate gross and fine motor

and perceptual-motor functions were characteristic of borderlinenormal intact performance. There were signs of mild impairment on

right-hand tactile-perceptual functions and diminished right-hand

motor speed. These deficits on the right side of the body suggested some (contralateral) left cerebral hemisphere dysfunction,

possibly involving more primary motor and somatosensory cortex

dysfunction. Additionally, he showed test-taking behaviors often

associated with organicity, such as rotations of paper and difficulty with organization of space on writing and copying tasks.

However, testing of all other left and right hemisphere-mediated

functions failed to identify any significant localized NP

deficits. Generally, the performance on other tests designed to

measure the integrity of coordinated brain functioning was in the

borderline impaired range. The "borderline range" interpretation

was based on a comparison of his test scores with those of standard scores of an adult normal population; his status was better

than average when these test scores were compared with standard

scores of an adult drug-abusing population. These NP deficits may

best be characterized as diffuse in nature and the result of both

developmental (predrug use) and PCP/polydrug abuse influences.

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Mastery level skills in WRAT Arithmetic revealed errors of subtraction, division, and multiplication, and little or no understanding of fractions, decimals, or percentiles. Fatigue was

assessed not to be a limiting factor in his performance because

this testing was performed early in the examination. The WAIS-R

yielded Verbal, Performance, and Full-Scale IQ scores in the low

dull to normal range. There were outstandingly low scores on

tests measuring verbal abstract reasoning and general knowledge

gained from experience (long-term attention and memory). However,

he scored better on tests measuring immediate recall (working

memory) of nonverbal and verbal information, and on tasks requiring the application of basic mathematic processes (simple mental

addition). These intellectual strengths provided examples of

well-learned crystallized functions and were probably the direct

result of 5 years of skill development as an attendant cashier

with fast food franchises.

It was recommended that special attention be given to complaints

of headaches and a much delayed medical/neurological evaluation.

The NP test results suggested that observed deficits were probably

more likely to be residual deficits from congenital (prenatal or

neonatal) insulting factors, aggravated by developmental problems

and recent drug abuse, than attributable solely to a current or

degenerative organic brain condition. However, his belief that

his headaches were caused by a "tumor or cancer" suggested a

diseased self-concept and other basic self-assessment issues.

Depending on the final diagnostic outcome, these headaches may

need concurrent medical (pharmacologic) and psychological treatment through counseling.

Diagnostic interview information revealed that a portion of his

interest in PCP was an attempt to self-medicate headache pain.

Notwithstanding the negative neurological test results, the conceptualization of the presenting problems based on NP test results

helped formulate the direction and development of treatment goals

and subsequent counseling efforts. Over the next several months,

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his cognitive functioning showed improvement and drug counseling

centered more on preventing recidivism to marijuana abuse.

Concerning his ability to fulfill the court-ordered probationary

requirement to obtain a GED and literacy level academic skills, he

was an excellent candidate for individual and/or group tutorial

services. His reading and spelling skills were well established

and it was predicted that arithmetic skills would advance quickly.

His attitude toward treatment was positive, and he was motivated

to pursue educational study as a prerequisite to other vocational

goal developments. Therefore, formal vocational interest testing

and counseling was also strongly recommended. This additional

counseling attention reinforced other treatment objectives commensurate with his potential, and helped establish values and goals

appropriate to his physical and mental health status.

Case Study #3

This was a 19-year-old white single female with a 5-year history

of chronic, moderate PCP use and heavy marijuana/alcohol abuse.

She also had experimented with LSD and cocaine freebasing numerous

times within the past 2 years. Throughout her history of substance abuse she experienced an increasing frequency of periods of

dazed consciousness and blackouts multiple times yearly, while

under the influence of alcohol. Further, she reported that other

family members had chemical dependency problems, though her

parents never abused drugs/alcohol.

This young woman had 13 years of education with computer skills

training, and had just obtained an entrance level position in the

programming field. However, her job performance and her ability

to maintain satisfactory interpersonal relationships had deteriorated. Recently, she had been jilted by her boyfriend. She was

self-referred for treatment with additional complaints of anxiety,

paranoid thinking and behavior, problems with memory, headaches,

dizziness, and intermittent "after-image" visual hallucinations.

Though she failed to attend a formal psychiatric assessment interview, she responded well to supportive psychotherapy with progress

in her mental status and general level of competency. Except for

several episodes of binge drinking, for the next 4 months she

remained drug abstinent while enhancing her performance at work,

sociability, and insight into her own behavioral and emotional

lifestyle. At this time, the purpose of the assessment was to

ascertain the presence, despite her response to treatment, of any

residual NP deficits.

All measures of gross and fine psychomotor coordinated activity,

as well as sensory-perceptual functions, were in the normal range,

with the exception of moderate left-handed finger agnosia.

latter finding suggested inefficient contralateral (

This

right) parieta1 functioning. Subtest scores on Performance IQ tasks and

results of the figural memory section of the RWMS revealed intact

performance. Complex auditory verbal versus rhythm discrimination

203
!test results further suggested anterior right cerebral hemisphere

dysfunction. This profile was characteristic of the early signs

and symptoms of an alcohol-related organic brain syndrome. However, based on the above mixed findings, recent psychotherapy

results, and her recently reduced drug/alcohol consumption, it

seemed likely that the mild but significant NP impairments

reflected residual NP deficits, while the intact performances

suggested the beginnings of recovery of function.

Diagnostic interview information confirmed WAIS-R Comprehension

subtest weaknesses in the use of practical judgment and common

sense in social situations. As such, the recommendation was for

future treatment sessions to focus on issues of reality testing,

decision making, interpersonal relations, and other expressive

psychological processes. The majority of IQ and NP performances

suggested a positive prognosis and good to excellent ability to

recover, assuming continuance of drug and alcohol abstinence.

Case Study #4

This was a 25-year-old black inner-city male with a history of

chronic, moderate levels of PCP abuse for 7 years, and intermittent, moderate levels of whiskey drinking for several years.

All PCP and alcohol abuse ended 3 months prior to the NP assessment, as determined by self-report and urinalysis results. He was

motivated to comply with all drug counseling requirements because

of an outstanding drug-related criminal charge. The major reason

for referral was to assess his current educational level, and his

memory and other neuropsychological functions. The drug counselor

also questioned whether complaints of recent memory problems were

symptomatic of a temporary (transient and reversible) condition,

or characteristic of a progressive or more permanent organic brain

dysfunction.

204
During the examination he was quite cooperative, and concerned

about his performance. He used a cautious approach to the various

tasks and sustained good attention throughout the examination. He

reported receiving some minimal special education assistance in

junior high school, but he dropped out in his senior year owing to

scholastic problems, though he subsequently earned a GED. He

reported earlier, limited involvement in amateur boxing, which he

quit because of being "punched dizzy" on numerous occasions. This

suggested a history of CHI. Though at the time unemployed, he

participated in classroom study of the bricklaying trade, but had

difficulty maintaining good vocational school grades due to problems in sustaining attention and recalling learned material.

On NP tests of gross motor activity and fine motor speed, he was

mildly impaired in comparison to adult norms. However, he was

able to attain normal performance levels with practice and direct

encouragement. It is important to note that all other NP tests of

sensory, perceptual, and conceptual functions were in the normal

range; his minimal errors are often made by normal, nonimpaired

individuals.

Measures of academic achievement showed mastery skills just above

functional literacy levels, but well below the ninth grade-level

skill development often required to successfully complete a GED

examination, which had been obtained several years ago. Measures

of intellectual functioning showed problems with tasks requiring

expressive language and use of practical judgment and common sense

in social situations. These findings, in part, may be attributable to cultural bias, lack of educational opportunity, and limited interpersonal or social experience. His major strengths were

his ability to analyze and synthesize abstract nonverbal information, and to attend to a task under conditions designed to create

frustration and stress. Further, he scored well on tests requiring inductive reasoning skills: both on the intelligence subtests

and on the NP measures.

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185-466 0 - 87 - 8
Considering the chronic history of PCP and alcohol abuse, the

anticipated finding was for more pronounced impairment of psychological functions. However, the NP and IQ scores reflected good

potential for recovery of function with sustained drug abstinence,

since there was little evidence of permanent deficit. An average

premorbid optimal estimate of intelligence was established, using

educational history, WAIS-R "best subtest" score, measures of recent and remote cognitive-memory functions, and abstract reasoning

skills. Further, diagnostic interview information suggested intact mental status prior to drug abuse. Collectively, these findings supported a diagnosis of a transient (toxic) organic brain

syndrome in early stages of recovery. Therefore, the complaints

of memory loss and associative concerns seemed to be symptomatic

of a temporary disorder. The prognosis was good to excellent,

assuming continued drug and alcohol abstinence. Consequently, it

was recommended that he continue to receive probationary supervision and mandatory drug counseling, in conjunction with a random

schedule for urinalysis surveillance to ensure drug abstinence. A

6- to 9-month period of drug abstinence was estimated to be necessary for more significant recovery of NP, IQ, and complex psychomotor functions. It was further recommended that he accept a more

active role in his own rehabilitation, to encourage the development of psychological mechanisms and interpersonal skills complementary to the objectives of the treatment plan and personal

goals.

TREATMENT AND RESEARCH IMPLICATIONS

The clinical information obtained from NP assessment and structured history taking provides a basis for understanding the multifaceted nature of brain functions and their relation to human

behavior. The use of NP results, in conjunction with other diagnostic information, to develop rehabilitation plans for PCP abusers can be invaluable in suggesting a prognosis. Thus, individual

treatment goals and expectations can better complement the cognitive-behavioral strengths and weaknesses of an individual in need

of drug abuse consultation.

For many PCP abusers, a thorough NP examination, followed by a

review of assessment results with the PCP abuser, should be a

treatment policy. This debriefing strategy, when used as a

planned intervention. can have powerful therapeutic implications.

Foremost, discrepancies between-the clinical findings and an

individual's own assessment of level and pattern of functioning

can be addressed. This provides an opportunity for the PCP abuser

to receive objective feedback on mental status and can enhance the

therapeutic alliance and commitment to treatment. Due to the behavioral nature of many of the tasks comprising the NP assessment,

individuals frequently have an intuitive understanding of their

own performance prior to a formal debriefing. In practice, this

process of active participation and self-assessment reduces psychological defensiveness and the tendency for denial.

206
Estimates suggest that PCP abusers sustain a greater frequency and

severity of NP deficits than other drug and/or alcohol abusers.

These deficits are probably related to a combination of developmental, toxicity, and idiosyncratic factors which differentially

affect CNS function. The complexity of NP diagnostic interpretation is further compounded in developing a prognosis and predicting the ability to recover. Issues of brain plasticity and

recovery of function need extensive research in direct relation to

specific treatment objectives.

Forensic Use of NP Assessments

The PCP abuser poses unique problems for law enforcement agencies

and the judicial system. McCarron et al. (1981), in reviewing

medical and behavioral characteristics of 1,000 PCP episodes

observed in medical emergency rooms, have noted the extremely high

incidence (35 percent) of violence and rage reactions. Possibly

because of anesthetic effects, and/or PCP uptake in limbic-mediated emotional centers, PCP abusers can sometimes behave with

superhuman strength, causing harm to self, others, and property.

Thus, it is not surprising that PCP abusers often incur criminal

charges ranging from simple possession and distribution to

homicide.

The NP evaluation of the PCP abuser may be useful in pretrial

investigation in a number of ways. In general, objective estimates of intellectual functioning and NP status at the time of

criminal incident (projected from later assessment) can suggest

limited versus intact capacity of the PCP abusers for appreciating

the criminality of their actions or indicate similar capacity for

conforming their behavior to the requirements of the law. Perhaps

more important, from a standpoint of ultimate outcome, NP screening techniques can suggest a prognosis for rehabilitation versus a

risk for recidivism, and aid judicial decision making by providing

an objective basis for sentencing that is equitable to both society and the PCP abuser.

REFERENCES

Government Accounting Office. Report to the Congress of the

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Grant, I.; Reed, R.; Adams, K.; and Carlin, A. Neuropsychological

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Neuropsychol 1:39-47, 1979.

Hartlage, L.C., and Mains, M. Novel diagnostic approaches to

neuropsychological organization. Clin Neuropsychol 2(4):161-

162, 1982.

Heaton, R.K., and Pendleton, M.G. Use of neuropsychological tests

to predict adult patients' everyday functioning. J Consult Clin

Psychol 49(6):807-821, 1981.

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Jastak, J.F., and Jastak, S. Wide Ranqe Achievement Test Manual.

Wilmington, DE: Jastak Associates, 1978. 96 pp.

Kolarik. G.M., and Vayhinger, B. PCP: A Treatment Manual.

Unpublished manuscript, Clinton, MD, 1983.

McCarron, M.M.; Schultze, B.W.; Thompson, G.A.; Conder, M.C.; and

Goetz, W.A. Acute phencyclidine intoxication: Incidence of

clinical findings in 1,000 cases. Ann Emerq Med 10:237-241,

1981.

Mider, P.A., and Lewis, J.E. Neuropsychological assessment of

polydrug abuse. In: Craig, R.J., and Baker, S.L., eds. Drug

Dependent Patients. Springfield, IL: Charles C. Thomas, 1981.

pp. 221-234.

Parsons, O.A., and Farr, S.P. The neuropsychology of alcohol and

drug use. In: Filskov, S.B., and Boll, T.J., eds. Handbook of

Clinical Neuropsychology. New York: Wiley-Interscience, 1981,

pp. 320-365.

Reitan, R.M. Investigation of the validity of Halstead's measure

of biological intelligence. A.M.A. Arch Neurol Psychiatry

73:28-35, 1955.

Reitan, R.M. Behavioral manifestations of impaired brain function

in aging. Paper presented at the Annual Meeting of the American

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Reynolds, C.R.; Willson, V.L.; and Clark, P.L. A four-test short

form of the WAIS-R for clinical screening. Clin Neuropsychol

5(3):111-116, 1983.

Russell, E.W. A multiple scoring method for assessment of complex

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Unpublished manuscript, Miami, FL, 1984.

AUTHORS

James E. Lewis, Ph.D.

Director, Psychology and Education Associates

Clinton, MD

Graduate Lecturer in Clinical Neuropsychology

The Catholic University of America

Washington, DC

Robert B. Hordan, M.A.

Directorate of Addictions, DICAP

Prince George's County Health Department

Suitland, MD

Drug Abuse Consultant

Washington, DC

208
Phencyclidine Intoxication

Margaret M. McCarron

BACKGROUND

At the Los Angeles County/University of Southern California

(LAC/USC) Medical Center, phencyclidine (PCP) intoxication

accounts for more emergency department visits and hospitalizations

than any other drug of abuse. Most of the areas of the hospital

are called upon to treat PCP intoxication and related problems.

Emergency physicians, internists, and psychiatrists treat the

majority of cases, but orthopedists, neurosurgeons, and general

surgeons are well acquainted with the traumatic events often

accompanying PCP use. Pregnant women smoke PCP before entering

the hospital for delivery; babies are born with PCP intoxication.

Small children become intoxicated with PCP in the home, and older

children use the drug for "kicks." Since 1979, an average of five

patients per day have been arrested and brought to the Prison

Service because of illegal acts performed under the influence of

PCP.

PCP is usually smoked on "Sherman" or "More" cigarettes that have

thick brown wrappers that absorb PCP liquid and still allow the

cigarette to be smoked. Ingestion of partially smoked PCP cigarettes can result in severe toxicity. About one hour from ingestion of such a cigarette, seizures may suddenly occur, followed by

coma, apnea, and hyperthermia.

Sometimes liquid PCP is ingested, often mixed with lemonade or

some alcoholic beverage. One man had eaten clams laced with PCP.

Solutions of PCP are also injected intravenously. Some patients

inject PCP two or three times a day for long periods of time.

Liquid PCP often contains volatile solvents that impart an "etherlike" odor to the patient, although PCP itself is odorless. PCP

is nonvolatile at room temperatures, but ether is highly volatile.

Undoubtedly, some of the acute reactions that occur after exposure

to street "PCP fumes"' are due to the effects of the ether and not

to PCP. Several reactions of this type have been observed, such

209
as a woman who became dizzy and nauseated and felt as if she were

about to faint when "PCP" fumes entered her apartment from a "PCP

laboratory" next door.

Another type of reaction that occurs when a person is inadvertently exposed to "PCP fumes" is acute anxiety. An example of this

was a policeman who smelled "PCP fumes" in the squad car while

transporting a person with PCP intoxication. The policeman was

examined and found to have a severe anxiety reaction with marked

hyperventilation and carpopedal spasms.

PCP can apparently be inhaled by a person working in a PCP laboratory when the laboratory catches fire. Eight acutely intoxicated

people were admitted to the LAC/USC Medical Center prison wards

with PCP toxicity and thermal burns incurred during explosions of

volatile chemicals in makeshift PCP laboratories (McCarron et al.

1981a).

PCP is also ingested in pill form , each tablet containing about 2

to 6 mg of PCP (Lundberg et al. 1976). PCP powder may be sniffed

or snorted, or incorporated into marijuana cigarettes.

TABLE 1. Routes of PCP use (1,000 patients)

Route Percent Using

Smoked 72.6

Sniffed/snorted 13.3

Ingested 12.3

Intravenous 1.8

Two or more routes 1.0

SOURCE: McCarron et al. 1981a.

In 42 percent of cases, PCP was used with another drug, usually

alcohol, marijuana, a barbiturate, or a narcotic.

Several analogues of PCP with similar pharmacological effects are

available on the streets. These include PCE (cyclohexamine), PHP

(phenyl-cyclohexyl-pyrrolidine, PCPP (phenyl-cyclo-pentyl-piperidine), and TCP (thienyl-cyclohexyl-piperidine) (Baselt 1982).

DIAGNOSIS

In a series of 1,000 cases of PCP intoxication (McCarron et al.

1981a), 87 percent of patients were male: 45 percent were black,

36 percent Caucasian, and 19 percent Hispanic. The youngest

patient was 13 years old and the oldest was 65, with a median age

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of 23 years; however, 65 percent of patients were 18 to 25 years

old. One patient had seven episodes of PCP intoxication.

Unlike other drugs of abuse, the diagnosis of PCP intoxication is

often difficult because of the wide spectrum of clinical findings

that occurs with this drug. PCP toxicity sometimes can be mistaken for delirium tremens, acute psychiatric illness, sedative/

hypnotic overdosage, amphetamine intoxication, or sedative/

hypnotic withdrawal syndromes.

History

A description of the patient's actions before admission to the

hospital often provides valuable clues to the diagnosis. Since

PCP seems to diminish the user's ability to integrate sensory

input into meaningful behavior (Pender 1971), symptoms and findings suggesting this problem should be sought. A demonstration of

sensory deprivation was provided by a patient who was found head

down in a dumpster filled with garbage. He was nude and the

weather was cold, but he didn't seem to be uncomfortable. He also

didn't mind the smell of garbage,

down position.

or the discomfort of the upsideIn one reported case, loss of pain sensation

resulted in an act of self-injury by biting of the forearms almost

to the bone (Grove 1979). Irrational acts, such as driving too

slowly on the freeway, or bizarre behavior, such as strolling down

the street nude or "standing in the park like a statue," may be

manifestations of PCP toxicity. Other general characteristics

include waxing and waning of the mental status or behavior and

evidence of increased strength.

Physical Findings

PCP affects the sensorium, behavior, and vital signs, and it may

affect motor and autonomic functions. Hypertension and nystagmus

are hallmarks of PCP intoxication. Nystagmus occurs in about 57

percent of patients, and hypertension occurs in about 48 percent.

Nystagmus may be horizontal, vertical, or rotary. The presence of

nystagmus, while helpful, does not provide the diagnosis because

all types of nystagmus may accompany other kinds of drug overdosage, such as sedative/hypnotic intoxication. The usual level

of blood pressure in patients with hypertension is 140-160/95-105

mm Hg (McCarron et al. 1981a) However, hypertensive crises may

occur with blood pressures as high as 200-300+/140+ nun Hg. Severe

hypertension may be accompanied by intracranial bleeding.

Sensorium. Patients with PCP intoxication can have a clear sensorium, or they can be disoriented, confused, stuporous, lethargic,

or comatose. Signs of cerebral stimulation, such as pressured

speech, verbigerations, and echolalia, may also occur.

chotic symptoms,

Frank psyincluding hallucinations, delusions, and paranoid

ideation, are not unusual.

211
Behavior. Some patients with PCP toxicity display inappropriate

behavior. Behavioral effects include muteness, staring, violence,

and agitation. Violent behavior occurred in 35 percent of people

with PCP intoxication who were examined on the prison wards of the

LAC/USC Medical Center (McCarron et al. 1981a).

Motor Signs. PCP causes grimacing, localized dystonic reactions,

generalized rigidity, catalepsy, athetosis, tremors, twitching,

coarse jerky movements, and grand ma1 seizures. Status epilepticus may occur. Deep tendon reflexes may range from hyperactive

to absent.

Autonomic Signs. The most common autonomic signs are profuse

diaphoresis, hypersalivation, bronchorrhea, and urinary retention.

Wheezing and severe bronchospasm occur occasionally. Pupils may

be any size.

Vital Signs. Although hypertension is common and may be severe,

hypotension can also occur. Tachycardia occurs in about 30 percent of cases. Severe tachypnea with respiratory rates as high as

88/min or respiratory depression with rates of 10/min or less may

be seen. Respiratory arrest and cardiac arrest may occur. Hyperthermia with temperatures as high as 108.0 °F is a life-threatening event and may be associated with submassive liver necrosis

(Armen et al. 1984).

Numerous deaths have been reported in people under the influence

of PCP. Most of the fatalities resulted from various kinds of

trauma, but some have been attributed to the direct effects of

PCP (Burns and Lerner 1978; Caplan 1979; Armen et al. 1984).

PATTERNS OF INTOXICATION

In adult patients, the manifestations of PCP use can be grouped

into nine clinical patterns of intoxication. Four of these are

called major patterns because they may be associated with severe

toxicity and often necessitate hospitalization. Patients with

major patterns are usually unpredictable; symptoms wax and wane,

and the patient may abruptly change from one pattern of intoxication to another. Five other symptom complexes are designated as

minor patterns since toxicity is usually mild and of short duration. Major Patterns consist of: coma, catatonic syndrome, toxic

psychosis, and acute brain syndrome. Minor Patterns are lethargy,

bizarre behavior, violent behavior, agitation, and euphoria

(McCarron et al. 1981b).

In determining the pattern of intoxication, the manifestations of

toxicity obtained by history should be considered, since many

patients with severe intoxication improve considerably by the time

they are admitted to a hospital. Nontraumatic rhabdomyolysis

occurs almost exclusively in patients who have experienced a major

pattern of PCP intoxication.

212
Major Patterns

Coma. Patients with PCP-induced coma are unresponsive to stimuli,

are nonverbal, and have closed eyes. Some patients may have no

other findings. Others may have any of the motor and autonomic

signs and disturbances of vital signs listed above. A triad of

coma-apnea-seizures occurs in this group.

Some comatose patients are unconscious for less than 2 hours, do

not show signs of severe toxicity, and have few complications. In

other patients, coma lasts from 2 to 24 hours, and symptoms are

more marked. Patients with severe toxicity, including status epilepticus and malignant hyperthermia, may remain in coma for 1 day

to 3 weeks. These patients often have respiratory or metabolic

acidosis. Comatose patients are susceptible to aspiration pneumonia and rhabdomyolysis. Head injury and intracerebral bleeding

should be considered as the cause of the comatose state.

Catatonic Syndrome. The essential characteristics of the organic

catatonic syndrome are (1) central nervous system excitement

alternating with stupor, and (2) catalepsy. Many patients are

mute and staring, and have generalized muscle rigidity or localized dystonic reactions. PCP catatonic syndrome often includes:

posturing, repetitive actions, grand ma1 seizures, nudism, agitation, violence, hallucinations, delusions, and verbigerations.

The patient may be alert and oriented, withdrawn or lethargic, or

have an acute brain syndrome. There is a high incidence of

rhabdomyolysis and hyperthermia in PCP-induced catatonic syndrome.

Some patients have the neuroleptic malignant syndrome or develop

it after administration of haloperidol.

The neuroleptic malignant syndrome is characterized by hyperthermia (temperature over 103 °F without evidence of infection),

altered sensorium, muscle rigidity, and autonomic disturbances,

usually profuse diaphoresis, hypersalivation, bronchorrhea, and

urinary retention.

Toxic Psychosis. Any patient who is not catatonic but has hallucinations, delusions, paranoid ideation, or other psychiatric

manifestations is classified as having toxic psychosis. These

patients are often difficult to differentiate from those with

acute agitated psychosis, and about 25 percent appear manic.

Motor and autonomic disturbances are less common in this group

than in any of the major patterns. Severe hypertension has been

noted. Rhabdomyolysis is unusual.

Acute Brain Syndrome. Any patient with disorientation, lack of

judgment, inappropriate affect, and loss of recent memory who was

not comatose or catatonic and has no discernible hallucinations,

delusions, or other psychiatric manifestations is included in this

pattern. Acute brain syndrome is the most common pattern of PCP

intoxication among patients brought to the emergency department at

LAC/USC Medical Center, accounting for 25 percent of the PCP

213
cases. All of the manifestations and complications of PCP toxicity can occur in this group. These patients are often misdiagnosed

as having delirium tremens.

Minor Patterns

Patients with the lethargy pattern of PCP toxicity may be clinically indistinguishable from patient with mild sedative/hypnotic

intoxication, although hypertension and grand mal seizures which

may occur with PCP intoxication, are not expected with sedative/

hypnotic overdose. The remaining minor patterns are differentiated as follows.

TABLE 2. Characteristics of minor PCP patterns

Pattern Sensorium Behavior

Bizarre behavior Alert & oriented Bizarre, violent or agitated

Violent behavior Alert & oriented Bizarre, violent or agitated

Agitation Alert & oriented Agitated

Euphoria Alert & oriented No behavioral disturbance

SOURCE: McCarron et al. 1981b.

Any of the motor or autonomic signs, and hypertension and/or

nystagmus may occur with any of the minor PCP patterns. Minor

patterns should not be diagnosed on physical examination in an

emergency department without adequate information about the patient's behavior and sensorium prior to admission. Many patients

with major patterns may be alert and oriented when they reach the

hospital. If no history is available, the patient is kept under

observation and rhabdomyolysis is ruled out.

Toxicology Tests

Urine concentrations of PCP determined by enzyme immunoassay did

not correlate with the state of intoxication at the time the urine

sample was taken. The test was negative in 15 percent of 1,000

patients with clinical evidence of PCP toxicity, many of whom

admitted taking PCP (McCarron et al. 1981a). Several of these

negative urines were analyzed for PCP analogues; none were found.

Serum concentrations of PCP determined by enzyme immunoassay in

405 patients also did not correlate with the state of intoxication

at the time the blood speciman was obtained, although the highest

PCP concentrations in the study were associated with major

patterns. However, some patients with major patterns had negative

214
tests or lower concentrations of PCP than some patients with minor

patterns (Walberg et al. 1983).

A radioimmune assay for PCP in saliva and serum showed that saliva

could be used as a specimen for PCP analysis (McCarron et al.

1984). Of 79 patients with acute PCP intoxication clinically, 70

had positive tests in both serum and saliva, two had positive

serum tests and negative saliva tests, and seven had negative

tests on both serum and saliva.

TREATMENT

The treatment of acute PCP toxicity depends on the pattern of

intoxication and the physical findings. On the prison wards of

the LAC/USC Medical Center, approximately 60 percent of patients

are treated and released within 24 hours. Most of these patients

have minor patterns of intoxication and no medical complications.

Another 10 percent of patients have minor problems with medical

complications, usually trauma.

Treatment of Minor PCP Patterns

For the most part, patients with minor PCP patterns are treated

symptomatically. Abnormalities in the vital signs are treated

with supportive care. Patients with grand mal seizures are given

IV diazepam in doses of 5 to 20 mg. Bizarre, violent, and agitated patients are placed in restraints to protect themselves and

others. Haloperidol 5 to 10 mg is given IM as needed. Localized

dystonic reactions are treated with 50 mg diphenhydramine IV. Few

of these patients require gastric lavage and none are given syrup

of ipecac. Each patient has a Hemastix test performed on urine.

If the test is positive, the urine is examined microscopically for

red blood cells. If no red blood cells are found, a tentative

diagnosis of myoglobinuria is made, serum chemistries are obtained, and the patient is held to rule out rhabdomyolysis. If

the uric acid and creatinine kinase (CK) values are normal, and

the patient is asymptomatic, he/she is discharged from the

hospital. Routine toxicology tests include urinary PCP, serum

alcohol, and hypnotic screen.

Treatment of Major PCP Patterns

All patients with major patterns of PCP intoxication are placed in

restraints. If the patient is comatose or catatonic, if multiple

intoxication is suspected, or if ingestion of PCP is suspected,

gastric lavage with activated charcoal is performed. If the patient is severely intoxicated, a nasogastric tube is inserted and

connected to suction in order to remove any PCP that is excreted

in the gastric juice, and arterial blood gases are obtained.

Metabolic acidosis is treated by administration of sodium bicarbonate. No attempt is made to acidify the urine. All patients

are given IV fluids. To combat hypoglycemia, 50 ml of 50 percent

215
dextrose solution IV is routinely administered. Status epilepticus is controlled with IV diazepam; if diazepam is ineffective,

the patient is treated with neuromuscular blockade in the medical

intensive care unit. Severe hypertension is treated with sodium

nitroprusside. Agitation or violence is controlled with chlorpromazine or haloperidol (Giannini et al. 1984), unless these drugs

are contraindicated by the presence of shock or hyperthermia, in

which case diazepam may be used. For temperatures above 105 °F,

dantrolene sodium in doses of 1 to 1.5 mg/kg is given in addition

to cooling measures.

All patients with major patterns are monitored for rhabdomyolysis

and renal failure. An early sign of rhabdomyolysis is an elevated

serum uric acid, associated with an increase in serum CK. Within

8 to 12 hours, the serum tests are repeated. If the uric acid

falls and the CK rises, rhabdomyolysis is likely. Renal function

tests may also be increased at this time. When the diagnosis of

rhabdomyolysis is made, the patient is treated with 40 mg furosemide IV once, and IV fluids. Urine myoglobin concentrations are

obtained. If the patient develops renal failure, hemodialysis or

peritoneal dialysis may be necessary. In all cases, multiple drug

intoxication, trauma, and rhabdomyolysis are ruled out or treated.

All patients are kept under observation until they are asymptomatic.

REFERENCES

Armen, R.; Kanel, G.; and Reynolds, T. Phencyclidine-induced

malignant hyperthermia causing submassive liver necrosis. Am J

Med 77:167-172, 1984.

Baselt, R.C., ed.

Chemicals in Man.

Phencyclidine-disposition of Toxic Drugs and

1982. 785 pp.

Davis, California: Biomedical Publications,

Burns, R.S., and Lerner, S.E. Phencyclidine deaths. J Am Coll

Emerg Phys 7:135-141, 1978.

Caplan, Y.H. Detection of phencyclidine in Medical Examiner's

cases. J Anal Toxicol 3:477-552, 1979.

Giannini, A.J.; Eighan, M.S.; Loiselle, R.H.; and Giannini, M.C.

Comparison of haloperidol and chlorpromazine in the treatment of

phencyclidine psychosis. J Clin Pharmacol 244:202-204, 1984.

Grove, V.E. Painless self-injury after ingestion of "angel dust."

JAMA 242:655, 1979.

Lundberg, G.D.; Gupta, R.C.; and Montgomery, S.H. Phencyclidine:

Patterns seen in street drug analysis. Clin Toxicol 9:503-511,

1976.

McCarron, M.M.; Schulze, B.W.; Thompson, G.A.; Conder, M.C.; and

Goetz, W.A. Acute phencyclidine intoxication: Incidence of

clinical findings in 1,000 cases.

1981a.

Ann Emerg Med 10:237-242,

McCarron, M.M.; Schulze, B.W.; and Thompson, G.A., Conder, M.C.;

and Goetz, W.A. Acute phencyclidine intoxication: Clinical

patterns, complications, and treatment.

297, 1981b.

Ann Emerg Med 10:290-

216
McCarron, M.M.; Walberg, C.B.; Soares, J.R.; and Baselt, R.C.

Detection of phencyclidine usage by radioimmunassay of saliva.

J Anal Toxicol 8:197-201, 1984.

Pender, J.W. Dissociative anesthesia. JAMA 215:1126-1130, 1971.

Walberg, C.B.; McCarron, M.M.; and Schulze, B.W. Quatitation of

phencyclidine in serum by enzyme immunoassay: Results in 405

patients. J Anal Toxicol 7:106-110, 1983.

AUTHOR

Margaret M. McCarron, M.D.

Professor of Medicine and Emergency Medicine

University of Southern California School of Medicine

LAC/USC Medical Center

1200 North State Street, Room 1102

Los Angeles, CA 90033

217
Diagnosis and Treatment of

Chronic Phencyclidine (PCP) Abuse

David A. Gorelick, Jeffrey N. Wilkins, and Carl Wong

INTRODUCTION

Phencyclidine (PCP) abuse remains a serious public health problem

in large urban areas of the United States, with recent trends suggesting increased use after a period of decline (Crider, this

volume). Most clinical and research attention has focused on the

psychiatric and medical manifestations of acute or subacute PCP

intoxication, especially the organic mental disorders (toxic

delirium, psychosis, or depression) that PCP can induce (McCarron

et al. 1981; McCarron, this volume; Sioris and Krenzelok 1978).

Much less attention has been paid to chronic PCP use per se, i.e.,

the substance use disorder itself. Such issues as the effects of

chronic PCP use, and the diagnosis, clinical characterization, and

treatment of chronic PCP abusers are rarely discussed in the published literature, even in detailed review articles (Davis 1982;

Pearlson 1981; Pradhan 1984). This paper reviews the literature

on inpatient and outpatient treatment of PCP abuse, outlines our

own experience with PCP users and abusers in one large, public,

urban hospital, and makes suggestions for future research based on

this information and animal research findings (Balster, this

volume).

We were able to find only five published studies on the inpatient

or residential treatment of PCP abusers (DeAngelis and Goldstein

1978; Fauman and Fauman 1980; Khajawall and Simpson 1981; Rawson

et al. 1981; Simpson et al. 1983), with a total sample size of 397

patients. Two of these studies are from the same 32-bed unit in a

large urban state hospital (Khajawall and Simpson 1981; Simpson et

al. 1983), and therefore may have included some of the same patients. Three are from residential therapeutic communities (RTC)

(DeAngelis and Goldstein 1978; Fauman and Fauman 1980; Rawson et

al. 1981). While all of these studies provide some sociodemographic and clinical data on their patients, only two give even

minimal short-term (i.e., during hospitalization) treatment outcome results, and none give any long-term (i.e., after hospital

discharge) outcome results. Khajawall and Simpson (1981) found

218
that only 6 percent of 182 consecutive adult PCP abusers completed

the entire rehabilitation program (minimum stay 45 days). The

average length of stay was 36 days. Most patients wanted only

detoxification treatment. DeAngelis and Goldstein (1978), studying adolescent patients (mean age 16 years) in an RTC, found that

the 22 "chronic PCP users" (using at least 3 to 4 times weekly)

had a significantly longer length of stay than the 42 non-PCP

users (108 days vs. 68 days), but not longer than the 23 occasional (once a week or less) PCP users (85 days). There was no difference between chronic and occasional PCP users in frequency of

aberrant behaviors or program rule infractions. Chronic users

were somewhat less likely than occasional users to show angry and

belligerent behaviors (46 percent vs. 80 percent occurrence), but

more likely to have sexual acting out (31 percent vs. 12 percent)

and delusions (12 percent vs. 0 percent).

All five published studies dealt with a young population, with

mean patient ages ranging from 16 years (DeAngelis and Goldstein

1978) to 23 years (Simpson et al. 1983). The oldest PCP patient

included was 46 years old (Khajawall and Simpson 1981). The

racial makeup of the study populations varied from 96 percent

white (Fauman and Fauman 1980) to 25 percent white (Khajawall and

Simpson 1981), presumably reflecting selection bias due to the

geographic location and funding mechanisms of the various treatment programs. The majority of patients in all studies (where

data were given) were male (54 to 80 percent), unmarried (79 to 87

percent), unemployed, and with less than 12 years education. The

mean durations of regular PCP use (3+ times weekly) were 2.4 to 4

years.

We found only one published systematic study of outpatient treatment for PCP abusers, involving 158 patients (73 percent male) of

a private clinic (Bolter et al. 1976). This study gave no treatment outcome data, but the authors did comment that treatment was

difficult because of the patients' strong psychological dependence

on PCP.

METHODS

Our own studies were conducted at the Brentwood Division of the

West Los Angeles Veterans Administration Medical Center.

Brentwood is the 450-bed psychiatric division of the Medical

Center, which serves a large catchment area in the central and

western Los Angeles basin and includes general psychiatry programs

(230 beds), substance abuse inpatient (80 beds) and outpatient

programs, an involuntary locked ward (15 beds), and several other

specialty programs. The substance abuse wards on which studies

were done are voluntary rehabilitation programs with scheduled

admissions and 4- to 6-week lengths of stay. They do not accept

acutely psychotic, violent, or suicidal patients, nor patients

requiring specialized medical attention (e.g., IV therapy or

cardiac monitoring).

219
PCP assays were performed in the hospital's Clinical Psychopharmacology Unit, using gas chromatography with nitrogen/phosphorus

detection after PCP was extracted from the raw samples by column

chromatography. The authenticity of PCP samples was occasionally

verified with gas chromatography/mass spectrography. (Assay

parameters had been adjusted to avoid false positive results from

substances known to be potentially interfering.) Assay sensitivity was 0.1 ng/ml, intraassay variability was 3 percent, and

interassay variability was 5 percent. Urine samples were refrigerated within 4 hours of collection and assayed within 4 days.

Sociodemographic and clinical data were collected by social worker

interview with the patient, usually within 2 days of admission.

It was rarely possible to confirm this data by contacting collateral sources of information or reviewing old records (if any).

RESULTS

General Psychiatry Inpatients

All inpatients admitted through the hospital emergency room over a

15-month period (June 1982 through August 1983) had urine samples

collected in the emergency room for later PCP assay. This represented 1,550 admissions of 1,384 individual patients, but did not

include all hospital inpatients (i.e., excluded those who were admitted from outpatient status). PCP was detected in the urine of

16.5 percent (255) of the total admissions and 15.5 percent (215)

of individual patients. In the vast majority of cases, the PCP

levels were low (less than 30 ng/ml in 85.0 percent).

Clinical data on 1,454 admissions (1,128 individual patients) was

obtained from hospital records. The most common primary discharge

diagnosis among the PCP-positive patients was alcohol dependence

(27.5 percent), followed by drug dependence (26.6 percent), schizophrenia (20.0 percent), and drug-induced psychosis (7.8 percent).

In terms of the proportion of patients with positive PCP assays,

the diagnoses ranked as follows: drug-induced psychosis (63.0

percent), followed by drug dependence (33.3 percent), alcoholic

psychosis (23.1 percent), and schizophrenia (13.7 percent). Even

among patients with primary discharge diagnoses of affective disorder, personality disorder, and neurosis, 8 to 12 percent had

PCP-positive urine on admission. The PCP-using patients (as

reflected by PCP-positive urine on admission) were admitted

throughout the hospital. The proportion of discharges that had

PCP-posltive urine varied from 23.8 percent from a mixed substance

abuse ward (20 beds) and 22.5 percent from the involuntary ward,

to 17.6 percent from general psychiatry wards and 13.1 percent

from the alcohol treatment ward (40 beds), There was no significant trend towards PCP-positive patients having a longer length of

stay in the hospital or more frequent admissions during the study

period.

A small pilot study was done to determine the clinical impact of

routine screening of urine for PCP on admission. Forty-one

220
inpatients on three different types of wards had their charts

reviewed 5 to 10 days after their admission to see whether the

result of their PCP urine assay, done on admission, was reflected

in their treatment plan (laboratory reports were sent to the wards

2 to 3 days after admission). In only 34 percent of cases was the

PCP assay result mentioned in the treatment plan. The substance

abuse wards did best, with 60 percent mention, followed by the

involuntary ward (21 percent), and general psychiatry wards (17

percent).

Substance Abuse Inpatients

Admission urine PCP assays were done on 155 consecutive males admitted over a g-month period (December 1982 to August 1983) to a

mixed abuse ward (20 beds). Forty-two patients (27 percent) had

PCP detected in their urine; another 14 (9 percent) gave a history

of PCP use. Of these, 14 (9 percent of the total sample) initially denied any PCP use, and 9 continued to deny use after they were

confronted with the laboratory results.

Patients were classified into PCP abusers or users by applying

DSM-III criteria to the history obtained from the admission interview. The 42 PCP-positive patients broke down into 20 PCP abusers

and 22 PCP users. All 14 patients who gave a history of PCP use,

but had negative urine assays, were considered nonabusers. The

PCP abusers were sig

more prior arrests

nificantly younger (32 vs. 40 years) and had

(2 vs. 1) than the users, but did not differ in

race, education level, marital status, or employment status.

Abusers differed from users in having much higher urine PCP levels

and more recent PCP use, but did not differ significantly from

users in number of prior drug abuse treatments, time since last

treatment, or abuse of other drugs. There was also no difference

between abusers and users in immediate treatment outcome, as reflected by length of stay in the program or reason for discharge.

A high proportion of both groups reported abuse of other drugs,

including alcohol (61 percent), opiates (38 percent), and marijuana (29 percent). All the PCP abusers in the sample had used

PCP for at least 2 years (55 percent more than 5 years); 35

percent used it at least daily. All but one abuser smoked his

PCP; the exception used it by insufflation.

The immediate treatment outcome resulted in less than half (47

percent) of the PCP abusers completing the treatment program. The

mean length of stay was just under 4 weeks.

There was a significant negative correlation between (log) admission urinary PCP level and self-reported time since last PCP use

(r=-0.53, p<0.001). Visual inspection of a graph of these two

variables suggested a possible biphasic elimination curve, with

the initial phase having a half-life of 5 to 7 days, and the later

phase a half-life of about 30 days. However, formal curve fitting

of these data to standard pharmacokinetic models (using BMDP

221
computer programs) showed the data to be equally consistent with a

monophasic elimination curve (i.e., with a one-compartment

pharmacokinetic model). The 42 patients with PCP-positive admission urines had weekly urine assays done thereafter, until a negative urine assay was obtained. No urine acidification treatment

was given to increase elimination. Thirty-seven patients showed a

monotonic decline in urine PCP levels, with negative assays by the

fourth or fifth week. The remaining five patients showed a significant increase in PCP levels at one or more measurement points,

but PCP reuse was suspected on clinical grounds. When analyzed by

computer curve fitting, these data were also equally consistent

with either a one- or two-compartment pharmacokinetic model.

Substance Abuse Outpatients

The Substance Abuse Service at the hospital includes a weekly outpatient therapy group for PCP abusers, run by psychiatric social

workers. The approach used is supportive, behavioral, and educational, with the goal of decreasing or eliminating drug-seeking

and drug-taking behavior, and increasing problem-solving skills.

Weekly urine samples for PCP assay and drug screen are required

for group membership, but patients are not automatically discharged from the group because of a positive urine test. The

results presented here are based on 24 patients who attended at

least one group session after the group was formed in February,

1984. The majority of patients (54 percent) were self-referred to

the clinic; 16 percent attended only because of probation or

parole conditions.

Outpatient group members were very similar to the inpatient PCP

abusers in most sociodemographic and drug-use characteristics.

Their mean age was 29 years, educational level 12.6 years, and

number of prior arrests 1.5. The majority of outpatients were

black (83 percent), unmarried (67 percent), and unemployed (67

percent). Their mean duration of PCP use was almost 8 years,

with, usually, no prior or recent substance abuse treatment.

Thirty-seven percent used PCP at least daily, always by smoking.

Like the inpatient PCP abusers, outpatients frequently (87 percent) reported abuse of other drugs: alcohol (46 percent), marijuana (46 percent), and cocaine (37 percent). Several outpatients

for whom cocaine was the preferred drug of abuse used PCP as a

"cheaper high" when cocaine was not affordable.

There was frequent group consensus on the psychological effects of

PCP and motivations for its use. The two main psychological effects often cited as maintaining PCP use were the feelings of

strength, power, and invulnerability it engendered; and a psychic

numbing that was used to self-medicate dysphoric affects, especially anger and rage ("I use PCP because I want to forget").

Some patients were attracted by the challenge of the risk in using

PCP, i.e., not knowing what would happen. Three types of acute

intoxication responses were described: stimulation, depression,

and hallucinogenic. Many patients reported being able to predict

222
which response they would have by the concentration of the PCP

that they used. Almost all patients had had religious experiences

while intoxicated: feelings of meeting God, impending death, etc.

Whatever the experience , all patients reported liking PCP use and

having great psychological difficulty in giving it up. This was

despite common adverse effects such as legal problems, difficulty

in working regularly, transient depression following cessation of

use, and uncomfortably warm sensations in the extremities (sometimes prompting patients to feel like taking off their clothes).

The outcome of this specialized outpatient group therapy was

mixed. Patients stayed in treatment for a mean of 14 weeks (range

2 to 60 weeks), and attended 67 percent (range 25 to 100 percent)

of the scheduled group sessions. Urine samples were positive for

PCP 47 percent of the time; patients reported PCP use 24 percent

of the weeks they attended. Over the 14 months of the group's

existence, 75 percent of members have stopped participating: 42

percent to enter treatment elsewhere (60 percent residential, 40

percent outpatient); 8 percent to go to jail; and 25 percent to

drop out of treatment completely. Of those 6 patients currently,

remaining in the group, only one has become completely drug free

(and has returned to full-time employment).

DISCUSSION

We found that about 15 percent of patients admitted to a large,

public, urban hospital had PCP present in their urine. This is a

substantially lower prevalence than the 43 to 78 percent previously reported from another large, public hospital in Los Angeles

(Aniline et al. 1980; Yago et al. 1981), but still suggests that

PCP use is not rare among psychiatric patients. The PCP use occurred in both substance abuse and general psychiatry patients and

in all diagnostic categories, not just identified substance abuse

patients. Therefore, routine screening for PCP might well detect

a significant number of unsuspected users in such a population.

For example, even on a voluntary inpatient substance abuse

program, admission urine screening detected 9 percent of newly

admitted patients who initially denied PCP use. It is tempting to

speculate on the clinical significance of PCP use in newly admitted psychiatric patients, i.e., what role it plays, if any, in

precipitating the admission. Only future longitudinal and prospective research can address this question. In any case, our

small pilot study suggests that specific training of clinical

staff may be necessary before results of PCP assays are incorporated into treatment planning for patients in whom PCP use is not

initially suspected.

The sociodemographic and clinical characteristics of our PCP abusers were similar to those previously reported in the literature,

except for a somewhat older age range. This indicates that chronic PCP use does occur outside the adolescent/young adult age

group, and suggests that future treatment and research efforts

should include older age groups.

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Our experience with inpatient and outpatient treatment of PCP

abuse was not very successful, similar to experiences reported in

the literature. A few authors have commented on the difficulties

in treating PCP abusers, citing their impaired attention span and

concentration, emotional lability, impulsiveness, poor group

interaction, and low tolerance for confrontation (Bolter 1980;

Bragg 1980). Systematic, controlled studies using appropriate

comparison groups are needed to validate these anecdotal observations and to determine whether they are effects of PCP use or

antecedent conditions (which perhaps might predispose to PCP use).

In particular, studies of the direct neuropsychological and

neurophysiological effects of chronic PCP use (over and above the

short-term effects of acute intoxication) would have important

treatment implications (Lewis and Hordan, this volume). Recent

studies of alcoholic patients suggest that neuropsychological

functioning at admission may be a significant predictor of treatment outcome (Donovan et al. 1984). There is no a priori reason

why a similar phenomenon might not occur with PCP abusers.

There are currently no systematic data to guide a decision on

inpatient vs. outpatient treatment. However, the cheap and easy

availability of PCP reported by outpatients in their living environments, and the frequent continued use of PCP by outpatients

suggest that a brief period of inpatient treatment might be useful

in initiating drug abstinence. There is clearly a strong need for

research on specific treatment modalities for PCP abuse.

Findings from psychopharmacological and neuropharmacological studies of PCP in animals suggest other potentially fruitful areas of

clinical research (Balster, this volume). The PCP drug stimulus

in animals does not generalize well to other drugs of abuse. This

has led to the hypothesis that PCP has a unique psychotropic

action, and that therefore PCP abusers would have a distinctive

pattern of drug use and tend to avoid use of other drugs. In

fact, clinical data from our own studies and the published literature show that the majority of PCP abusers regularly use other

drugs, either concurrently or sequentially. A possible explanation for this lies in the variety of behavioral effects produced

by PCP in animals. Both stimulant and sedative effects of PCP

have been reported in various animal paradigms, analogous to the

variety of intoxication responses reported by patients. This suggests that PCP may be considered at least somewhat interchangeable

with other drugs of the stimulant and CNS depressant classes.

Furthermore, PCP might be considered effective self-medication for

a variety of psychopathologic states, e.g., the stimulant effects

might be attractive to those with dysthymic symptoms, and the the

sedative effects to those with anxiety symptoms. Careful psychiatric studies of representative samples of PCP abusers in the

sober state (along with corroborative information about psychiatric history) are needed to test these hypotheses.

224
Almost all the PCP abusers we studied had a "psychological dependence" on PCP, i.e., an inability to give up drug use despite

serious adverse consequences, coupled with a conscious desire to

use the drug (craving). No patient described clear evidence of

physical (physiological) dependence, either in terms of tolerance

or a withdrawal syndrome. (However, we did not systematically

evaluate patients for these phenomena.) Anecdotal reports of

fourfold tolerance to PCP have been published (Burns and Lerner

1981). Animal studies have found moderate (two- to fourfold)

tolerance to PCP, probably involving metabolic, pharmacodynamic,

and behavioral adaptation processes (Balster and Woolverton 1981;

Freeman et al. 1984). There is also some animal evidence for a

PCP withdrawal syndrome. Balster and Woolverton (1980) noted a

marked syndrome occurring in rhesus monkeys who self-administered

very large IV doses (up to 10 mg/kg/day or more) for over a month.

Bruxism, oculomotor hyperactivity, tremor, diarrhea, and piloerection appeared within 8 hours of drug cessation, and peaked at

24 hours. Slifer et al. (1984) found a much milder syndrome in

monkeys who received a continuous IV infusion of PCP (1.2 mg/kg/

day) for 10 days. The principal withdrawal effect was a disruption of conditioned lever pressing for food, which appeared within

8 hours of drug cessation and resolved over the next week. An

acute PCP dose temporarily reversed the behavioral disruption,

supporting its interpretation as a withdrawal phenomenon. These

findings suggest that, while physical dependence on PCP can exist,

it probably requires long-term regular exposure to relatively high

levels.

Tennant and colleagues (Tennant et al. 1981; Ayd 1981) studied 26

long-term (at least 3 months) daily PCP abusers and described the

following syndrome occurring within 1 day of drug cessation:

depression, anxiety, irritability, restlessness, anergia, sleep

disturbance, confused thoughts, and strong craving for PCP. It is

not clear how long this syndrome lasted, since none of the eight

untreated patients returned to the clinic for follow-up. The 18

patients treated with desipramine (50 to 150 mg/day open-label)

reported a rapid and substantial reduction in symptoms, which

helped 15 of them become drug free during a 2-week follow-up

period. Given the probable role of withdrawal symptoms and drug

craving in promoting continued drug use (and relapse from abstinence), further systematic, controlled research in this area, including double-blind medication trials with random assignment of

subjects to treatment groups, would appear very worthwhile.

Our pharmacokinetic data indicate that detectable PCP levels may

remain in the urine for 4 to 5 weeks after the last use, similar

to previous reports (Khajawall and Simpson 1983). The observed

elimination kinetics were equally consistent with a one- or twocompartment model, but methodological problems with our data make

225
any conclusions highly tentative. The time variable was based on

patient self-report, making its accuracy uncertain. Although the

PCP level itself was measured accurately, the PCP dose yielding

that level varied among patients in an unknown fashion (since no

data on dose could be collected).

REFERENCES

Aniline, 0.; Allen, R.E.; Pitts, F.N., Jr.; Yago, L.S.; and Pitts,

A.F. The urban epidemic of phencyclidine use: Laboratory

evidence from a public psychiatric hospital inpatient service.

Biol Psychiatry 15:813-817, 1980.

Ayd, F.J., Jr. Desipramine therapy for withdrawal from chronic

phencyclidine (PCP) dependence. Int Drug Ther Newsletter

16(8):31-32, 1981.

Balster, R.L., and Woolverton, W.L. Tolerance and dependence to

phencyclidine. In: Domino, E.F., ed. PCP (Phencyclidine):

Historical and Current Perspectives. Ann Arbor: NPP Books,

1981. PP. 293-306.

Balster, R.L., and Woolverton, W.L. Continuous access phencyclidine self-administration by rhesus monkeys leading to physical

dependence.

Bolter, A.

Psychopharmacology (Berlin) 70:5-10, 1980.

Issues for inpatient treatment of chronic PCP abuse. J

Psychedelic Drugs 12:287-288, 1980.

Bolter, A.; Heminger, A.; Martin, G.; and Fry, M. Out-patient

clinical experience in a community drug abuse program with

phencyclidine abuse. J Toxicol Clin Toxicol 9:593-600, 1976.

Bragg, L. Outpatient treatment issues and strategies for acute

and chronic PCP abusers. J Psychedelic Drugs 12:289-292,

The effects of PCP in man: A

1980.

Burns, R.S., and Lerner, R.E.

review. In: Domino, E.F., ed. PCP (Phencyclidine): Historical and Current Perspectives. Ann Arbor: NPP Books, 1981. pp.

449-469.

Davis, B.L. The PCP epidemic: A critical review. Int J Addict

17:1137-1155, 1982.

DeAngelis, G.G., and Goldstein, E. Long term treatment of adolescent PCP abusers. In: Petersen, R.C., and Stillman, R.C., eds.

Phencyclidine (PCP) Abuse: An Appraisal. National Institute on

Drug Abuse Research Monograph, DHEW Pub. No. (ADM) 78-728.

Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1978.

pp. 254-271.

Donovan, D.M.; Kivlahan, D.R.; and Walker, D.R. Clinical limitations of neuropsychological testing in predicting treatment outcome among alcoholics. Alcoholism Clin Exp Res 8:470-475, 1984.

Fauman, M.A., and Fauman, B.J. Chronic phencyclidine (PCP) abuse:

A psychiatric perspective.

1980.

J Psychedelic Drugs 12:307-315,

Freeman, A.S.; Martin, B.R.; and Balster, R.L. Relationship

between the development of behavioral tolerance and the biodisposition of phencyclidine in mice. Pharmacol Biochem Behav

20:373-377, 1984.

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Khajawall, A.M., and Simpson, G.M. Characteristics of chronic

phencycyclidine abusers. Am J Drug Alcohol Abuse 8:301-310, 1981.

Khajawall, A.M., and Simpson, G.M. Peculiarities of phencyclidine

urinary excretion and monitoring. J Toxicol Clin Toxicol

19(8):835-842, 1983.

McCarron, M.M.; Schulze, B.W.; Thompson, G.A.; Conder, M.C.; and

Goetz, W.A. Acute phencyclidine intoxication: Clinical patterns, complications, and treatment. Ann Emerg Med 10:290-297,

1981.

Pearlson, G.D. Psychiatric and medical syndromes associated with

phencyclidine (PCP) abuse. Johns Hopkins Med J 148:25-33, 1981.

Pradhan, S.N. Phencyclidine (PCP): Some human studies. Neurosci

Behav Rev 8:493-501, 1984.

Rawson, R.A.; Tennant, F.S., Jr.; and McCann, M.A. Characteristics of 68 chronic phencyclidine abusers who sought treatment.

Drug Alcohol Depend 8:223-227, 1981

Simpson, G.M.; Khajawall, A.M.; Alatorre, E.; and Staples, F.R.

Urinary phencyclidine excretion in chronic abusers. J Toxicol

Clin Toxicol 10:1051-1059, 1983.

Sioris, L.J.,and Krenzelok, E.P. Phencyclidine intoxication: A

literature review. Am J Hasp Pharm 35:1362-1367, 1978.

Slifer, B.L; Balster, R.L.; and Woolverton, W.L. Behavioral dependence produced by continuous phencyclidine infusion in rhesus

monkeys. J Pharmacol Exp Ther 230:399-406, 1984.

Tennant, F.S., Jr.; Rawson, R.A.; and McCann, M.A. Withdrawal

from chronic phencyclidine (PCP) dependence with desipramine.

Am J Psychiatry 138:845-847, 1981.

Yago, K.B.; Pitts, F.N., Jr.; Burgoyne, R.W.; Aniline, O.; Yago,

L.S.; and Pitts, A.F. The urban epidemic of phencyclidine (PCP)

use: Clinical and laboratory evidence from a public psychiatric

hospital emergency service. J Clin Psychiatry 42:193-196, 1981.

ACKNOWLEDGEMENTS

Jessica Friedman, M.S.W., and Kathy Rayman, M.S.W., helped conduct

outpatient group therapy. Geoffrey Smith and Brian Derrick performed the PCP assays. Alan Forsythe, Ph.D., and Denise Paz,

Ph.D., performed the computer programming and statistical

analysis. Candace Young and Frieda Fisher helped with data

management. William Bax, Joseph Wade, Charles Bennett, Gertie

King, Dennis Miles, Jimmie Pickett, Frank Porter, Deborah

Richardson, and Alice Roberts collected urine samples.

227
AUTHORS

David A. Gorelick, M.D., Ph.D.

Jeffrey N. Wilkins, M.D.,

Psychiatry Department, Brentwood Divison

West Los Angeles VA Medical Center

and UCLA School of Medicine

11301 Wilshire Boulevard

Los Angeles, CA 90073

Carl Wong, M.S.W.

Social Work Service, Brentwood Division

West Los Angeles VA Medical Center

11301 Wilshire Boulevard

Los Angeles, CA 90073

228
Legal Issues Associated With

PCP Abuse—The Role of the

Forensic Expert

Steven E. Lerner and Richard S. Burns

It is not uncommon for individuals under the influence of phencyclidine to come to the attention of the criminal justice system.

Increasingly, there is a need for forensic experts to advise and

testify in cases involving PCP and other psychoactive drugs. With

the publication of a paper on acute intoxication and fatalities

from PCP use, we began to receive requests from attorneys to evaluate PCP-related cases (Burns et al. 1975). We have now consulted

in over 400 civil and criminal cases and have testified in municipal, superior, and Federal courts from Hawaii to Washington, D.C.

In this chapter, we will examine some of the issues that are frequently raised in both criminal and civil PCP-related litigation.

Most jurors and many courts have limited knowledge about psychoactive drugs, including PCP. From our experience, it is not

uncommon for the average juror to believe that the effects produced by PCP are no different from those produced by other drugs.

For this reason, jurors must be educated if they are to be expected to make informed decisions about complex issues with which they

have little or no familiarity. It is possible, in a limited

amount of time, using visual aids, to provide a jury with a basic

understanding of PCP, through expert testimony. We have found

that a general discussion, prior to testimony, of the specifics of

a case, covering PCP's history, street pharmacology including

modes of administration, patterns of use, duration of effects,

signs and symptoms of intoxication, toxicological screening, and

effects on brain functioning provide an adequate foundation for

many issues that jurors must consider (Lerner and Burns 1978).

The following case histories illustrate some of the issues faced

by PCP abusers, law enforcement personnel, and the courts.

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CRIMINAL LITIGATION

Case 1. Determination of Implied Malice Associated With Driving

While Intoxicated

Prior to 1981, in California, the most serious charge possible for

death occurring as a result of alcohol- or drug-related vehicular

homicide was the crime of vehicular manslaughter with gross negligence. That year, the California Supreme Court decided that second degree murder could be charged when the facts surrounding a

vehicular homicide supported a finding of "implied malice." Under

California law, implied malice exists where the killing results

from an intentional act, the natural consequences of which are

dangerous to life, which act was deliberately performed by a person who knows that his conduct endangers the life of another, and

who acts with conscious disregard for life. Under this definition, it is not necessary to prove that a defendant intended to

kill another. Proof of the subjective state of mind of the intoxicated driver is critical in the determination of whether the

driver was acting with implied malice and therefore guilty of

murder. Elements of knowledge and cognitive thinking ability must

be proven.

In People vs. Ernesto Rangle Juarez1, the issue of PCP and its

effects upon a person's state of mind became the focal point of

the trial. The prosecution sought to prove that Juarez intentionally used PCP, was aware that using PCP and driving an automobile

was dangerous to human life, and acted with conscious disregard

for human life. The defense sought to prove that Juarez's use of

PCP was unintentional, and that the effect of the PCP was to

render him incapable of being aware of the consequences of his

conduct and unable to control his conduct; therefore, Juarez was

not guilty of murder.

Summary of facts. The factual situation was important in the

trial, for the resolution of the PCP issue, Evidence produced at

the trial revealed that around noon on March 6, 1982, Juarez was

driving his automobile in the City of South San Francisco, with

three of his friends as passengers. The men smoked what Juarez

claimed to be a joint of marijuana in his automobile, while parked

in a store parking lot. Juarez claimed that he took only one or

two inhalations from the joint. He then drove from the parking

lot and became involved in two minor traffic accidents within a

span of 30 seconds. Accelerating rapidly, he fled the scene. A

South San Francisco police officer on patrol in the area saw

Juarez's automobile and gave chase. Juarez took evasive action

when the officer activated his emergency lights and siren, and

Juarez's automobile reached speeds of 65 to 70 miles per hour. As

the automobile approached a curve in the roadway, Juarez failed to

control the automobile, which went into oncoming traffic lanes and

hit the victim's car head-on, killing the victim instantly. A

great deal of evidence was produced concerning Juarez's conduct

and action after the accident. Juarez was not significantly

230
injured in the collision , although paramedics found him somewhat

dazed. Police officers and medical personnel testified that he

answered questions appropriately. His speech was slurred, and he

appeared to be extremely intoxicated or under the influence of

drugs. Approximately 1 hour after the accident, blood and urine

samples were obtained for toxicological screening. The analysis

revealed a PCP blood level of 30 ng/ml and a PCP urine level of

2.1 μg/ml. No alcohol was detected.

Prior to the collision, Juarez had been on probation for sales of

narcotics and had been reporting to an adult probation officer.

The officer testified concerning a 2-year period of probation

during which Juarez continually used PCP, as evidenced by toxicological screening, a condition of probation. This information was

introduced by the prosecution to show Juarez's awareness of PCP

and its effect upon him.

Expert Testimony. Drug abuse experts testified on both sides.

The prosecution's expert used slides and a motion picture to inform the jury of the effects of PCP. He testified that a person

with a PCP blood level of 30 ng/ml would be considered under the

influence of this drug, and should display nystagmus and have difficulty with coordination. A person with this blood level would

be classified as being in an acute confusional state (Burns and

Lerner 1981). This level would not necessarily mean that an individual would not be conscious of what he was doing, nor would he

be unable to control his conduct. Emphasis was placed on Juarez's

behavior on the day of the collision. Important factors presented

to the jury were his history of PCP abuse, his driving ability

throughout the entire incident, and his conduct and behavior after

the collision. In addition, testimony was given regarding the

substantial evidence of what was referred to as reality-oriented,

goal-directed behavior exhibited by Juarez both before and after

the collision. This testimony enabled the prosecution to argue

that, despite PCP intoxication, Juarez was aware of his conduct

and had the ability to make conscious decisions regarding his

conduct. Under the prosecution's theory, this reality-oriented,

goal-directed behavior was evidence of Juarez's state of mind of

implied malice.

On this issue, the defense called a drug abuse expert who testified to Juarez's state of mind. The defense expert testified that

for a person to be aware that his conduct is dangerous to another

and in order for him to make a conscious decision to refrain from

such activity, or to act without regard to such known danger, he

must be able to engage in abstract thinking. A PCP blood level of

30 ng/ml would result in a high likelihood that there would be

gross impairment of the ability of the defendant to think

abstractly.

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Outcome. After consideration by the jury, defense testimony was

rejected and Juarez was found guilty of second degree murder.

This was the first time in the history of the State that an individual was convicted of murder based upon an automobile collision

while under the influence of PCP.

Case 2. Diminished Capacity Associated With PCP Intoxication

The diminished capacity defense associated with PCP intoxication

has frequently been used as an explanation of an individual's

conduct. In 1981, this explanation was the sentral issue in the

case of People vs. Richard Cavesuella et al. that became known as

the Mt. Madonna murders.

Summary of facts. In Watsonville, California, a town located near

the City of Santa Cruz, two youth gangs became embroiled in a turf

war that ended with the brother of Cavesuella receiving a shotgun

wound to the head, which resulted in a severe, permanent brain

injury. Gang and family pride led Cavesuella to seek to avenge

his brother's injury. With a friend, he ventured into so-called

neutral territory, to a party at a fairgrounds. There, they

encountered two young males (15 and 16 years of age) associated

with the rival gang. After drinking to the point of intoxication,

the youths were invited out for more beer.

During a ride to a nearby park called Mt. Madonna, the youths were

terrorized and one was stabbed. Very quickly, it became clear

that Cavesuella was interested in revenge for his brother's

shooting. Both youths protested that they were not in the other

gang, nor had they been involved in the shooting. Their protests

were to no avail. They were subsequently harrassed, interrogated,

and stabbed repeatedly. There were approximately 140 stab wounds

to the two bocies that were deposited by the side of a road.

Trial strategies. The defense described the killings as

"frenzied," so that they could attempt to use the manslaughter

instruction. In essence, a killing committed in the heat of

passion, or upon a sudden quarrel, that is not premeditated or

deliberated is manslaughter at most. The defense strategy was to

make the drug be the culprit in the case. PCP had been given wide

media attention and had been highlighted as causing indiscriminate

fits of rage and/or violence. Toxicological screening had not

been conducted at the time of Cavesuella's arrest. Nevertheless,

the defense attempted to prove that Cavesuella had taken PCP and

was under the influence of the drug at the time of the killings.

The prosecution's main trial issue was to counteract or show the

jury that, even assuming Cavesuella ingested PCP, his acts were

reality-oriented; goal-directed in such a way that the drug did

not prevent him from meditating, deliberating, or harboring

malice. This was accomplished by cross-examination of the defense's drug expert and presentation of testimony by the prosecution's drug expert. The defense expert was questioned repeatedly

232
about different facts in the case that showed the presence of

reality-oriented, goal-directed behavior on the part of

Cavesuella. In those areas, he indicated the presence of an

intellectual capacity to premeditate and deliberate. While the

expert still stuck with his opinion that Cavesuella was diminished

because of the use of PCP, he conceded that he had not read the

crime reports or much of the information that was utilized in

cross-examination of his testimony.

Testimony by the prosecution's expert was that it was possible

Cavesuella had taken PCP at some time. Whether or not he did on

the night of the killings could not be determined. However,

Cavesuella's actions were inconsistent with someone who, under the

influence of PCP, is significantly impaired.

Outcome. The jury deliberated for 2 weeks before deciding that

Cavesuella was guilty of first-degree murder with special circumstances. He was sentenced to life imprisonment without the

possibility of parole.

CIVIL LITIGATION

Case 3. Death Associated With Law Enforcement Intervention

It is not uncommon for civil actions to be brought against law

enforcement personnel who have come into contact with individuals

under the influence of PCP.

Honolulu et al.

Helen A. Burns vs. City and County of

represents an issue that is being brought before

the courts with increasing frequency.

Summary of facts. On the night of May 10, 1979, officers from the

Honolulu Police Department responded to a call that a disturbance

was taking place at a night club frequented by sailors as well as

by "locals." The first officers to arrive observed a group of

sailors in the parking lot. A shirtless young man in this group

was asked for some identification and gave one officer a card that

identified him as Richard Burns. One officer went into the club

to find out what had happened.

As the other officer approached, Burns yelled "Watch your back!"

causing the officer to turn around, but no one was there. Burns's

skin appeared to be covered with perspiration, and he appeared to

have been involved in a fight. He would occasionally spit on the

sidewalk and try to wipe it up with a handkerchief or rag. Once

in a while he would yell "Watch your back!" and/or "Is it over?"

The officer suspected that Burns was on drugs. Once Burns

attempted to run past the officer, who was just barely able to

restrain him. Although the officer was much larger, Burns pulled

away with such ease that the officer knew if he had to hold him

there was going to be a problem.

Additional officers arrived as the crowd grew, and Burns continued

his bizarre behavior. A decision was made to remove Burns and

233
defuse the situation that seemed to be building; the supervising

officer ordered him arrested for disorderly conduct. Burns backed

into an officer who applied what was described as a neck hold as

the officers struggled to handcuff him. There was disagreement as

to whether Burns actually lost consciousness after this first

hold, although he did go limp, and handcuffs were placed on his

wrists. Burns was immediately back up on his feet, kicking wildly

in all directions. This time an officer managed to apply a carotid restraint hold. In addition, a belt was placed around his

feet. This hold was applied for not more than a fraction of a

minute by all accounts.

All three officers got up from Burns at the same time. The supervising officer stated that Burns looked like anybody who was unconscious; he saw nothing out of the ordinary. Several minutes

had passed after application of the second hold (there was a dispute about how many holds had been applied), at which time the

officers discovered that Burns was not breathing and applied

cardiopulmonary resuscitation. Burns, however, was dead.

It was later learned that Burns had accosted two female employees

in a restroom. A struggle had ensued, during which a bouncer

applied a neck hold; he had been kicked in the head by someone

wearing a hard shoe; he was either bounced against or bounced

himself against a wall, and had slipped from the grasp of five or

six well-built men.

Issues at trial. The decedent's mother and his estate brought an

action that came to trial in Federal court against the City and

County of Honolulu for intentionally, recklessly, or negligently

causing his death. The propriety of the arrest was never questioned by the plaintiff, only the manner in which it had been

handled. Much of the plaintiff's case focused on attempting to

prove an alleged third choke hold. The third hold was supposedly

witnessed by a security guard, from a rooftop parking lot, who observed one officer come back after the second hold and "strangle"

Burns for up to 14 seconds. No one else observed this, and testimony from other witnesses was that this officer had gone back into

the bar after the second hold.

The medical examiner for the City and County of Honolulu ruled

that the cause of Burns's death was asphyxiation. Laboratory

analysis confirmed the presence of PCP in his body. However, it

was the medical examiner's opinion that PCP did not play a role in

the death. It was later learned that the medical examiner's

knowledge of PCP was limited to articles he had read that were

written by experts subsequently retained by the City and County of

Honolulu.

These experts had been requested to determine the cause of death

and to evaluate the officers' conduct in this matter. At trial,

they testified that the medical examiner was in error regarding

the cause of death. There were no statements made that anyone had

234
cut off the decedent's air supply for the minimum time required

for asphyxiation. It was their opinion that Burns had died from

an idiosyncratic reaction from a combination of control hold(s)

and PCP (Burns and Lerner 1978). Testimony was also offered that,

under the circumstances, and with the absence of any knowledge by

police of the effects of PCP, the conduct of the officers was

appropriate. It was stressed that traditional control holds may

be ineffective in controlling someone under the influence of PCP.

For this reason, law enforcement training in signs and symptoms of

PCP intoxication and appropriate methods of control was extremely

important. However, in this case, it would not be reasonable to

expect officers to have this specialized training, since PCP had

not been recognized as a problem in Hawaii.

Outcome. After a week of deliberation, the jury returned a finding of no improper conduct by the police in effecting the arrest.

They did find the City and County of Honolulu 20 percent negligent

in failing to discover sooner that Burns was not breathing, and

negligent in administering CPR. However, under Hawaii law, negligence must be more than 51 percent for a cash award.

SUMMARY

These cases illustrate some of the complex issues associated with

PCP-related litigation. The concept that malice is implied when

an experienced drug user commits a crime while under the influence

of the drug is not held in most states, at the present time.

The authors have now reviewed in detail four cases of unexpected

death following the use of neck holds in PCP-intoxicated individuals. In all of the cases, multiple carotid compression holds

had been attempted, according to the history. Skin abrasions,

hemorrhage into the soft tissues of the neck, and fractures of the

hyoid bone and thyroid cartilage provide structural evidence of

the application of substantial force to the neck. On autopsy,

there has been no evidence of lethal injuries to the bronchial

tree, brain, or heart.

Drugs related to PCP are known to alter the carotid sinus reflex.

Mechanical stimulation of the carotid sinus in the neck normally

results in a slowing of heart rate and a decrease in blood

pressure. Carotid sinus stimulation, coupled with the effects of

PCP on blood vessels, might result in a marked fall in the blood

pressure that could lead, ultimately, to death. Individuals

intoxicated with PCP may be at a higher risk to complications of

carotid compression neck holds. Hence, additional cases would be

expected to become medicolegal issues.

FOOTNOTES

1. Charles J. Smith, Deputy District Attorney, County of San

Mateo, contributed case information.

235
2. Arthur Danner III, District Attorney, County of Santa Cruz,

contributed case information.

3. Adrienne Sepaniak King, former Deputy Corporation Counsel,

City and County of Honolulu, contributed case information.

REFERENCES

Burns, R.S.; Lerner, S.E.; Corrado, R.; James, S.H.; and Schnoll,

S.H. Phencyclidine--states of acute intoxication and fatalities. West J Med 123(5):345-349, 1975.

Burns, R.S., and Lerner, S.E. The effects of PCP in man: A review. In: Domino, E.F., ed.

and Current Perspectives.

469.

PCP(Phencyclidine): Historical

Michigan: NPP Books, 1981. pp. 449-

Lerner, S.E., and Burns, R.S. Phencyclidine use among youth:

History, epidemiology and acute and chronic intoxication. In:

Peterson, R.C., and Stillman, R.C., eds. Phencyclidine Abuse:

An Appraisal. Research Monograph 21.

National Institute on Drug Abuse

DHEW Pub. No. (ADM) 78-728. Washington, D.C.: Supt.

of Docs., U.S. Govt. Print. Off., 1978. pp. 66-118.

AUTHORS

Steven E. Lerner, Ph.D.

Doctors Lerner, Burns and Associates

P.O. Box 1093

Larkspur, CA 94939

Richard S. Burns, M.D.

Department of Neurology

Vanderbilt University School of Medicine

Nashville, TN 37232

236
The Long-Term Effects on

Neurodevelopment in Infants

Exposed Prenatally to PCP

Judy Howard, Vickie Kropenske, and Rachelle Tyler

Abuse of phencyclidine hydrochloride (PCP) is a national problem

that has reached epidemic proportions in urban areas of the United

States. The drug is inexpensive, readily obtainable, and is usually used in combination with other drugs such as marijuana, heroin, cocaine, and alcohol (Golden et al. 1982). The routes of PCP

use include inhalation, ingestion and parenteral administration.

In Los Angeles County, the number of PCP abusers seen in emergency

rooms rose from 1,567 in 1980 to 3,001 in 1983, an increase of 92

percent. In addition, approximately 30 percent of these individuals were women of child-bearing age, who reported that their first

use of PCP was at the age of 20 years (Husson 1984).

With the increased use of PCP by young women, pediatricians have

begun to identify the newborn's neurobehavioral symptoms after in

utero exposure. In 1980, Golden et al. were the first to document

the placental transfer of PCP in humans and to describe the resulting neurobehavioral symptoms. They reported on one infant

whose mother had smoked an average of six joints per day of marijuana dusted with PCP. The behaviors emerging shortly after birth

included extreme jitteriness , coarse flapping movements in response to slight auditory or tactile stimuli, nystagmus, poor

visual tracking, and hypertonicity. At 2 months of age, the infant continued to have coarse tremors, roving eye movements, and

hypertonicity. Furthermore, the infant had dysmorphic features.

Subsequent to this report, Strauss et al. (1981) described two

other infants who had been exposed prenatally to PCP. These infants also displayed signs of irritability, tremulousness, and

increased muscle tone. However, no congenital anomalies were

noted.

More recently, Chasnoff et al. (1983) have described the behavior

of seven infants whose mothers used PCP daily throughout their

pregnancies as well as using various other drugs intermittently.

As compared to a control group of 27 infants, the PCP-exposed newborns had rapid changes in their levels of consciousness, with

lethargy alternating with irritability. Furthermore, these

237

185-466 0 - 87 - 9
infants were very sensitive to auditory stimuli and had tremors

and facial grimacing.

The effects of PCP in its purest form, as a single drug, have been

studied in animals. In 1977, Cooper et al. noted the placental

transfer of PCP in pigs. In fact, they found that plasma levels

in the piglet were 10 times higher than in the sow. Other animal

studies support marked neurobehavioral changes in the newborn, but

have yet to incriminate PCP as a teratogen (Goodwin et al. 1980;

Tonge 1973; Tenor 1974). A more specific description of the

behavior of monkeys that had received PCP was given by Balster and

Chait in 1976. The monkeys had nystagmus and rhythmical limb

movements, and were unable to track visually.

While the aforementioned studies have described the manifestations

of in utero exposure to PCP by human and animal fetuses as well as

behaviors adult monkeys who had received only PCP, the longterm consequences of prenatal abuse have not been described.

Therefore, this report will elaborate upon our observations of the

effects of PCP upon the growth and development of 12 neonates

between 2 and 18 months of age, whom we have followed from August

1983 to March 1985.

DESCRIPTION OF INFANTS

During an 18-month period the growth and development of eight male

and four female infants exposed prenatally to phencyclidine was

observed.

The Ballard Screening System (Ballard et al. 1977) was used to

determine the gestational ages for the five preterm and five fullterm neonates born at UCLA. Maternal dates and physical exam

established the gestational ages for the two full-term infants

born at community hospitals. The average gestational age for all

infants was 37.75 weeks with a range of 33 to 42 weeks. The five

preterm infants had a mean gestational age of 34.6 weeks with a

range of 33 to 36 weeks. The average gestational age for the

seven full-term infants was 40 weeks with a range of 38-42 weeks.

The 12 neonates included in this study had a mean birth weight of

2,481 grams (10 percent), a mean frontal-occipital head circumference of 31.5 cm (10 percent), and a mean crown-to-heel length

of 47 cm (25 percent). Among preterm infants the respective mean

weight, head circumference, and length were 1,804 grams [referent

to the norms established by Lubchenco et al. (1966). this weight

fell at the 10th percentile], 29 cm (10th percentile), and 42 cm

(25th percentile). Full-term infants averaged a birth weight of

2,964 grams (25 percent), head circumference of 33 cm (10 percent), and length of 49 cm (25 percent). Two of the preterm

neonates were small for gestational age. All infants were normocephalic and no congenital anomalies were apparent.

238
Urine toxicology screens from the mothers and infants were

obtained during the labor and delivery and/or postnatal periods.

All specimens were analyzed by EMIT (Enzyme Immunoassay Technique), an enzyme method based upon the competitive bonding of an

enzyme and an antibody. This method yields a positive result with

concentrations of 75 ng of PCP/ml or greater (Rubenstein et al.

1972).

For all 12 mother-infant pairs, either the mother or the infant's

toxicology report was subsequently positive for PCP. In nine

cases, the screens for both mother and infant were positive. In

two cases, the mother's results were positive and the infant's

were negative. In one case, the infant had a positive result

while the mother's test was negative. Test sensitivity, specimen

handling procedures, and delays in obtaining specimens undoubtedly

contributed to the inconsistency in paired results. Cocaine,

codeine, and glutethemide, in addition to phencyclidine, were

identified in the urine toxicology screens of two mothers and

their neonates.

All infants developed deviant neurobehavioral symptoms within the

first 24 hours of life. Most commonly, the neonates were found to

have symptoms of irritability, tremors, and hypertonicity. Bizarre eye movements and staring spells were seen in 25 percent of

infants. Poor sucking, lethargy, diarrhea, and facial twitching,

symptoms commonly associated with prenatal opiate exposure, were

seen infrequently in these PCP-addicted infants.

In addition, the temperature, pulse, and respiratory rates for 10

infants were reviewed for evidence of drug effects on autonomic

nervous system function. However, no abnormal patterns were noted

during the course of hospitalization.

In 58 percent of cases, symptomatic treatment with Valium, phenobarbital, or paregoric, for a period ranging from 2 to 14 days,

was required to control drug effects. However, in 42 percent of

the cases, symptoms were successfully managed with more conservative measures such as swaddling, use of a pacifier, decreased

environmental stimulation and excessive handling, and modification

of feeding schedules and techniques. Although all infants remained symptomatic, only two neonates continued to require medication at the time of discharge.

In addition to normal neurobehavioral symptoms, 67 percent of

infants were also noted to have one or more medical problems during the perinatal period including respiratory distress, meconiumstained amniotic fluid, hyperbilirubinemia, anemia, syphilis,

omphalitis, and electrolyte imbalances. Meconium staining and

respiratory distress were the most commonly observed problems for

both preterm and full-term infants. However, among preterm neonates, respiratory problems were noted with much greater frequency, and the severity of the preterms' early respiratory problems

239
continued to lower l-minute Apgar scores. Eighty percent of preterm Infants had Apgar scores below 7 at 1 minute, compared to 14

percent of full-term infants with low 1-minute scores. Among 43

percent of full-term infants, the sole identified medical problem

was abnormal neurobehavioral signs. In contrast, during the perinatal period, 80 percent of preterm infants experienced three or

more medical problems in addition to withdrawal symptoms.

TABLE 1. Incidence of neonatal medical problems

Medical Problem

Preterm Term Combined Groups

n=5 n=7 n=12

n(%) n(%) n(%)

Withdrawal symptoms

Jittery

Irritable

Hyperreflexia/hypertonic

Hypertonic

Abnormal eye movements

Poor suck

Lethargic

Diarrhea

Prematurity

Meconium

Respiratory distress

Hyperbilirubinemia

Anemia

SGA

Syphilis

Electrolyte imbalances

Omphalitis

5 (100)

1 ( 20)

2 ( 40)

2 ( 40)

1 ( 20)

2 ( 40)

2 (40)

1 ( 20)

5 (100)

2 (40)

3 ( 60)

2 (40)

1 (20)

2 (40)

1 (20)

2 (40)

1 (20)

7 (100)

4 ( 57)

3 ( 43)

1 ( 14)

2 ( 29)

-

-

-

-

3 ( 43)

2 ( 29)

1 ( 14)

1 ( 14)

-

1 ( 14)

-

-

12 (100)

5 ( 42)

5 ( 42)

3 ( 25)

3 ( 25)

2 ( 17)

2 ( 17)

1 ( 8)

5 ( 42)

5 ( 42)

5 ( 42)

3 ( 25)

2 ( 17)

2 ( 17)

2 ( 17)

2 ( 17)

1 ( 8)

The medical problems and slow weight gain of the preterm infants

contributed to their prolonged hospitalization. The five preterm

infants remained in the hospital an average of 24 days with a

range of 10 to 37 days. At UCLA, infants between 33 and 37 weeks'

gestational age routinely require 10 days of hospitalization. The

seven full-term infants had a mean hospital stay of 8 days with a

range of 4 to 14 days. While the average length of hospitalization at UCLA is routinely 2 1/2 days for full-term infants, the

stay for these essentially healthy infants was extended to monitor

their neurological status, and to taper or stabilize medications.

At the time of discharge , all infants were placed in the homes of

relatives or foster parents. In the State of California, a child

born withdrawing from drugs or alcohol is considered to be abused

and must be reported to child protection agencies (Los Angeles

County 1982). Therefore, all the infants reported in this paper

240
were identified as having been abused, were referred for court

supervision, and were placed in foster homes or with extendedfamily members during the period of follow-up observation.

TABLE 2. Summary of neonatal data

Data

Preterm

n=5

n(%)

Term

n=7

n(%)

Combined

Groups

n=12

n(%)

Sex

Male 5(100)

Female -

Gestational age

(

34.6 ± 1.5

Birth weight grams) 1,804 ± 170

Head circumference 29 ± 0.7

Birth length 42 ± 2.8

Apgar scores

1 minute 4.4 ± 2.9

5 minutes 6.8 ± 2.9

6 at 1 minute 4(80)

Withdrawal

Mild (no meds.) 2(40)

Moderate (meds. 2 weeks) 3(60)

Length of hospitalization 24.6 ± 9.7

3(43)

4(57)

40 ± 1.3

2,964 ± 366

33 ± 0.6

49 ± 2.2

8(67)

4(33)

7 ± 2.7 5.9 ± 2.9

8.4 ± 1.2 7.6 ± 2.1

1(14) 5(42)

3(43) 5(42)

4(57) 7(58)

8.7 ± 3.1 15.3 ± 10.3

37.75 ± 3.1

2,481 ± 664

31.5 ± 2.2

47 ± 4.3

GROUTH PARAMETERS

The physical growth scales used are those published by the

National Center for Health Statistics: percentiles which are

based upon the work of Lubchenco et al. in 1966. The infant's

weight, height, and head circumference were adjusted for sex and

corrected for prematurity.

At an age of 35 weeks, the mean weight and head circumference were

at the 10th percentile and height was at the 25th percentile. By

18 months of age, five infants had a mean weight between the 25th

and 50th percentile, and a mean height at the 75th percentile.

The mean head circumference of the four males was at the 10th

percentile. The one female's head circumference was at the 50th

percentile.

DESCRIPTION OF MOTHERS

Maternal data were obtained during interviews with the mothers

following delivery and by review of the maternal and infant

medical records.

241
The mean maternal age for the 12 mothers included in this study

was 25.8 years, with a range of 20 to 31 years. Mother's race

was: 75 percent black, 17 percent white, and 8 percent Hispanic.

All were low income. Eighty-three percent of the women were

multiparas with an average of 5.2 previous pregnancies and 2.7

live births.

TABLE 3. Summary of maternal demographic data

Maternal Status

Preterm Term Combined Groups

n=5 n=7 n=12

n(%) n(%) n(%)

Age

Race

Black

Hispanic

White

Gravida

Para

Marital status

Single

Married

Separated

Divorced

27.6 ± 3 24.6 ± 3.7 25.8 ± 3.5

4(80) 5(71)

1(20) 1(14)

9(75)

2(17)

1(14) 1(8)

4.1 ± 1.3 5 ± 3.5 4.8 ± 2.7

2.2 ± 1.7 4 ± 2.8 3.3 ± 2.4

4(80) 5(71) 9(75)

-

1(20)

1(14)

1(8)

- 1(14) 1(8)

Criteria developed in the National Institute of Medicine Study

(Gortmaker 1979) was used to establish the adequacy of prenatal

care. In 67 percent of our 12 cases, prenatal care during pregnancy was inadequate. However, among mothers of preterm infants,

care was inadequate in all cases. Thirty-three percent of all

mothers received no prenatal care.

TABLE 4. Characteristics of prenatal care

Level of Care

Preterm

n=5

n(%)

Term Combined Groups

n=7 n=12

n(%) n(%)

Adequate

Intermediate

Inadequate

-

-

5(100)

2(29)

2(29)

3(43)

2(17)

2(17)

8(67)

242
Mothers of preterm infants were also more likely than mothers of

full-term infants to have obstetrical complications at the time of

delivery. Eighty percent of mothers of preterm infants had three

or more obstetrical complications. Possible complications included premature labor. oremature rupture of membranes, prolonged

rupture of membranes', Caesarean section, chorioamnionitis, and

marginal placenta abruption. In contrast, only one mother of a

full-term infant developed obstetrical complications during the

perinatal period.

However, the pregnancies of 67 percent of all mothers were complicated by a variety of medical problems including anemia, hepatit

B, syphilis, and psychiatric emergencies. At the time of delivery, 57 percent of mothers of full-term infants and 80 percent of

mothers of preterm infants were noted to have had one or more

medical problems during the pregnancy. Seventy-five percent of

all mothers smoked.

is

TABLE 5. Incidence of maternal perinatal obstetrical and medical

complications

Complications

Preterm

n=5

n(%)

Term Combined Groups

n=7 n=12

n(%) n(%)

Premature labor 5(100)

Premature rupture of 5(100)

membranes

Prolonged rupture of 3( 60)

membranes

Caesarean section 2( 40)

Marginal placental 1( 20)

abruption

Chorioamnionitis 2( 40)

Anemia 2( 40)

Hepatitis B 1( 20)

Syphilis 1( 20)

Psychiatric hospitalization 1( 20)

Smoking 4( 80)

-

-

5(42)

5(42)

- 3(25)

1(14) 3(25)

- 1( 8)

- 2(17)

1(14) 3(25)

1(14) 2(17)

1(14) 2(17)

1(14) 2(17)

5(71) 9(75)

Maternal reports of drug use during pregnancies reflected a pattern of polydrug exposure during the gestational period. In only

two cases was phencyclidine the sole reported drug of abuse.

Alcohol, marijuana, and cocaine were commonly used in varying combinations with PCP. The extent of reported maternal use of phencyclidine ranged from daily smoking of PCP-laced cigarettes to

"one-time" use 3 months prior to delivery. Fifty-eight percent of

women reported smoking as the primary route of ingestion.

percent of cases, the method of use is unknown.

243
Information regarding the long-term history of drug abuse was

available for eight mothers: four who delivered full-term infants

and four mothers of preterm infants. The average number of years

of drug use for this group of mothers was 7.4 years, with a range

of 3 to 15 years.

TABLE 6. Incidence of reported maternal drug use during

pregnancy

Drug Used

Preterm Term Combined Groups

n=5 n=7 n=12

n(%) n(%) n(%)

PCP

Alcohol

Marijuana

Cocaine

Valium

Doriden

Heroin

5(100) 7(100) 12(100)

4( 80)

3(60)

2( 29) 6( 50)

2( 29)

2( 40) 1( 14)

5( 42)

1(20)

3( 25)

- 1( 8)

1( 20) - 1( 8)

- 1( 14) 1( 8)

Of the 10 mothers who delivered at UCLA Medical Center, one returned for the scheduled 6-week follow-up appointment. Twentyfive percent of all mothers have had repeat pregnancies.

DESCRIPTION OF THE INFANTS' POSTDISCHARGE ENVIRONMENT

Following their hospitalization , all infants were placed with

foster parents or in the care of extended-family members. Four

infants were discharged to relatives and eight infants were placed

in foster care. Later, two of the foster children were also

placed with extended families.

During the follow-up period, no infant was returned to the care of

the mother. In 25 percent of cases, the child was essentially

abandoned after delivery. While, in the remaining 75 percent of

cases, the mothers expressed a strong desire to care for their

infants, none of the parents was able to complete a drug rehabilitation program and/or successfully sustain a drug-free life style,

conditions stipulated by the court as the basis for reunification.

Furthermore, there was evidence from previous childrearing patterns that the mothers who already had children would have difficulty managing the caretaking responsibility for the new infant,

if the parents' drug use continued.

Of mothers who had older children (58 percent), 85 percent already

had one or more of their offspring in foster placement or in the

care of extended-family members. In addition, physical and

244
developmental evaluations of six children who were living with two

of the mothers at the time of this delivery revealed significant

developmental delays in two of the children, and emotional and

school problems among the four siblings. Medical neglect was also

evident in all six children.

After discharge , all infants were followed by a team composed of a

pediatrician with subspecialty training in Child Development, a

public health nurse, and a social worker. In order to maintain

contact with the foster families and relatives who had responsibility for the care of the infant, team members made regular home

visits and had frequent telephone contact with the infants' caretakers. During the first 3 months of placement, infants were seen

(an average of twice per month) for follow-up visits at home or in

the UCLA Child Development Clinic. Phone conferences with caretakers were held on a biweekly basis. During the following 3

months, clinic and home visits were tapered to once per month and

phone contacts were made biweekly.

Team members provided and coordinated referrals to a variety of

community agencies, and supported caretakers in learning about

normal infant development, sleep-wake patterns, and feeding schedules and appropriate foods. Caretakers were also helped to understand the infants' developmental strengths, what would effectively

soothe him/her, and what play activities were appropriate at

certain ages.

The team also assisted the infants' caretakers with obtaining

appropriate medical care and treatment. The primary health care

of 58 percent of the infants was received from physicians who

lived within the foster family's community; 42 percent of infants

returned to the UCLA Pediatric Clinic for routine pediatric

follow-up. In order to promote optimal medical care for all infants, team members provided the primary physician with summaries

of the child's birth history, developmental progress, and information regarding the medical treatment and management of the PCPexposed infant.

The intent of these specialized follow-up services to families was

to provide education, support, and anticipatory guidance in order

to maintain a nurturing and stable environment for the high-risk

infant. In 67 percent of the 12 cases, the infant did remain in

the same home environment throughout the follow-up period. There

were, however, four infants who had multiple changes in placement

following discharge. Among these four cases, three infants were

placed in two different homes within the first 2 months of life.

Thereafter their placements were stable. The fourth infant experienced four placements during the first 9 months, two placements being with foster parents and two with relatives.

245
DEVELOPMENTAL OUTCOME OF INFANTS

In order to determine the infants' behaviors in the areas of gross

motor, fine motor, adaptive, language, and personal-social development, the standardized Gesell Developmental Evaluation (Gesell &

Amatruda 1954) was administered to them. This examination provides a developmental age (DA) and developmental quotient (DQ)

(ascertained by dividing the chronological age into the developmental age) in each of the five areas of behavior, and an aggregate DA and DQ. For those infants born preterm, correction for

their gestational age was made. The average DQ is 100.

The DQ's of eight infants who had a mean age of 34.5 weeks are

described in table 7. The DQ's of five infants who had a mean age

of 17.75 months are described in table 8.

TABLE 7. Gesell developmental evaluation of 8 infants at 34.5

weeks (±4.6)

Developmental Area Developmental Quotient

Gross motor 106 ± 32.9

Fine motor 81 ± 18.7

Adaptive 90 ± 20.1

Language 96 ± 14

Personal-social 103 ± 19

Aggregate score 96 ± 18

TABLE 8. Gesell developmental evaluation of 5 infants at 17.75

months (±1.1)

Developmental Area Developmental Quotient

Gross motor 114 ± 14

Fine motor 86 ± 12.9

Adaptive 93 ± 17.5

Language 86 ± 11.1

Personal-social 90 ± 8.4

Aggregate score 94 ± 11.3

The evaluation results are mildly worrisome; however, the quality

of the infants' behaviors are very worrisome. In the area of fine

motor development, the infants performed in the low normal range.

Furthermore, the items used to score fine motor behaviors do not

identify deviant movements required for the fine motor act. For

instance, each of these infants displayed abnormal movement

246
patterns when attempting to grasp small objects. The movements of

the arms were awkward and the positioning of the hands was peculiar in that the fingers were held in an extended, splayed

position. There was a palmar approach to the cube, with overextension of the mark and an overhand approach. When the infants

attempted to retrieve a small pellet, they would bat at the pellet

with their palms, and seemed to have difficulty flexing their

extended fingers. Some infants were very persistent in their

attempts to grab the objects, other were easily frustrated.

Paralyses and weaknesses were not seen. Tactile and/or proprioceptive dysfunction are possible causes for these peculiar movements of the arms and hands.

The infants' gross motor milestones were obtained well within the

normal range. However, observations of their early attempts to

walk independently revealed awkward leg movements and placement of

their feet. These movements improved over time as did the total

arm movements.

Eye movements were noted to be deviant in 25 percent of the

infants during the neonatal period. Nystagmus and darting eye

movements were seen. Also, a glazed stare associated with total

body stillness was frequently seen during the first 6 weeks.

The infants' adaptive or playing behaviors with the test objects

showed the infants to be spontaneous in their approach to the toys

and to demonstrate an interest in manipulating them. Some infants

were easily frustrated by their inability to manipulate the

objects due to their fine motor difficulties. However, there was

no evidence of gross retardation in the emerging cognitive areas.

Language skills were more difficult to evaluate. The infants'

caretakers reported age-appropriate vocalizations. However, at

clinic and home visits, we found the infants to be less vocal

during the 1-hour session than we would have anticipated.

A further area of concern is the infants' personal-social development. During the latter half of the first year, we noted seemingly appropriate eye contact with their primary caretakers as

well as joyful expressions. However, during the first half of the

second year, the primary caretakers expressed concern about the

infants' emerging interactive and affective behaviors. These

infants seem more prone to oppositional behavior demonstrated by

temper tantrums, and less enjoyment of social interaction with the

adults in their environment.

DISCUSSION

The clinical characteristics of newborns exposed prenatally to PCP

are similar to behavior patterns of infants born addicted to heroin and/or methadone. In 1973, Wilson et al. described the early

development of infants of heroin-addicted mothers. The neurobehavioral symptoms of the newborn included tremors, irritability,

247
and hypertonia. Following discharge from the hospital, these

infants continued to be agitated and restless. By the second half

of the first year, the infants slept for longer periods of time

and became less irritable. However, between 1 and 2 years of age,

the authors noted increased activity levels and impaired attention

span.

Clinical experience with the infants exposed primarily to PCP prenatally is remarkably close to Wilson et al. These neonates are

difficult to console, have alternating periods of lethargy and

irritability, and are unable to control the tremors of their

extremities when unswaddled. Vasomotor instability, diarrhea, and

voracious sucking movements are infrequently seen in the PCPexposed infants who were followed. Chasnoff et al. (1983) compared these behaviors in infants exposed prenatally to PCP to

those of adults who have acute intoxication.

McCarron's paper (this volume) describes the behaviors of 1,000

adults admitted to an inpatient service with acute symptoms of PCP

intoxication. She states that some of the patients have appropriate behavior while many have mute and staring episodes, bizarre

facial grimacing, localized dystonic reactions, rigidity, tremors,

coarse jerky movements, and nystagmus. Thus, there is similarity

between the acutely intoxicated adult's behavior and that of the

newborn with a positive urine toxic screen for PCP.

Following the initial period of observation, the infants frequently continued to be highly irritable and sensitive to tactile and

auditory stimuli during the first half of the year. They were

also unable to adjust to a sleep-wake cycle that contained extended periods of sleep during the night (Parmelee 1977). In addition, some infants continued to demonstrate sudden changes in

motor tone, ranging from hypotonia during sleep to rigidity that

would awaken them and cause intense crying. By 9 months of age,

most infants had become easier to manage because of increasing

sleep periods and lessening of irritability.

As the infants were emerging into a more predictable pattern of

behavior, the deviant fine motor movements became apparent.

Central nervous system maturation progresses in a cephalo-caudal

manner, allowing for differentiation of fine motor movements, as

those seen in the pincer grasp by 9 months (Gesell et al. 1954).

Fair evaluation of the fine motor system was not possible until

the last quarter of the first year.

The observations of fine motor problems in infants born to heroin

addicts has also been described by Wilson et al., in 1973. She

notes the discrepancy between the gross motor skills of the

infants and fine motor abilities during the first year. Furthermore, in 1979, Wilson et al, described the development of

preschool children between 3 and 6 years of age, born to heroinaddicted mothers. They performed poorer on measures of visual,

tactile, and auditory perception, were more active, and had

248
greater difficulties in the process of organization than the

children born to mothers who did not use drugs. The poor fine

motor abilities of these preschoolers were attributed to their

poor attention span and persistence rather than to a central

nervous system dysfunction. Unfortunately, these preschoolers'

fine motor movements were not described.

The most recent studies addressing the outcome of infants exposed

to drugs prenatally tend to stress the importance of the perinatal

problems and the poor environment. Lifschitz et al. (1985) studied the effects of prenatal exposure to heroin and methadone on

head growth and neurodevelopmental performance in preschool children. They found that the factors associated with postnatal head

growth were birth weight, interpartum risk, and race. Furthermore, the increased incidence of low-average and mildly retarded

intellectual performance in the drug-exposed children was related

to the amount of prenatal care, prenatal risk, and the home

environment. The amount of narcotics used by the mother during

her pregnancy was not a significant factor. The narcotic index

used in their data analysis was solely based upon the mothers'

report of drugs taken during their pregnancies. Experience

indicates that these reports are not reliable and, in addition,

the quality of the street drugs is notoriously uneven.

Chasnoff et al. (1984) have reported on the developmental outcome

of three groups of children, from birth until 2 years of age. The

methadone, polydrug, and control groups demonstrated a downward

trend in scores in the Bayley Scales of Infant Development. Their

interpretation is that the infants' environment and subsequent

lack of stimulation has a more direct influence on long-term

development than does maternal use of drugs during pregnancy.

These findings are in contrast to the developmental outcome of the

PCP infants reported in this paper. In spite of the consistent,

nurturing environments, these infants have consistently demonstrated borderline abilities in fine motor, adaptive, language and

personal-social development.

The effects of PCP, heroin, and methadone upon the developing

fetus may indeed be different. We have found that the PCP infants

are more deviant in their development than the reported development of the heroin and methadone infants. Our concerns about

stating that drug use by the mothers during pregnancy does not

affect developmental outcome are great.

Information from well-controlled animal studies that focus on the

effects of prenatal exposure to single and polydrug use will be of

great value. Further evaluation of the fine motor movements that

appear to be clearly neurologically deviant in the PCP-exposed

infants is essential. The emerging socialization skills during

the second year of life also need more detailed evaluations.

249
Future effort:; in this area of study must be collaborative.

Psychopharmacologists, biochemists, neurologists, psychiatrists,

pediatricians, psychologists, and other health care providers need

to share their observations about the effects of drugs upon the

various organ systems as well as upon the behavior of the species

studied. Clinically, we recognize that drug levels in most

instances cannot be detected in the urine for more than 3 days

after last use (Baumgartner et al., in press). Furthermore, within this 3-day period, we cannot determine when or how much of the

drug(s) was taken. Thus, we have a difficult time defining the

groups we are to study. Attrition of subjects is another problem.

However, it has been our experience that an intensive service

program incorporated in the research design lessens this problem.

By combining the knowledge gained about drugs from animal studies,

quantifying the drugs in the system, carefully assessing the

neurobehavioral activities of the developing infant through videotape analysis, and stabilizing the infants' environments, we will

learn about the effects of the drugs upon the developing fetus.

REFERENCES

Ballard, J.L.; Dazmaier, K.; and Driver, M. A simplified assessment of gestational age. Pediatr Res 11:372, 1977.

Balster, R.L., and Chait, L.D. The behavioral pharmacology of

phencyclidine. Clin Toxicol 9:513, 1976.

Baumgartner, W.; Hill, U.; Tallos, J.; and Blahd, W. Detection of

drug use by RIA analysis of hair. Paper presented to Society of

Nuclear Medicine, Western Regional Meeting. To be published as

a supplement to September, 1984 issue of Clinical Nuclear

Medicine.

Chasnoff, I.J.; Burns, W.J.; Hatcher, R.P.; and Burns, K.A. Phencyclidine: Effects on the fetus and neonate. Dev Pharmacol

Ther 6:404-408, 1983.

Chasnoff, I.J.; Schnoll, S.H.; Burns, W.J.; and Burns, K. Maternal nonnarcotic substance abuse during pregnancy:Effects on

infant development. Neurobehav Toxicol Teratol 6:277-280, 1984.

Cooper, J.E.; Cummings, A.J.;and Jones, The placental transfer of phencyclidine in the pig: Plasma levels in the sow and

its piglets. J Physiol (Lond) 267:178-188, 1977.

Gesell, A., and Amatruda, C.S. Developmental Diagnosis. New

York: Paul B. Hoeber, Inc., 1954. 538 pp.

Golden, N.L.; Sokol, R.J.; and Rubin, I.L. Angel dust: Possible

effects on the fetus. Pediatrics 65:18-20, 1980.

Golden, N.L.; Sokol, R.J.; Martier, S.; and Miller, S.I. A practical method for identifying angel dust during pregnancy. Am J

Obstet Gynecol 142(3):359-361, February, 1982.

Goodwin, P.J.; Perez, V.J.; Eatwell, J.C.; Palet, J.L.; and

Jaworski, M.T. Phencyclidine: Effects of chronic administration in the female mouse on gestation, maternal behavior, and

the neonate. Psychopharmacology (Berlin) 69:63-67, 1980.

Gortmaker, S. The effects of prenatal care upon the health of the

newborn. Am J Public Health 69(7):653-660, July 1979.

250
Husson, B.S. Trends

County, California

Trends in Selected

National-Institute

and Epidemiology of Drug Abuse Los Angeles

1980-1983. In: Epidemiology of Drug Abuse:

Cities, June 1984. Vol. I. Rockville, MD:

on Drug Abuse, 1984. pp. 84-107.

Lifschitz, M.H.; Wilson, G.S.; Smith, E.O.; and Desmond, M.M.

Factors affecting head growth and intellectual function in

children of drug addicts. Pediatrics 75:269-274, 1985.

Los Angeles County. County Counsel Opinion, July 16, 1982. Los

Angeles: Office of the County Counsel.

Lubchenco, L.O.; Hansman, C.; and Boyd. E. Intrauterine growth in

length and head circumference as estimated from live births at

gestational ages from 26 to 42 weeks. Pediatrics 37:404-408,

1966.

Parmelee, A.H. Remarks on receiving the C. Anderson Aldrich

Award. Pediatrics 59:389-395, 1977.

Rubenstein, J.L.; Schneider, R.; and Ullman, E. Homogenous enzyme

immunoassay. Biochem Biophys Res Commun 47:846, 1972.

Strauss, A.A.; Modanlou, H.D.; and Bosu, S.K. Neonatal manifestations of maternal phencyclidine (PCP) abuse. Pediatrics 68:550-

552, 1981.

Tenor, S.R. Permanent alterations in 5-hydroxytryptamine metabolism in discrete areas of rat brain following exposure to drugs

during the period of development. Life Sci 15:245-249, 1974.

Tonge, S.R. Neurochemical teratology 5-hydroxyindole concentrations in discrete areas of rat brain after the pre- and neonatal

administration of phencyclidine and imipramine. Life Sci

12:481-486, 1973.

Wilson, G.S.; Desmond, M.M.; and Verniaud, W.M. Early development

of infants of heroin-addicted mothers. J Dis Child 126:457-462,

1973.

Wilson, G.S.; McCreary, R.; Kean, J.; and Baxter, J.C. The development of preschool children of heroin-addicted mothers: A

controlled study. Pediatrics 63:135-141, 1979.

AUTHORS

Judith Howard, M.D.

Associate Professor

Vickie Kropenske, PHN

Rachelle Tyler, M.D.

Department of Pediatrics

UCLA Intervention Program

UCLA Medical Center

Los Angeles, CA

251
Clinical Observations in the

Treatment of Adolescent and

Young Adult PCP Abusers

David H. Fram and Nancy Stone

INTRODUCTION

Over the past 20 to 25 years, drug abuse has become a major public

health issue in this country. An "epidemic" of abuse commenced in

the sixties that had not been seen before (Wilford 1981). Drug

abuse has, however, always been pandemic. People have always

sought out psychoactive substances for their euphoriant properties. Individuals impaired by the excessive use of such substances have always been a concern. Our society has taken both

therapeutic and law enforcement approaches to dealing with the

problems of drug abuse. Our country's unsuccessful experiment

with Prohibition in the twenties and early thirties demonstrated

the difficulties of legislatively attempting to change culturally

accepted ways of handling psychoactive substances. More recently,

the disregard for laws regulating the use of marijuana and other

substances have demonstrated the continuing difficulty of legislating contraculturally.

The concern over most substances of abuse arises from the effect

of the drug use on the individual's health or social functioning.

Negative attitudes toward the use of substances may be founded

upon a desire to limit the damage done to individuals, or to limit

the burden on society of supporting chronically intoxicated individuals, who have diminished ability to care for themselves.

Antisocial activities engaged in during illegal procurement of

drugs, or behavior resulting from impaired judgment while intoxicated may present a hazard to persons other than the drug abuser.

The illegal distribution system for drugs provides, of course, a

significant danger to the community from both individual and organized illegal activities that such a system fosters. It is

generally accepted that the primary impetus for antisocial activity is the procurement of drugs, rather than the effect of drugs.

The problem of phencyclidine (PCP) abuse has an added dimension.

In addition to the antisocial activities involved in procurement,

PCP has effects on the user that may evoke dangerous, bizarre, or

252
deviant behavior. These effects may be considered undesirable by

the user, or may be sought after. Our understanding of this drug

needs to take into account not only the PCP user's desire for euphoria, but also the user's acceptance of, often seeking of, the

behavioral effects.

The work of the Psychiatric Institute of Washington and the

Metropolitan Psychiatric Group provides considerable opportunity

for clinical observations of PCP users. Much of the author's

professional time and nearly all of mine is spent evaluating and

treating disturbed individuals with severe drug dependence problems, or supervising the work of our staff members, who collaborate with us. Our programs and practices treat about 150

patients, of whom approximately 20 are PCP abusers. There are

about 500 admissions per year including approximately 75 who use

PCP. Psychiatric Institute of Washington is a private psychiatric

hospital in Washington, D.C., which has clinical services for both

adolescent and adult substance abusers. Metropolitan Psychiatric

Group is the group practice that conducts much of the treatment at

Psychiatric Institute. While the Psychiatric Institute has maintained drug treatment services for more than 10 years (Capodonno

et al. 1984), recently it became necessary to organize a special

admissions service to treat PCP users, because of the particular

difficulties in engaging these patients in treatment.

PCP has been a drug of abuse in Washington, D.C. for the entire 15

years that this author have been working with drug abusers. Until

the past few years, it tended to be used either unknowingly, as an

adulterant of other drugs, or as one of many drugs used by polydrug users. A few disturbed young people may have used it as the

drug of preference to enhance their disturbances. It was, initially, a drug primarily used by young, white, middle-class users.

Recently there has been a marked change in the patterns of its use

in the District of Columbia. PCP has become the drug of choice

for many users. Its use has become more widespread, and it is now

used in the black community, where it had not been seen much

before.

CLINICAL OBSERVATIONS--YOUNG ADULTS

When asked why they use PCP, young people frequently answer, "to

get high." Drug users want "to get high" for the easily obtainable pleasure that is, for the young, worth the adverse effects

and other costs. Young people also use drugs to be part of the

group. The term "peer pressure" is often used to describe this

phenomenon. I think that "peer example" or "following the crowd"

describes the phenomenon better. I have rarely heard of anyone

being forced or pressured to use drugs. Rather, being a member of

the drug culture is highly valued, and the use of drugs, including

PCP, comes as a result.

We need to understand better why being a member of the drug

culture became so highly valued. Until the sixties, drug abuse

253
was mostly the domain of the "inner city" and the criminal subculture. At that time, however, a major social change commenced,

in which the recreational use of illicit substances, especially

marijuana and cocaine, eventually became a part of the dominant

culture. In addition, we saw the development of the subculture of

heavy drug users, made up of individuals often exhibiting markedly

deviant behavior. Both of these developments had their roots in

the disaffection of the sixties, with its widespread rejection of

traditional "establishment" values by youth, often focused around

a rejection of our country's involvement in the Vietnam War.

I think that it is important to attempt to understand these sociocultural aspects of drug abuse. Perhaps we can then better understand why a drug like PCP, after being around for a time, suddenly

becomes fashionable. Perhaps also, as we understand these phenomena of social change better, we can develop more effective means

of primary prevention, and perhaps foster social change that might

discourage the use of such drugs.

Another important problem is why some drug users prefer PCP, while

others avoid it. The answers are probably found in biological and

psychological variations in individuals, and also in the constituents of different mixtures of PCP available on the street. I have

found it instructive to discuss this point with drug abusers who

avoid PCP. Some have never used it because of the horror stories

they have heard. I have worked with several dozen young drug

abusers who tried PCP and did not like it. Some reported experiencing paranoia, frightening hallucinations, or dysphoria, which

they did not want to repeat. Others described an intense loss of

control, far in excess of what they could tolerate. They felt

that they would be dominated by the use of PCP, if they continued

to use it.

Other drug abusers, however, who continued to use PCP, described

experiences that they intentionally sought. For many, the experience appears to be a relatively mild one, in which the user has a

pleasant intoxication that lasts several hours and then wears off.

Such users, although often aware of the bizarre or violenceproducing experiences of others, have never experienced such episodes themselves. Some report having used PCP repeatedly, for

many years, without experiencing any effects other than a simple

high. Clinical observation of these people, furthermore, does not

demonstrate deterioration of intellectual functioning or obvious

personality change. For these users, PCP offers an inexpensive,

pleasant high. It is often the discovery of their use of substances by someone else, such as an employer in the case of an

adult, or a parent in the case of an adolescent, that brings such

individuals into treatment.

Another group of users appears to seek the bizarreness and lack of

control that PCP offers. These individuals, who are likely to

manifest much psychopathology apart from the drug abuse, are often

threatening and violent. They perceive the actions of others as

254
being threatening, and deny the significance of their own actions.

Two cases are instructive. Both were PCP users in late adolescence who came for treatment after getting in trouble with the

law. One had wrecked his truck after hearing PCP-induced voices

commanding him to do so. He spoke of how much he loved to be violent and hurt others. He did have some inhibitions about expressing violence, so found PCP the optimal drug for "putting him in

the mood" to be violent.

The second patient, a 19-year-old, was, upon entering my office,

immediately suspicious, irritable, irrational, and showed characteristic decreased psychomotor activity and intense staring

expression. As the person who does most of the outpatient intake

evaluations for the adult drug program, I have become very wary of

new patients who enter with characteristics of PCP use. When the

patient casually mentioned, early in the interview, that he had

just been released from jail on a charge of assaulting a police

officer, I wondered to myself if he had a weapon in the umbrella

he was carrying--on a warm, sunny day. He became agitated and

threatening in the course of the interview, and eventually had to

be escorted from my office by the police. The following morning

he called, apologetic, but not comprehending why I and my staff

responded to him the way we had. He remembered everything, but

lacked an appreciation of the emotional impact of his actions.

Later the same day, intoxicated again, he called to scream threats

and profanity over the phone.

Both of these young men appeared to use PCP to enhance a desired

loss of control. PCP-induced loss of control also raises forensic

considerations. A few years ago, I received a call from a lawyer

defending a young man accused of assault during a robbery. At

issue was the question of possible diminished criminal responsibility, as the defendant acknowledged using PCP before the alleged

incident. He had been noted to be more brutal in his treatment of

the victims of the assault than his nonintoxicated cohorts. The

lawyer was trying to build an insanity defense. I declined to

become involved in the case, as I believe that individuals should

be held responsible for actions committed while intoxicated. I

have been pleased to note the legal trend away from considering

the altered states of mind induced by drugs as grounds for diminished criminal responsibility for acts committed while in a druginduced condition.

Another important area for consideration is that of the addictionand dependence-producing potential of PCP. Our observations are

that PCP does not produce classical physical addiction in the

sense of the development of tolerance and withdrawal symptoms. It

does, however, produce drug craving, although to a lesser degree

than does heroin. Users apparently develop a compulsion to repeat

the PCP experience, but do not seem to organize their lives around

drug-seeking behavior as do heroin users.

255
CLINICAL OBSERVATIONS--ADOLESCENTS

Some of the same factors that apply to all adolescents with chemical abuse dependency problems contribute to the use of PCP. A

principal developmental task of adolescence is that of separating

from parents and consolidating one's identity as a separate person, who will be able to cope with independence. Adolescents will

often engage in activities of which parents disapprove, to assert

their independence and protect themselves from a felt need to return to emotional dependency. Furthermore, adolescents rely on

peers, who may also be using street drugs, for information about

the world as well as for support for their self-esteem. The capacity for denial and for risk-taking, and the need for excitement,

all make experimentation with illicit drugs attractive to adolescents. Adolescents have a remarkable capacity for denial. The

argument often goes that "drugs won't hurt me," "I know lots of

people that use drugs all the time and make good grades, play on

the football team," and so forth. Adolescent drug users will frequently maintain that the real problem is that adults are trying

to scare them, that parents are gullible and believe everything

they hear about drugs. Thus, the early adolescent's egocentric

and immature sense of the world, the initial pleasurable effects

of drug use, and the possible biological vulnerability to chemical

dependence implement the use of street drugs as an attempt to

solve some of the problems of adolescence. Biological vulnerability to chemical dependence, which may account for the progression

in some adolescents from experimentation to dependence, is an area

for further research.

A personality type that leads to a preference for PCP as the drug

of choice has not been identified. Experience has shown that disturbed adolescents for whom PCP is a drug of choice have histories

indicating significant depression, feelings of hopelessness, powerlessness, and dysphoria, prior to the use of PCP. The feelings

of power and invulnerability obtained from PCP use seem to be

sought by some, while others appear to seek the feeling of "numbness" that this drug provides. Many adolescents with PCP psychosis who have been admitted to Psychiatric Institute have characteristics like those described in PCP users admitted to

psychiatric facilities elsewhere (DeAngelis and Goldstein 1978).

They exhibit minimal coping skills, including lack of employable

skills, limited academic skills, and minimal meaningful interpersonal relationships. Depression, and a sense of alienation and

hopelessness about themselves and the future are also observed.

This profile, however, does not distinguish PCP-using adolescents

from many other adolescents seen, who do not use PCP. As yet,

there is no satisfactory explanation for why some adolescents with

this profile abuse PCP and others do not.

TREATMENT CONSIDERATIONS

The literature regarding treatment of PCP users is not encouraging

(Graeven and Sharp 1981; Russ and Wang 1979). Our experience has

256
been similar to others in that the percentage of patients who remain only for detoxification, then leave the hospital against medical advice, is discouragingly high. This pattern is particularly

seen in patients over 17, who are legally adults and make their

own decisions about treatment.

Treatment of the Intoxicated Patient

An initial evaluation of the intoxicated patient is needed to determine the level of care indicated. Some patients, although

frequent users, may have sufficient ego strength, behavioral control, and capacity to form a treatment alliance to commence treatment in an outpatient setting. Their repeated PCP intoxications

may continue for a time, but the intoxication picture is

sufficiently benign to allow an outpatient program to be conducted

safely, and with a reasonable chance of success.

Other patients require hospitalization. Some present with a psychotic picture: paranoia, irritability, agitation, and a tendency

to violent behavior. The diagnosis of this condition is often not

too difficult to make. Patients tend to readily acknowledge their

use of PCP. Moreover, the irritable, easily angered, suspiciously

staring, rigid person with impaired reasoning is not hard to spot.

Urine testing for drugs can be done to verify the diagnosis when

there is doubt.

Psychoses, when they occur, appear to be due to drug effect interacting with a vulnerable personality organization (Luisada 1978).

Our experience has been that some adolescents with borderline

personality disorders, as well as adolescents at risk of schizophrenic decompensation, may have this vulnerability. Although we

do not have hard data to support the hypothesis that patients with

PCP psychoses that are most resistant to treatment have the poorest long-term prognosis (Erard et al. 1980), our observations have

been that persistence of symptoms of psychosis after the first 2

to 3 weeks of treatment often correlates with extended periods of

impairment.

When hospital treatment is indicated, we have found that a closed,

highly structured, intensely staffed setting is required. Until

recently, when we started getting greater numbers of referrals of

PCP abusers, we treated those who came on our general drug-dependence services. The PCP abusers were very difficult to manage,

resistant to treatment, and frequently left treatment early. We

established, on our locked intensive care unit, a separate admissions service with therapy sessions and educational sessions

focused on PCP problems. Following this 2-week program of evaluation and acute treatment, the patient is then sent to continuing

treatment, either in a residential/hospital setting for general

drug patients or to our outpatient PCP-specialized program.

Pharmacotherapy for PCP-intoxicated patients is delayed. For the

first 48 hours of admission we avoid all psychotropic medication,

257
if possible, and try to manage the patient by placing him in a

quiet, secure environment with a few people to relate to. After

this period, we encourage the patient to take haloperidol in order

to ameliorate the psychotic process as much as possible.

Although it has not been proven that acidification of the urine to

increase PCP excretion alters the duration of the symptoms of psychosis, it appears appropriate to facilitate excretion of PCP from

the adipose tissue in which it is stored in any PCP user (Done

1980). Maintaining the urine pH at an acid level for several

weeks, even though the mental status is normal, is advised. It is

important to test the pH of the urine to ensure compliance with

the acidification. We have found that PCP becomes detectable in

acidified urine for a time, even after being undetectable in alkaline urine, in previously intoxicated individuals. We have not

found a change in mental status to result from such acidification

treatment and resultant enhanced PCP excretion.

Finding ways to enhance the treatment alliance and decrease denial

are major tasks of the hospital phase of treatment. One method

used to engage the patient is to engage the family actively.

Staff spend a lot of their time talking with families, educating

them, increasing their understanding of what has happened to their

ill family members, and also helping the family to change habitual

ways of relating to the patient, patterns that have facilitated or

"enabled" rather than discouraged drug use. Often a change in

family interaction can make the difference in success or failure

of treatment. For example, families are often very tolerant of

deviation or irresponsible behavior. Members will continue to

support or cover for their family members, fearing that patients

will be hurt if held accountable for their actions. In fact, the

family members' tolerance has often reinforced the deviant

behavior. The family sessions help the family members understand

this and also provide support for behavioral change.

Narcotics Anonymous (NA)

Another important focus in developing a workable treatment plan

for these patients is promoting their involvement with Narcotics

Anonymous, or NA. The phenomenal growth of NA in the Washington,

D.C. area over the past 2 to 3 years may be the most hopeful thing

that has happened with regard to the drug problem in recent years.

Good hospital programs, good detoxification techniques, talented

therapists and counselors are weak forces, compared to the pressures that reinforce drug use in the outside community. In our

experience, Alcoholics Anonymous has been useful in the past for

only a limited number of drug abusers, as many drug-dependent

individuals do not identify sufficiently with the dominant alcoholic group, therefore do not remain involved in Alcoholics

Anonymous. Narcotics Anonymous is an organization of people who

have experienced the drug-use lifestyle, rejected that lifestyle,

and are developing another. NA provides a drug-free model for the

recovering person, a social milieu, and a value system that

258
promotes continued abstinence. NA members state their beliefs

loudly and publicly, and provide needed support for each other,

especially at times of weakness. Membership in and identification

with NA provides, for many, the counterforce needed to withstand

the lure of the drug-abusing peer group. Consequently, a major

thrust in the PCP admissions service, as well as the other components of the drug-dependence services, is to acquaint the patient

with NA and persuade him of the importance of membership and

participation.

Aftercare Treatment

The outpatient aftercare phase of the program is where the difficult long-term changes in the individual's relation to drugs take

place. Changes commenced in the protective inpatient environment

are tested in the outside environment. We recommend that our patients attend a group therapy program for recovering PCP abusers,

which meets twice weekly and includes regular monitored urine

testing and family involvement. We recommend this program be

attended for no less than 6 months. We further recommend daily

attendance at NA initially, and continued involvement with NA

indefinitely.

Even with the intense involvement of the inpatient program and a

carefully devised treatment plan, many drop out of outpatient

treatment and return to drug use. Nevertheless, we have found

various psychotherapeutic strategies and methods worthwhile.

An educational, behavior modification approach should be taken

with the patient. Education about chemical dependency is most

important. Expected behavioral changes must be clearly conceived

and communicated to the patient. Evaluation of vocational status

and skill development require attention.

The patient can be taught to recognize the impulsiveness and sense

of powerlessness that leads to the return of use of this drug.

The patient can be introduced to alternatives to a chemicallyinduced sense of invulnerability, and encouraged to practice these

alternatives.

The treatment staff must be aware of countertransference issues,

and anticipate relapses and failures. For both patient and staff,

it helps to define and accept limited goals. Appropriate security

measures are necessary, so that staff can feel safe; also, staff

need to be educated about not taking unnecessary risks in handling

these patients. Staff frustration has to be recognized and

managed.

CONCLUSION

Treating the PCP abuser remains a dangerous and frustrating

business. To date, our therapeutic measures have less effect than

they do with abusers of other drugs. Part of the solution to the

259
problem of PCP abuse may be an understanding of why drug abuse has

become acceptable in our society. It may then be possible to

devise appropriate primary prevention measures, so that the abuse

of other drugs will not develop as has that of PCP.

REFERENCES

Capodonno, A.E.; Fram, D.H.; Holden, R.; and Targum, S.D. The

outpatient treatment of heroin addicts with methadone: A twoto five-year follow-up study. The Psychiatr Hosp 15:25-30,

1984.

DeAngelis, G.C., and Goldstein. E. Treatment of adolescent phencyclidine (PCP) abusers.

1978.

Am J Drug Alcohol Abuse 5:339-414,

Done, A.K.; Aronow, R.; and Miceli, J.N. Pharmokinetic bases for

the diagnosis and treatment of acute PCP intoxication. J

Psychedelic Drugs 12:253-258, 1980.

Erard, R.; Luisada, P.V.; and Peele, R. The PCP psychosis:

Prolonged intoxication or drug-precipitated functional illness?

J Psychedelic Drugs 12:235-251, 1980.

Graeven, D.B., and Sharp, J.G. Initiation, motivation, and cessation of phencyclidine use. J Psychol 108:43-57, 1981.

Luisada, P.V. The phencyclidine psychosis: Phenomenology and

treatment. In: Peterson, R.C., and Stillman, R.C., eds.

Phencyclidine Abuse: An Appraisal. National Institute on Drug

Abuse Research Monograph 21. DHEW Pub. No. 78-728. Washington,

D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1978. pp.

241-253.

Russ, C., and Wong, D. Diagnosis and treatment of the phencyclidine psychosis: Clinical observations. J Psychedelic Drugs

11:277-282, 1979.

Wilford, B.B. Drug Abuse. Chicago: American Medical

Association, 1981. pp. 3-19.

AUTHORS

David H. Fram, M.D.

Program Director, Adult Drug Dependence Services

Psychiatric Institute of Washington

Chairman, Metropolitan Psychiatric Group

2020 K Street, N.W.

Washington, DC 20006

Nancy Stone, M.D.

Attending Psychiatrist, The Gateway Program

Psychiatric Institute of Washington

Member, Metropolitan Psychiatric Group

4460 MacArthur Blvd., N.W.

Washington, DC 20037

260
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6 EFFECTS OF LABELING THE "DRUG ABUSER": AN INQUIRY. Jay R.

Williams, Ph.D. NCDAI out of stock

GPO out of stock NTIS PB #249 092/AS $11.95

7 CANNABINOID ASSAYS IN HUMANS. Robert Willette, Ph.D., ed.

GPO out of stock NCDAI out of stock

NTIS PB #251 905/AS $18.95

8 Rx: 3x/WEEK LAAM - ALTERNATIVE TO METHADONE. Jack Blaine, M.D.,

and Pierre Renault, M.D., eds. NCDAI out of stock

Not available from GPO NTIS PB #253 763/AS $18.95

9 NARCOTIC ANTAGONISTS: NALTREXONE PROGRESS REPORT. Demetrios

Julius, M.D., and Pierre Renault, M.D., eds.

GPO out of stock NCDAI out of stock

NTIS PB #255 833/AS $18.95

10 EPIDEMIOLOGY OF DRUG ABUSE: CURRENT ISSUES. Louise G. Richards,

Ph.D., and Louise B. Blevens, eds. NCDAI out of stock

GPO out of stock NTIS PB #266 691/AS $24.95

11 DRUGS AND DRIVING. Robert Willette, Ph.D., ed.

NCDAI out of stock

GPO Stock #017-024-00576-2 $5.50 NTIS PB #269 602/AS $18.95

12 PSYCHODYNAMICS OF DRUG DEPENDENCE. Jack D. Blaine, M.D., and

Demetrios A. Julius, M.D., eds. NCDAI out of stock

GPO out of stock NTIS PB #276 084/AS $18.95

13 COCAINE: 1977. Robert C. Petersen, Ph.D., and Richard C.

Stillman, M.D., eds. NCDAI out of stock

GPO Stock #017-024-00592-4 $6 NTIS PB #269 175/AS $24.95

14 MARIHUANA RESEARCH FINDINGS: 1976. Robert C. Petersen, Ph.D.,

ed. NCDAI out of stock

GPO out of stock NTIS PB #271 279/AS $24.95

15 REVIEW OF INHALANTS: EUPHORIA TO DYSFUNCTION. Charles Wm. Sharp,

Ph.D., and Mary Lee Brehm, Ph.D., eds. NCDAI out of stock

GPO out of stock NTIS PB #275 798/AS $30.95

16 THE EPIDEMIOLOGY OF HEROIN AND OTHER NARCOTICS. Joan Dunne

Rittenhouse, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #276 357/AS $24.95

17 RESEARCH ON SMOKING BEHAVIOR. Murray E. Jarvik, M.D., Ph.D., et

al., eds. NCDAI out of stock

GPO out of stock NTIS PB #276 353/AS $30.95

262
18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS.

Norman A. Krasnegor, Ph.D , ed. NCDAI out of stock

GPO out of stock NTIS PB #276 337/AS $18.95

19 THE INTERNATIONAL CHALLENGE OF DRUG ABUSE. Robert C. Petersen,

Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #293 807/AS $30.95

20 SELF-ADMINISTRATION OF ABUSED SUBSTANCES: METHODS FOR STUDY.

Norman A. Krasnegor, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #288 471/AS $24.95

21 PHENCYCLIDINE (PCP) ABUSE: AN APPRAISAL. Robert C. Petersen,

Ph.D., and Richard C. Stillman, M.D., eds. NCDAI out of stock

GPO Stock #017-024-00785-4 $7 NTIS PB #288 472/AS $30.95

22 QUASAR: QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS OF

ANALGESICS, NARCOTIC ANTAGONISTS, AND HALLUCINOGENS. Gene Barnett,

Ph.D.; Milan Trsic, Ph.D .; and Robert Willette, Ph.D.; eds.

GPO out of stock NCDAI out of stock

NTIS PB #292 265/AS $36.95

23 CIGARETTE SMOKING AS A DEPENDENCE PROCESS. Norman A. Krasnegor,

Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-00895-8 $6 NTIS PB #297 721/AS $24.95

24 SYNTHETIC ESTIMATES FOR SMALL AREAS: STATISTICAL WORKSHOP PAPERS

AND DISCUSSION. Jos. Steinberg, ed. NCDAI out of stock

GPO out of stock NTIS PB #299 009/AS $24.95

25 BEHAVIORAL ANALYSIS AND TREATMENT OF SUBSTANCE ABUSE. Norman A.

Krasnegor, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #80-112428 $24.95

26 THE BEHAVIORAL ASPECTS OF SMOKING. Norman A. Krasnegor, Ph.D.,

ed. (Reprint from 1979 Surgeon General's Report on Smoking and

Health.)

GPO out of stock NTIS PB #80-118755 $18.95

27 PROBLEMS OF DRUG DEPENDENCE, 1979: PROCEEDINGS OF THE 41ST

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. L.S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-00981-4 $9 NTIS PB #80-175482 $42.95

28 NARCOTIC ANTAGONISTS: NALTREXONE PHARMACOCHEMISTRY AND

SUSTAINED-RELEASE PREPARATIONS. Robert Willette. Ph.D., and

Gene Barnett, Ph.D., eds. NCDAI out of stock

GPO out of stock NTIS PB #81-238875 $24.95

29 DRUG ABUSE DEATHS IN NINE CITIES: A SURVEY REPORT. Louis A.

Gottschalk, M.D., et al. NCDAI out of stock

GPO out of stock NTIS PB #80-178882 $18.95

263
30 THEORIES ON DRUG ABUSE: SELECTED CONTEMPORARY PERSPECTIVES. Dan

J. Lettieri, Ph.D.; Mollie Sayers; and Helen W. Pearson, eds.

NCDAI out of stock

GPO Stock #017-024-00997-1 $10 Not available from NTIS

31 MARIJUANA RESEARCH FINDINGS: 1980. Robert C. Petersen, Ph.D.,

ed.

GPO out of stock NTIS PB #80-215171 $24.95

32 GC/MS ASSAYS FOR ABUSED DRUGS IN BODY FLUIDS. Rodger L. Foltz,

Ph.D.; Allison F. Fentiman, Jr., Ph.D.; and Ruth B. Foltz.

GPO out of stock NTIS PB #81-133746 $24.95

33 BENZODIAZEPINES: A REVIEW OF RESEARCH RESULTS, 1980: Stephen I.

Szara, M.D., D.Sc., and Jacqueline P. Ludford, M.S., eds.

GPO Stock #017-024-01108-8 $5 NTIS PB #82-139106 $18.95

34 PROBLEMS OF DRUG DEPENDENCE, 1980: PROCEEDINGS OF THE 42ND

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01061-8 $8 NTIS PB #81-194847 $36.95

35 DEMOGRAPHIC TRENDS AND DRUG ABUSE, 1980-1995. Louise G.

Richards, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #82-103417 $18.95

36 NEW APPROACHES TO TREATMENT OF CHRONIC PAIN: A REVIEW OF

MULTIDISCIPLINARY PAIN CLINICS AND PAIN CENTERS. Lorenz K.Y.

Ng, M.D., ed.

GPO out of stock NTIS PB #81-240913 $24.95

37 BEHAVIORAL PHARMACOLOGY OF HUMAN DRUG DEPENDENCE. Travis

Thompson, Ph.D., and Chris E. Johanson, Ph.D., eds.

NCDAI out of stock

GPO Stock #017-024-01109-6 $7 NTIS PB #82-136961 $30.95

38 DRUG ABUSE AND THE AMERICAN ADOLESCENT. Dan J. Lettieri, Ph.D.,

and Jacqueline P. Ludford, M.S., eds. A RAUS Review Report.

GPO Stock #017-024-01107-O $4.50 NCDAI out of stock

NTIS PB #82-148198 $18.95

39 YOUNG MEN AND DRUGS IN MANHATTAN: A CAUSAL ANALYSIS.

Richard R. Clayton, Ph.D., and Harwin L. Voss, Ph.D.

GPO Stock #017-024-01097-9 $5.50 NCDAI out of stock

NTIS PB #82-147372 $24.95

40 ADOLESCENT MARIJUANA ABUSERS AND THEIR FAMILIES. Herbert

Hendin, M.D., Ann Pollinger, Ph.D., Richard Ulman, Ph.D., and

Arthur Carr, Ph.D. NCDAI out of stock

GPO out of stock NTIS PB #82-133117 $18.95

41 PROBLEMS OF DRUG DEPENDENCE, 1981: PROCEEDINGS OF THE 43RD

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

Not available from GPO NTIS PB #82-190760 $42.95

264
42 THE ANALYSIS OF CANNABINOIDS IN BIOLOGICAL FLUIDS. Richard L.

Hawks, Ph.D., ed.

GPO Stock #017-024-01151-7 $5 NTIS PB #83-136044 $18.95

43 PROBLEMS OF DRUG DEPENDENCE, 1982: PROCEEDINGS OF THE 44TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #83-252-692/AS $42.95

44 MARIJUANA EFFECTS ON THE ENDOCRINE AND REPRODUCTIVE SYSTEMS.

Monique C. Braude, Ph.D., and Jacqueline P. Ludford, M.S., eds. A

RAUS Review Report. NCDAI out of stock

GPO Stock #017-024-01202-5 $4 NTIS PB #85-150563/AS $18.95

45 CONTEMPORARY RESEARCH IN PAIN AND ANALGESIA, 1983. Roger M.

Brown, Ph.D.; Theodore M. Pinkert, M.D., J.D.; and Jacqueline P.

Ludford, M.S., eds. A RAUS Review Report. NCDAI out of stock

GPO Stock #017-024-01191-6 $2.75 NTIS PB #84-184670/AS $13.95

46 BEHAVIORAL INTERVENTION TECHNIQUES IN DRUG ABUSE TREATMENT. John

Grabowski, Ph.D .; Maxine L. Stitzer, Ph.D., and Jack E.

Henningfield, Ph.D., eds.

GPO Stock #017-024-01192-4 $4.25 NTIS PB #84-184688/AS $18.95

47 PREVENTING ADOLESCENT DRUG ABUSE: INTERVENTION STRATEGIES.

Thomas J. Glynn, Ph.D .; Carl G. Leukefeld, D.S.W.; and

Jacqueline P. Ludford, M.S., eds. A RAUS Review Report.

GPO Stock #017-024-01180-1 $5.50 NTIS PB #85-159663/AS $24.95

48 MEASUREMENT IN THE ANALYSIS AND TREATMENT OF SMOKING BEHAVIOR.

John Grabowski. Ph.D., and Catherine S. Bell, M.S., eds.

GPO Stock #017-024-01181-9 $4.50 NCDAI out of stock

NTIS PB 84-145-184 $18.95

49 PROBLEMS OF DRUG DEPENDENCE, 1983: PROCEEDINGS OF THE 45TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01198-3 $12 NTIS PB 85-151553/AS $36.95

50 COCAINE: PHARMACOLOGY, EFFECTS, AND TREATMENT OF ABUSE. John

Grabowski, Ph.D., ed.

GPO Stock #017-024-01214-9 $4.50 NTIS PB 85-150381/AS $18.95

51 DRUG ABUSE TREATMENT EVALUATION: STRATEGIES, PROGRESS, AND

PROSPECTS. Frank M. Tims, Ph.D., ed.

GPO Stock #017-024-01218-1 $4.50 NTIS PB 85-150365/AS $18.95

52 TESTING DRUGS FOR PHYSICAL DEPENDENCE POTENTIAL AND ABUSE

LIABILITY. Joseph V. Brady, Ph.D., and Scott E. Lukas, Ph.D., eds.

GPO Stock #017-024-0204-1 $4.25 NTIS PB 85-150373/AS $18.95

53 PHARMACOLOGICAL ADJUNCTS IN SMOKING CESSATION. John Grabowski,

Ph.D., and Sharon M. Hall, Ph.D., eds.

GPO Stock #017-024-01266-1 $3.50 NCDAI out of stock

265
54 MECHANISMS OF TOLERANCE AND DEPENDENCE. Charles Wm. Sharp,

Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01213-1 $8.50

55 PROBLEMS OF DRUG DEPENDENCE, 1984. PROCEEDINGS OF THE 46TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01242-4 $9.50

56 ETIOLOGY OF DRUG ABUSE: IMPLICAlIONS FOR PREVENTION. Coryl LaRue

Jones, Ph.D., and Robert J. Battjes, D.S.W., eds.

GPO Stock #017-024-01250-5 $6.50

57 SELF-REPORT METHODS OF ESTIMATING DRUG USE: MEETING CURRENT

CHALLENGES TO VALIDITY. Beatrice A. Rouse, Ph.D., Nicholas J.

Kozel, M.S., and Louise G. Richards, Ph.D., eds.

GPO Stock #017-024-01246-7 $4.25 NCDAI out of stock

58 PROGRESS IN THE DEVELOPMENT OF COST-EFFECTIVE TREATMENT FOR DRUG

ABUSERS. Rebecca S. Ashery, D.S.W., ed.

GPO Stock #017-024-01247-5 $4.25 NCDAI out of stock

59 CURRENT RESEARCH ON THE CONSEQUENCES OF MATERNAL DRUG ABUSE.

Theodore M. Pinkert, M.D., J.D., ed.

GPO Stock #017-024-01249-1 $2.50

60 PRENATAL DRUG EXPOSURE: KINETICS AND DYNAMICS. C. Nora Chiang,

Ph.D., and Charles C. Lee, Ph.D., eds.

GPO Stock #017-024-01257-2 $3.50

61 COCAINE USE IN AMERICA: EPIDEMIOLOGIC AND CLINICAL PERSPECTIVES.

Nicholas J. Kozel, M.S., and Edgar H. Adams, M.S., eds.

GPO Stock #017-024-01258-1 $5

62 NEUROSCIENCE METHODS IN DRUG ABUSE RESEARCH. Roger M. Brown,

Ph.D., and David P. Friedman, Ph.D., eds.

GPO Stock #017-024-01260-2 $3.50

63 PREVENTION RESEARCH: DETERRING DRUG ABUSE AMONG CHILDREN AND

ADOLESCENTS. Catherine S. Bell, M.S., and Robert Battjes,

D.S.W., eds.

GPO Stock #017:024-01263-7 $5.50

64 PHENCYCLIDINE: AN UPDATE. Doris H. Clouet, Ph.D., ed.

GPO Stock #013-024-01281-5 $6.50

65 WOMEN AND DRUGS: A NEW ERA FOR RESEARCH. Barbara A. Ray, Ph.D.,

and Monique C. Braude, Ph.D., eds.

GPO Stock #017-024-01283-1 $3.25

266
66 GENETIC AND BIOLOGICAL MARKERS IN DRUG ABUSE AND ALCOHOLISM.

Monique C. Braude, Ph.D., and Helen M. Chao, Ph.D. eds.

GPO Stock #017-024-01291-2 $3.50 NCDAI out of stock

67 PROBLEMS OF DRUG DEPENDENCE, 1985. PROCEEDINGS OF THE 47TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01292-1 $18

68 STRATEGIES FOR RESEARCH ON THE INTERACTIONS OF DRUGS OF ABUSE.

Monique C. Braude, Ph.D., and Harold M. Ginzburg, M.D., J.D ,M.P.H.,

eds.

GPO Stock #017-024-01296-3 $6.50 NCDAI out of stock

69 OPIOID PEPTIDES: MEDICINAL CHEMISTRY. Rao S. Rapaka, Ph.D.;

Gene Barnett, Ph.D .; and Richard L. Hawks, Ph.D., eds.

GPO Stock #017-024-1297-1 $11

70 OPIOID PEPTIDES: MOLECULAR PHARMACOLOGY, BIOSYNTHESIS, AND

ANALYSIS. Rao S. Rapaka, Ph.D., and Richard L. Hawks, Ph.D., eds.

GPO Stock #017-024-1298-0 $12

71 OPIATE RECEPTOR SUBTYPES AND BRAIN FUNCTION. Roger M. Brown,

Ph.D.; Doris H. Clouet, Ph.D .; and David P. Friedman, Ph.D., eds.

GPO Stock #017-024-01303-0 $6

72 RELAPSE AND RECOVERY IN DRUG ABUSE. Frank M. Tims, Ph.D., and

Carl G. Leukefeld, D.S.W., eds.

GPO Stock #017-024-01302-1 $6

73 URINE TESTING FOR DRUGS OF ABUSE. Richard L. Hawks, Ph.D., and

C. Nora Chiang, Ph.D., eds.

GPO Stock #017-024-1313-7 $3.75

74 NEUROBIOLOGY OF BEHAVIORAL CONTROL IN DRUG ABUSE. Stephen I.

Szara, M.D., D.Sc., ed.

GPO Stock #017-024-1314-5 $3.75

75 PROGRESS IN OPIOID RESEARCH. PROCEEDINGS OF THE 1986 INTERNATIONAL NARCOTICS RESEARCH CONFERENCE. John W. Holaday, Ph.D.;

Ping-Yee Law, Ph.D .; and Albert Herz, M.D., eds.

GPO Stock #017-024-01315-3 $21

76 PROBLEMS OF DRUG DEPENDENCE, 1986. PROCEEDINGS OF THE 48TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-1316-1 $16

IN PRESS

77 ADOLESCENT DRUG ABUSE: ANALYSES OF TREATMENT RESEARCH.

Elizabeth R. Rahdert, Ph.D. and John Grabowski, Ph.D., eds.

267

U.S. GOVERNMENT PRINTING OFFICE : 1987 0 - 185-466
DHHS Publication No. (ADM)87-1443

Alcohol, Drug Abuse, and Mental Health Administration

Printed 1986 Reprinted 1987