US DEPARTMENT OF HEALTH EDUCATION AND WELFARE • Public Health Service • Alcohol Drug Abuse and Mental Health Administration
Behavioral Tolerance: Research

and Treatment Implications

Editor:

Norman A. Krasnegor, Ph.D.

NIDA Research Monograph 18

January 1978

DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National lnstitute on Drug Abuse

Division of Research

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RockviIle. Maryland 20657

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

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The NIDA Research Monogroph series iS prepared by the Division of Research of

the National Institute on Drug Abuse Its primary objective is to provide critical reviews of research problem areas and techniques. the content of state-of-the-art

conferences, integrative research reviews and significant original research its

dual publication emphasis iS rapid and targeted dissemination to the scientific

and professional community

Editorial Advisory Board

Avram Goldstein, M.D

Addiction Research Foundation

Polo Alto California

Jerome Jaffe, M.D

College Of Physicians and Surgeons

Columbia University New York

Reese T Jones, M.D

Langley Porter Neuropsychitnc Institute

University of California

San Francisco California

William McGlothlin, Ph D

Department of Psychology UCLA

Los Angeles California

Jack Mendelson. M D

Alcohol and Drug Abuse Research Center

Harvard Medical School

McLeon Hospital

Belmont Massachusetts

Helen Nowlis. Ph.D

Office of Drug Education DHEW

Washington DC

Lee Robins, Ph.D

Washington University School of Medicine

St Louis Missouri

NIDA Research Monograph series

Robert DuPont, M.D.

DIRECTOR, NIDA

William Pollin, M.D.

DIRECTOR, DIVISION OF RESEARCH, NIDA

Robert C. Petersen, Ph.D.

EDITOR-IN-CHIEF

Eunice L Corfman, M.A.

EDITOR

Eleanor W. Waldrop

MANAGING EDITOR

Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857
Behavioral Tolerance: Research and

Treatment Implications
ACKNOWLEDGMENTS

The technical review upon which this monograph is based was

capably planned, conducted, and reported by staff of Macro

Systems, Inc., Silver Spring, Maryland, under NIDA Contract

No. 271-75-1139. The review took place at Rockville,

Maryland, on June 23 and 24, 1977.

Library of Congress catalog card number 77-93034

DHEW publication number (AIM) 78-551

Printed 1977

NIDA Research Monographs are indexed in the Index Medicus.

They are selectively included in the coverage of BioSciences

Information Service, Chemical Abstracts, Psychological

Abstracts, and Psychopharmacology Abstracts.
Foreword

Tolerance to the effects of abused substances has long been implicated

as a causal factor in addiction. Such tolerance is not based entirely

on pharmacologic processes; recently the role played by nonpharmacologic factors has become an area of increasing research interest and

potential clinical importance. An understanding of the mechanisms of

tolerance is a key element in our eventually understanding the larger

question of human dependence upon such substances, and ultimately will

be useful for developing improved strategies for prevention and

treatment.

Aspects of tolerance are being investigated across a broad range of

drugs, in humans as well as a variety of animal species. At present,

no agreement exists on the mechanisms underlying behavioral tolerance,

but as data continue to be added to the base of empirical knowledge,

a theoretical synthesis may be approached.

The technical review at which the papers in this monograph were presented was held at the National Institute on Drug Abuse on June 23-24,

1977. At that meeting, past and present research findings on

behavioral tolerance in substance abuse were presented; theoretical

and experimental approaches to investigation in this field were compared and contrasted; an attempt was made to develop a working definition of behavioral tolerance as it applies to substance abuse; and

possible new initiatives for investigating the concept within clinical

research and experimental treatment research settings were discussed,

The central purpose of this monograph is to share what was communicated

at the technical review, so as to stimulate further interest among the

scientific and medical communities in the part played by nonpharmacologic factors in drug tolerance and dependencies, and thus to further

the accumulation of new knowledge.

William Pollin, M.D.

Director

Division of Research

National Institute on Drug Abuse

v
Jack D. Blaine, M.D.

Research Psychiatrist

Clinical-Behavioral Branch

Division of Research, NIDA

5600 Fishers Lane

Rockville, Maryland 20857

Howard D. Cappell, Ph.D.

Head, Psychology

Addiction Research Foundation

33 Russell Street

Toronto, Ontario, Canada M5S2Sl

Stuart M. Deikel, M.A.

Department of Psychology

McGill Universitv

Montreal, Quebec; Canada H3C3Gl

representing

Brooks Carder, Ph.D.

Scientist

Synanon Research Institute

P.O. Box 786

Marshall, California 94940

Peter B. Dews, M.D., Ph.D.

Head, Laboratory of Psychobiology

Department of Psychiatry

Harvard Medical School

25 Shattuck Street

Boston, Massachusetts 02115

John L. Falk, Ph.D.

Professor of Psychology

Rutgers University

Busch Campus

New Brunswick, New Jersey 08903

Douglas P. Ferraro, Ph.D.

Professor of Psychology

University of New Mexico

Albuquerque, New Mexico 87131

Reese T. Jones, M.D.

Associate Professor in Residence

Department of Psychiatry

University of California

401 Parmassus Avenue

San Francisco, California 94143

Technical Review Participants

Eugene Le Blanc, Ph.D.

Director, Strategic Planning

and Research Branch

Addiction Research Foundation

15 Overlea Boulevard

Toronto, Ontario, Canada M4A1A9

Charles P. O’Brien, M.D., Ph.D.

Director, Drug Dependence Treatment and Research Center

c/o Veterans Admin. Hospital

University and Woodland Avenues

Philadelphia, Pennsylvania 19104

Constantine X. Poulos. Ph.D.

Scientist, Clinical Psychology

Addiction Research Foundation

Toronto, Ontario, Canada M5S2Sl

Pierre F. Renault, M.D.

Chief, Clinical-Behavioral Branch

Division of Research, NIDA

5600 Fishers Lane

Rockville, Maryland 20857

Charles R. Schuster, Ph.D.

Professor of Psychiatry

University of Chicago

950 East 59th Street

Chicago, Illinois 60637

Shepard Siegel, Ph.D.

Professor of Psychology

McMaster University

Hamilton, Ontario, Canada L8S4Kl

James H. Woods, Ph.D.

Associate Professor of Pharmacology

University of Michigan

Ann Arbor, Michigan 48104

Technical Review Moderator

Norman A. Krasnegor. Ph.D.

Deputy Chief, Cl&&al-Behavioral

Branch

Division of Research, NIDA

5600 Fishers Lane

Rockville, Maryland 20857

v i
Contents

FOREWORD

William Pollin . . . . . . . . . . . . . . . v

TECHNICAL REVIEW PARTICIPANTS . . . . . . . . . . . . . vi

INTRODUCTION

Norman A. Krasnegor . . . . . . . . . . . . 1

I. CONCEPTUALIZATION

Theoretical Basis of Behavioral Tolerance:

Implications of the Phenomenon for Problems of Drug Abuse

Charles R. Schuster. . . . . . . . . . . . . 4

Behavioral Tolerance

P. B. Dews. . . . . . . . . . . . . . . . 18

II. NARCOTICS

A Pavlovian Conditioning Analysis of Morphine

Shepard Siegel. . . . . . . . . . . . . . . 27

Narcotic Tolerance and Operant Behavior

James H. Woods and John Carney. . . . . . . . . . 54

Conditioning Effects of Narcotics in Humans

Charles P. O'Brien, Thomas Testa, Joseph Ternes,

and Robert Greenstein. . . . . . . . . . . . . 67

III. ETHANOL

Tolerance as a Behavioral Phenomenon:

Evidence From Two Experimental Paradigms

A. E. Le Blanc, C. X. Poulos, and H. D. Cappell. . . . 72

IV. MARIHUANA

Environmental Influences-on Marihuana Tolerance

Brooks Carder. . . . . . . . . . . . . . . 90

Behavioral Tolerance to Marihuana

Douglas P. Ferraro. . . . . . . . . . . . . . 103

Behavioral Tolerance:

Lessons Learned From Cannabis Research

Reese T. Jones. . . . . . . . . . . . . . . 118

vii
V. STIMULANTS

Behavioral Tolerance to Cocaine

William R. Woolverton and Charles R. Schuster. . . . 127

VI. DEPRESSANTS

Behavioral and pharmacological Components of

Phenobarbital Tolerance

Maisy Tang and John L. Falk. . . . . . . . . . 142

LIST OF MONOGRAPHS. . . . . . . . . . . . . . 149

viii
Introduction

Norman A. Krasnegor, Ph.D.

Tolerance to a substance can be demonstrated by the observation

that repeated administrations of a fixed dose lead to a diminution of effect. Alternatively, one can demonstrate tolerance by

showing that a substance’s original effect, diminished in magnitude after sequential exposures to a fixed dose, can be reinstated

by an increase in that dose. An understanding of how tolerance

influences the dependence processes associated with chronic habitual drug and alcohol use is essential for those who work in the

field of substance abuse research because of its reported necessary

role in the maintenance of drug addiction and alcoholism. According to this view, drug and alcohol addicts become physically

dependent, in part, because the initial effects of a substance

diminish with repeated use. In order to attain the original

effect that a substance produces in a user, therefore, larger or

more frequent doses are consumed. The problem is further compounded for addicts because the diminished response to a fixed

dose of an abused substance may lead to the onset of withdrawal

symptoms. Thus, the development of tolerance to a substance can

contribute to the dependence process by escalating the need for

more of that substance to attain a desired effect or to postpone

or eliminate abstinence symptoms.

Pharmacologists generally divide the study of tolerance into two

broad categories: dispositional and functional. The former subsumes all studies on a substance’s effect when changes occur which

limit the amount of a substance that bathes its target cells. Such

investigations encompass research on altered absorption, distribution, inactivation and/or excretion of a substance from the body.

Also included under this rubric is the study of physiological

tolerance, i.e., investigations of the altered responsivity of

the target cells themselves.

Studies of functional tolerance include all other investigations

of tolerance, which are excluded from the dispositional category

because the results obtained are not readily understood within

the framework of extant pharmacological and/or physiological

theories. Behavioral tolerance is an example par excellence of

functional tolerance. Study of this phenomenon is important

1
because it represents a significant conceptual advance. The experimental evidence available shows conclusively that nonpharmacological

factors can play a significant role in the development of tolerance.

The evidence presented in this monograph demonstrates the relevance

of behavioral and environmental variables for this area of research.

Even more important, the studies described in this monograph stress

the necessity to take the experimental history and the organism’s

interaction with its environment into account when designing research

protocols on tolerance.

Behavioral tolerance can be understood in three ways: empirically,

descriptively, and theoretically (Ferraro, this volume). As an

empirical term, it is defined relative to the procedures necessary

and sufficient to observe it. As a descriptive term, it is defined

relative to the aggregate of individual empirical relationships

which together constitute the basis for making generalizations and

predictions concerning it. As a theoretical term, it is defined

relative to underlying mechanisms of action which serve to provide

a meta- level explanation for the observed empirical relationships.

Behavioral tolerance is used in each of the three ways in this monograph. In this respect, it accurately reflects the state-of-the-art

of such research.

At present, there is no acceptable empirical definition for the

concept of behavioral tolerance. The consensus of those present

at the meeting which led to the publication of this monograph was

that the necessary and sufficient conditions and procedures operationally to demonstrate behavioral tolerance are not known. There

is an emerging descriptive definition of the concept based upon the

continuing empirical work being generated; there is no clear consensus, however, as to whether behavioral tolerance represents the

development of tolerance to the behavioral effects of a substance

or the effects of behavior on the development of tolerance to the

substance’s effects.

issue.

Further research may help to clarify this

There are several theoretical definitions of behavioral tolerance.

The elegant experiments of Siegel implicate the role of classical

conditioning processes. Carder discusses the possible importance

of stress in the development of tolerance. Others, such as Ferraro

and Woolverton and Schuster implicate operant principles in the

development of tolerance. While there is by no means a consensus,

it is apparent that those who have identified learning theory as a

mechanism, including Siegel and O’Brien, will actively pursue this

line of inquiry. (All of these investigators, this volume.)

It is unclear at present whether research in behavioral tolerance

is orthogonal to other types of research paradigms designed to

study tolerance in general. Suffice it to say that as the empirical

data accumulate, all those who study tolerance will have to integrate such information into their approaches and experimental

designs. Future research designed to elucidate the concept of

behavioral tolerance could productively focus upon the environment

in which the substance abuse occurs. Thus, studies should be

2
undertaken which investigate the abuser in the social setting and

physical surroundings where the habit was acquired and maintained.

In addition, the emerging field of human behavioral pharmacology of

substance abuse can serve as a framework within which the relationship of self-administration of substance(s) to the development of

tolerance can be investigated. Of particular interest would be

studies undertaken to determine: why tolerance to a substance

develops in some individuals but not others; the relationship of

tolerance to the dependence process; and tolerance to the reinforcing

effects of substances. Data collected in the human behavioral

pharmacology laboratory could serve as a guide for designing studies

of substance abuse in the natural environment. For example, the

underlying relevant physiological parameters which define the subjective phenomenon of “craving” could then be related to relevant

stimuli which occur in the natural environment and help clinicians

to treat more effectively those who are dependent.

The possibilities for future research in the field of behavioral

tolerance are rich and varied. If what already has been accomplished

is an accurate prologue to what will come, we can look forward to

much new knowledge which will contribute significantly to our understanding of the dependence processes associated with substance abuse.

I am pleased that the National Institute on Drug Abuse has helped

contribute to the emergence of this new and exciting field of inquiry

and am hopeful that the work presented in this monograph will help

to stimulate new and productive research.

3
I. CONCEPTUALIZATION

Theoretical Basis of Behavioral

Tolerance:

Implications of the Phenomenon

for Problems of Drug Abuse

Charles R. Schuster, Ph.D.

Most studies in the area of behavioral pharmacology involve the determination of the effects of a number of different doses of a drug

on a particular behavior. For accuracy in the determination of a

drug’s potency, such dose-response studies are designed to minimize

the interaction of previous drug experience with the effects of each

subsequent dose. These studies are essential to determine the profile of behavioral actions of different classes of pharmacologic

agents. There are a number of reasons, however, for studying the

behavioral actions of drugs given repeatedly under conditions where

prior dose experience is likely to modify its subsequent actions.

The most compelling reason for conducting such studies is that this

is the usual manner in which drugs are taken both for therapeutic

reasons and when they are abused.

The most common change produced by prior experience with a drug is

a decrease in responsiveness to its effects. When an organism becomes less sensitive to the actions of a drug by virtue of past experience with the drug, we refer to this change as acquired tolerance.

If acquired tolerance to one drug confers tolerance to a second drug,

we refer to this phenomenon as cross-tolerance.

Investigations of the conditions leading to the development of drug

tolerance as well as the mechanisms underlying this change in sensitivity are important areas of investigation for several reasons.

Tolerance development complicates the use of a drug in therapeutic

conditions demanding its repeated administration. Further, studies

of drug tolerance are extremely important in the area of drug abuse,

since this phenomenon may be responsible for many of the problems

associated with the repeated administration of a drug. The seemingly

unending increase in the amount of opiate drugs used by addicts is

but one obvious example of the relevance of the study of tolerance

to the problems of drug abuse. Of fundamental importance is determining the interrelationship between tolerance development and the

development of dependence upon a drug. This interrelationship will

be discussed in a later section of this paper.

On the basis of different experimental strategies, pharmacologists

have operationally defined tolerance in several ways. Tolerance may

be defined as a diminished effect with successive administration of

4
the same dose of a drug. Tolerance may be further characterized by

experiments demonstrating that it is necessary to increase the dose

of a drug in order to produce the intensity and/or duration of action

originally observed. The most precise manner for defining and quantifying tolerance is to determine dose-response relationships both

before and after repeated exposure to a drug. In such experiments a

parallel shift in the dose-response curve to the right is an indication that tolerance has developed. In addition, measuring the degree

of shift may provide an estimation of the degree of tolerance developed. (There are, however, same reservations regarding the precision

of such estimates in whole organism research which will be discussed

in a later section.)

Although tolerance is the most common change seen with repeated administration of a drug, in some instances the reverse occurs.

Such increased responsiveness to a drug following its repeated administration is termed sensitization. Such sensitization has been reported, for example, for certain of the actions of cocaine (Downs and

Eddy 1932; Post 1977; Stripling and Ellinwood 1977; Tatum and Seevers

1929). Although this paper will confine itself to studies of behavioral tolerance, it should be pointed out that identical research

strategies are used to study sensitization to a drug.

Subsequent to the establishment of the fact that tolerance does develop to a particular drug, a second stage of research involves the

investigation of the mechanisms underlying this change in sensitivity.

Many drugs have been investigated in this manner and certain general

classes of mechanisms producing tolerance have been established. Tolerance develops to any drug which can induce the synthesis of enzymes

responsible for its degradation. Certain barbiturates, for example,

are known to increase the concentration of liver microsomal enzymes

responsible for their degradation. Thus, when barbiturates are taken

repeatedly, we would expect a more rapid elimination of the drug from

the body, with a consequent decrease in the intensity and/or duration

of the actions of the drug. When amphetamines are administered repeatedly, food intake may be suppressed. Such altered food ingestion

causes a change in the pH of the urine, with a consequent effect upon

reabsorption of the drug in the kidney. In this case, the drug’s

disposition is being affected indirectly by a change produced in the

organism’s eating behavior. When the decreased sensitivity to a drug

is explicable on the basis of its altered absorption, distribution,

inactivation and/or excretion from the body, we refer to this change

as dispositional tolerance. This mechanism, however, cannot account

for the tolerance to drugs observed when drug concentrations are

equal at the target organs of tolerant and non-tolerant organisms.

Under these circumstances, the term functional tolerance is used to

suggest some adaptation of the organism to the drug-induced physiologic perturbation. Thus, the term “functional” is used in instances

where tolerance cannot be explained on the basis of the drug’s altered

disposition.

The term “tolerance” is used in relation to a variety of effects. For

example in the pharmacologic literature we may read that “cardiovascular tolerance” develops to a drug. Such a term is used purely descriptively to imply that: 1) the drug had some cardiovascular effect, and

5
2) this effect diminished with repeated administration of the drug.

It is in this descriptive sense that I intend to use the term "behavioral tolerance.” As this term is being used in this paper it has no

mechanistic implications but rather simply means that a drug has some

behavioral action which diminishes with its repeated administration.

This change in sensitivity to the behavioral actions of a drug may

be because of its altered disposition or any functional mechanism.

An excellent review by Kalant et al. (1971) has covered the variables

affecting the development of dispositional tolerance to different

classes of drugs. In the present chapter, I will concentrate on functional tolerance to behaviorally active drugs, since it is in this

area that environmental variables may have influence. Before considering these environmental variables affecting functional behavioral tolerance, we will consider: 1) the strategies for studying

behavioral tolerance; 2) strategies for discriminating between functional and dispositional tolerance, and 3) pertinent pharmacologic

variables affecting functional tolerance to the behavioral actions

of drugs.

I. STRATEGIES FOR STUDYING BEHAVIORAL TOLERANCE

Potentially any behavior which is affected by a drug could be used in

studies of tolerance development. For investigations of the rate and

extent of tolerance development, however, the behavior must be quantifiable. Further, there are advantages to using within-subject everimental designs for investigating the effects o repeated administration of a drug. With such designs it is essential that the behavior

be stable over long periods of time approximating the duration of the

repeated drug regimen. The methods of operant conditioning have been

shown to generate behavioral baselines which are ideal for the study

of both the acute and chronic effects of drugs (Seiden and Dykstra

1977; Thompson and Schuster 1968). These methods emphasize the maintenance of behavior over periods of days, weeks, and months. Further,

a wide range of behaviors can be brought under experimental control

and precisely measured using these procedures. These attributes make

this methodology extremely valuable for the study of drug tolerance.

A study from my own laboratory illustrates how such procedures may be

used (Fischman and Schuster 1974). In this study, effects of chronic

intravenous administration of d-methamphetamine were determined

in rhesus monkeys trained to lever press on a Fixed-Ratio 10 schedule

of food reinforcement for two hours each day. These animals received

an intravenous infusion of drug every three hours beginning at a dose

of .0625 mg/kg/infusion. After tolerance developed to the behavioral

suppressant effects of the drug, the dose was systematically increased

over a six to ten month period to dosage levels as high as 6.5 mg/kg/

. . It should be obvious that in order to interpret the effects .

of drugs given repeatedly over an eight to ten month period we must

have a procedure which would have generated a stable behavioral baseline if drug had not been given. The methods of operant conditioning

are particularly well suited for this purpose, since they have been

shown to produce behavioral baselines which remain stable over years

(Ferster and Skinner 1957).

6
In most studies of the effects of repeated administration of a drug

on operant behavior, the animals are brought under the discriminative

control of lights or tones, and performance is maintained by food

or water presentation or the cessation of an aversive stimulus. It

is possible, however, to use drugs as discriminative or reinforcing

stimuli (Schuster and Balster 1977; Schuster and Johanson 1974;

Schuster and Thompson 1969). These studies have obvious implications

for the problem of drug abuse. It is of great importance to investigate the development of tolerance to these stimulus functions of

drugs. Unfortunately, relatively little systematic work has been

done in this area. Recent evidence (Shannon and Holtzman 1976) suggests that tolerance does develop to the discriminative stimulus

effects of morphine. However, no systematic studies of tolerance

development to the reinforcing actions of morphine have been carried

out. Balster and Schuster (1973) presented data showing that there

was little change in the reinforcing actions of cocaine over a period

of several months. If tolerance developed to the reinforcing actions

of the drug, the number of injections taken daily would be expected to

increase, and this was not found to be the case. On the other hand,

tolerance to the reinforcing actions of cocaine was suggested by the

fact that one of the animals in this experiment had a longer past

history of self-administering cocaine, and this animal showed a much

higher level of intake than the other animals in the study. Clearly,

more systematic work must be done to determine whether tolerance develops to the reinforcing actions of cocaine. Such work is now in

progress in my laboratory and the data strongly suggests that tolerance to the reinforcing actions of cocaine does not develop.

Observations from my own laboratory also indicate that tolerance does not

develop to the reinforcing actions of d-methamphetamine (Fischman

and Schuster 1973). This study used two rhesus monkeys previously

treated with gradually increasing doses of d-methamphetamine administered intravenously every 3 hours for a period of eight months.

During and after the chronic d-methamphetamine regimen it was established that these animals were tolerant to the disruptive effects

of the drug on DRL performance maintained by food (Fischman and

Schuster 1977). Subsequently, we determined the rate of lever pressing for intravenous infusions of d-methamphetamine delivered under

an FR-10 schedule during a Z-hour daily experimental session. Animals were tested with three doses of d-methamphetamine (0.025, 0 .05

and 0.1 mg/kg/infusion) . Figure 1 shows the mean number of drug

infusions delivered at each dose of d-methamphetamine. As has previously been shown (Bolster and Schuster 1973), there is an inverse

relationship between dose and the number of infusions earned. For

comparison purposes the mean number of infusions earned by a group

of 5 monkeys never exposed to the chronic drug regimen is also shown

in Figure 1 for the dose of 0.05 mg/kg. As can be seen there is no

difference in the amount of d-methamphetamine self-administered by

the two groups of animals. clearly these observations need confirmation in a more systematic manner. Nonetheless, they strongly suggest that exposure to very high doses of d-methamphetamine does not

alter the animal’s subsequent responsiveness to the reinforcing

actions of the drug. It is important to note that these same animals

7
FIGURE 1

Dose of d-methamphetam ine

(mg /kg / infusion)

were tolerant to the disruptive effects of d-methamphetamine on their

food-maintained DRL performance. The important point in the present

context is that through the use of operant conditioning procedures,

tolerance to the discriminative and reinforcing effects of drugs can

be studied. More research in this area is needed and should be a

high priority item because of its implications for the problems of

drug abuse.

To summarize, it is the position of this paper that the methods of

schedule-controlled operant conditioning are uniquely suited for the

study of the changes in responsiveness to the repeated administration

of drugs.

II. METHODS FOR DISCRIMINATING BETWEEN DISPOSITIONAL AND

FUNCTIONAL TOLERANCE

Following the observation that tolerance develops to the behavioral

actions of a drug, it is important to determine whether this change

in responsiveness is due to changes in the disposition of the drug

or to functional adaptations to the drug. Ideally, to make this dis8
crimination we would determine whether the concentrations of the

drug are the same in the brains of tolerant and nontolerant animals.

If the concentrations of the drug are the same in the brains of tolerant and nontolerant animals, we infer that the lowered sensitivity

to the drug must be due to some functional change in the organism.

If there is a lower drug concentration in the brains of tolerant

animals, this suggests that at least in part, the decreased drug

responsiveness is caused by dispositional changes. To rule out the

involvement of functional changes as well requires giving tolerant

animals an increased amount of the drug sufficient to equalize brain

concentrations. Only if both groups are then equally responsive

may we conclude that the tolerance is completely attributable to

dispositional factors.

These ideal strategies, however, are rarely obtainable in practice.

With many drugs we are not certain whether metabolites may be pharmacologically active. If they are, then their concentration in the

brain as well as the parent compound must be assayed. There is also

a question of whether whole brain levels of these substances are the

appropriate level of analysis or whether regional distribution of

the drug and its metabolites should be measured. In any case, these

“ideal” procedures are beyond the capability of most laboratories

studying behavioral tolerance. Fortunately there is an alternative

strategy which can be utilized to determine whether tolerance to a

drug is functional or dispositional. This strategy is based upon

the fact that changes in a drug’s disposition in the body should

result in comparable changes in responsiveness to all of the behavioral actions of a drug. Conversely, it is unlikely that functional

tolerance would develop at the same rate or to the same extent to

all of a drug’s behavioral actions. Thus, if one can demonstrate

differential tolerance development to the various behavioral effects

of a drug, this strongly suggests that the mechanism is functional.

A particularly powerful strategy for showing differential tolerance

development is the use of a multiple schedule of reinforcement.

This strategy is illustrated in a study by Schuster et al. (1966).

In this study rats were trained to lever press on a multiple fixedinterval (FI)-DRL schedule of reinforcement. When these animals were

given repeated administration of d-amphetamine, tolerance developed

to the rate-increasing effects in the DRL component but not in the

FI component. Clearly, changes in the disposition of d-amphetamine

cannot account for the selective tolerance development to the actions of the drug in only one component of the multiple schedule.

This strategy for determining whether behavioral tolerance is functional or dispositional does depend upon the selection of the right

behavioral measures. In instances where functional tolerance develops to all the behavioral measures taken, it is impossible to differentiate between functional and dispositional tolerance. This

outcome appears unlikely, however, if a broad sample of behavior is

obtained.

9
III. PHARMACOLOGIC VARIABLES AFFECTING TOLERANCE TO THE

BEHAVIORAL ACTIONS OF DRUGS

A. Dosage Regimens

As mentioned in the introduction there are a variety of experimental strategies for demonstrating tolerance development to a drug.

In most behavioral experiments investigating the effects of repeated

administration of a drug, only one dose of the drug is used. If the

effects of this dose diminish with repeated administration, we conclude that tolerance has developed to the drug. In most instances

this approach is adequate for this conclusion. It is conceivable,

however, that changes in response to the repeated administration of

the drug might result from its accumulation rather than tolerance.

It is impossible to determine this unless full dose-response relationships are known. For example, an early study of dl-amphetamine

tolerance used rats trained on a DRL 17.5 sec. schedule of reinforcement (Schuster and Zimmerman 1961). The acute effect of dl-amphctamine was to increase the animal’s response rate. With daily administration of dl-amphetamine, response rates showed progressively

smaller increments. This was interpreted as demonstrating tolerance

development to the actions of dl-amphetamine on the animal’s DRL performance . An alternative explanation of this decrease could be that

with repeated daily administration the dl-amphetamine accumulated;

therefore, functionally the daily dose was increasing. Since the

actions of dl-amphetamine on DRL are biphasic (low doses increase

rate and high doses decrease rate), the decreased responding observed

could simply represent the effects of a gradually increasing daily

dosage level.

One simple manipulation to rule out this alternative interpretation

is to determine whether the original effect of the drug can be obtained

in tolerant animals by increasing the drug dose administered. This

manipulation is a truncated version of the ideal strategy which involves

determining a full dose-response curve before, during, and after the

chronic drug regimen. Whenever possible this strategy should be utilized. There are, however, some limitations to the use of this ideal

strategy in attempting to quantify the degree of tolerance development.

These limitations are based upon the fact that when we obtain a doseresponse relationship using a behavioral measure, it is highly unlikely that we are dealing with a single effect which varies only

quantitatively. This is particularly true when dealing with drug

effects which cause a decrease in the rate of an operant response,

since many unrelated factors may produce this common outcome. It is

argued that a parallel shift in the dose-response curve indicates

that we are dealing with the same drug effect. This presumes, however, that the variability in the dose-response relationships is

small enough meaningfully to discriminate differences in slopes of

the dose-response curves. Unfortunately, behavioral measures often

show large variations in response to drugs, thus limiting the usefulness of looking for parallel shifts in dose-response relationships.

Clearly this indicates that for quantitative work we must make every

effort to improve our behavioral control procedures. It seems quite

plausible to speculate that the mechanisms responsible for disruption

10
of operant performances will vary as a function of the dose of a drug.

For example, a low dose of amphetamine might disrupt a food-reinforced

lever pressing operant simply because of drug-induced interoceptive

changes which function as novel stimuli. As dose is increased the

drug may disrupt the ongoing operant by virtue of its interaction with

the food deprivation state of the organism. At still higher doses,

the drug may elicit stereotypical behaviors, which are greater in

strength and incompatible with the operant response. Tolerance may

develop to any or all of these actions of the drug. Clearly, the

development of tolerance to the novel stimulus effects of the drug

could cause a shift in the dose-response curve to the right. However,

it is questionable whether in the redetermination we are estimating

the degree of tolerance to the novel stimulus effects of the drug or

obtaining an unchanged dose response curve for an effect with a higher

threshold. This strongly suggests that to investigate fully the development of tolerance to a drug, several dosage levels should be used

as the dose given repeatedly.

B. The Selection of Dose for the Chronic Drug Regimen

In the previous section, I have suggested that more than one

dose should be studied when investigating whether and to what extent

tolerance develops to the behavioral actions of a drug. With drugs

which induce enzymes responsible for their degradation, maximal tolerance develops to doses producing maximum enzyme levels. Therefore,

studies of this type of tolerance may use relatively high doses of

the drug. With functional tolerance, however, the selection of doses

is more complicated. If the functional tolerance represents some

form of homeostatic adaptation, this adaptation may only be possible

across a limited dose range. For behavioral studies, doses somewhere

between the ED-25 and ED-75 determined when the drug is given acutely

are most appropriate for repeated administration. Higher doses may

be tested, but only after tolerance develops to lower doses. If the

dose selected for repeated administration causes a complete suppression of the behavior being studied, this may prevent or at least delay the development of compensatory mechanisms which result in tolerante. This is particularly true if the compensatory mechanisms are

behavioral in nature and require reinforcement for their strengthening

and maintenance. More will be said about this in a later section.

C. Frequency of Drug Administration

Recent work in my laboratory has suggested that more than one

type of tolerance can develop to the behavioral actions of the same

drug when given with different frequencies. Amphetamines given once

daily immediately prior to a session in which rats or monkeys perform on a DRL schedule of reinforcement show the development of tolerance to the drug (Campbell and Seiden 1973; Schuster et al. 1966;

Schuster and Zimmerman 1961). Such tolerance development has been

shown to be critically dependent upon whether the drug is given before the session or after the session (Campbell and Seiden 1973).

When the drug is given chronically after the session, no tolerance

develops to its behavioral actions.

11
This suggests that there is an interaction between the drug and the

performance contingencies. On the other hand, we have recently found

a marked degree of tolerance to the behavioral actions of d-methamphetamine in rhesus monkeys who did not perform in their behavioral

task during the repeated drug regimen. In this case, the repeated

drug regimen consisted of twice daily intramuscular injections of

d-methamphetamine in gradually escalating dosages from 0.5-16 mg/kg/

injection. Following this regimen, the animals showed a 2-4 fold

decrease in sensitivity to the disruptive actions of the drug. Neurochemical analysis of the brains of similarly treated monkeys have

shown an irreversible depletion in brain monoamines (Seiden et al.

1976). Since the actions of amphetamines in the brain are mediated

through monoamines, it seems entirely probable that the tolerance

observed in these animals is attributable to the decreased availability of monoamines. Such depletions of monoamines are not seen when

low doses of the drug are given to animals daily and hence this cannot be the explanation for tolerance developed when injections are

given only once daily. Thus, the mechanism responsible for behavioral

tolerance may critically depend on the frequency of administration of

the drug during the chronic regimen.

Clearly, systematic investigations of drug tolerance should include

the investigation of various doses given at various frequencies.

Only in this manner is it possible to define the various conditions

under which tolerance may develop. Although such research projects

are ambitious, there is no way of shortcutting the task.

IV. ENVIRONMENTAL VARIABLES AFFECTING TOLERANCE DEVELOPMENT TO THE

BEHAVIORAL EFFECTS OF DRUGS

In the past few years, studies have begun to appear in the pharmacologic literature demonstrating that environmental variables are of

considerable importance in the development of functional tolerance to

behaviorally active drugs. In this section I would like to review

some of my own work which has convinced me of the central importance

of the reinforcement contingencies as a variable affecting behavioral

tolerance to a drug. In 1961, I co-authored a paper with Dr. Joseph

Zimmerman on the effects of repeated administration of dl-amphetamine

to rats trained to lever press on a DRL 17.5 second schedule of milk

reinforcement. In this study we observed that the initial effects of.

dl-amphetamine were to increase the animals’ lever press rate and, as a

&sequence, decrease the number of reinforcements received. With

repeated administration, however, the animals showed a gradual decline in response rate, a shift in the Inter Response Time (IRT) distribution toward control patterns, and an increase in the number of

reinforcements received. Since the effect of the drug declined with

repeated administration, we concluded that partial tolerance had developed. In a second study we repeated the original experiment with

the addition of obtaining a measure of the animals’ general activity

every other day. Thus animals were tested on alternate days in the

activity apparatus and the operant chamber under the DRl schedule of

milk reinforcement. The initial effects of dl-amphetamine were to

increase general activity and increase 1ever responding in the DRL

sessions. With daily administration of the drug we again observed a

gradual shift in the animals’ DRL performance towards that observed

12
under nondrug conditions. In contrast, drug-induced general activity increments were sustained throughout the course of the chronic

drug regimen. This development of selective tolerance to one of the

behavioral actions of dl-amphetamine and not to another strongly

suggested to us that this tolerance was functional and not dispositional. Further, we speculated that the decline in reinforcement

frequency in the DRL sessions might have contributed to the development of functional tolerance to the drug. Since there were no reinforcement contingencies associated with the general activity session,

the drug-induced behavioral change did not “cost” the animal anything

and therefore no tolerance developed.

A later experiment (Schuster et al. 1966) was designed specifically

to investigate the role of reinforcement contingencies in the developent of functional tolerance to the amphetamines. In this study

three rats were trained to lever press on a multiple DRL 30 sec-FI 30

sec schedule of food reinforcement. Following training and the determination of a dose-response curve for single administrations of damphetamine, the animals were given 1.0 mg/kg of d-amphetamine daily

for 30 consecutive days. Initially for all three-animals d-amphetamine produced a decrement in reinforcement frequency in the DRL component of the multiple schedule. With repeated administration of the

drug, however, rate increases and/or temporal patterning of lever

pressing gradually returned toward control values with a consequent

increase in reinforcement frequency. For two of these animals damphetamine caused a rate increase in the FI component but no change

in reinforcement frequency. These increased rates in the FI component were maintained over the entire 30 days of the chronic drug regimen. In the third animal, d-amphetamine initially produced a rate

decrease and a fall in frequency of reinforcement in the FI component.

With repeated administration of the drug, rate and reinforcement

frequency returned to control values. These data strongly suggest

that tolerance to changes in response rate developed only when these

changes produced a decrease in reinforcement frequency. The tolerance developed whether the drug induced increases in responding (DRL)

or decreases (FI) provided that the rate change decreased the frequency

of reinforcement. In a second experiment in this series rats were

trained to lever press in order to avoid an electric shock delivered

every 30 seconds. Four of the animals trained under these contingencies continued to receive a number of electric shocks in each daily

session. When given 1.0 mg/kg of d-amphetamine for 35 consecutive

days their lever press response rate remained consistently elevated.

That is, tolerance did not develop to the rate increasing effects of

d-amphetamine. It is to be noted that because of the increased response rate the number of shocks received was markedly reduced during

the chronic drug regimen.

The data from all of these experiments prompted us to put forth a formal hypothesis stating that: “Behavioral tolerance will develop in

those aspects of the organism’sbehavioral repertoire where the action

of the drug is such that it disrupts the organisms behavior in meeting the environmental requirement for reinforcements. Conversely,

where the actions of the drug enhance, or do not affect, the organism's

behavior in meeting reinforcement requirements, we do not expect the

development of behavioral tolerance.” It was not our intention to

13
put forth this reinforcement-loss hypothesis as an alternative to

other physiological theories of drug tolerance. Rather, we intended

to stress that the interaction of the contingencies of reinforcement

with the drug-induced behavioral change is an extremely important

variable affecting the development of functional tolerance to a drug.

It is beyond the scope of this paper to review those studies which

have derived data which support or refute our hypothesis. I am certain it will get a few bruises in the other papers presented

in this monograph. It seems clear to me that any such simple hypothesis regarding the interaction of drug effects with contingencies

of reinforcement would need great elaboration in order to take into

consideration all of the other pharmacologic and environmental variables affecting functional tolerance. To do this at the present

time, however, would be largely speculative, since relatively few

systematic studies of behavioral tolerance have been done. We need

more data before we can further refine our hypothesis. I am in hopes

that this symposium may suggest those variables which should be systematically studied in relationship to the reinforcement-loss hypothesis.

V. IMPLICATIONS OF BEHAVIORAL TOLERANCE FOR PROBLEMS OF DRUG ABUSE

We have all been asked by the sponsors of this monograph to speculate

about the implications of behavioral tolerance for the problems of

drug abuse. Before beginning such speculation, I would like to state

that in my opinion we need more systematic experimentation before we

can begin properly to appreciate the interrelations between tolerance and the abuse of a drug. Clearly, tolerance develops to most, if

not all, drugs commonly abused in our society. An understanding of

the pharmacology of these drugs, including the mechanisms underlying

the development of tolerance to their behavioral actions, is essential

if we are to make any real progress in comprehending the problems of

drug abuse.

Now let me indulge in some speculations regarding the importance

of studies of behavioral tolerance to the problems of drug abuse.

As stated previously, the chronic administration of a drug for nontherapeutic reasons is complicated by the development of tolerance.

The seemingly inexorable escalation of daily dosage which characterizes the abuse of most drugs clearly involves one of the consequences

of the development of tolerance. It is not at all clear, however,

when such dosage escalation is due to the development of tolerance

to the reinforcing effects of a drug or to some other effects which

may have initially limited the intake of the drug. For example, when

rhesus monkeys are allowed unlimited access to intravenous morphine

delivered on an FR-1 schedule of reinforcement they show a gradual

increase in responding for the first 40-50 days (Deneau et al. 1969).

Thereafter, the number of injections received daily remains stable.

It is tempting to attribute the original increase in drug intake to

the development of tolerance to the reinforcing effects of the drug.

Equally possible, however, is that originally the animals’ intake was

suppressed by the direct effects of morphine on lever-pressing behavior. As the animals become tolerant to the response-suppressing

effects of the drug, the number of injections could increase. Clearly,

14
this matter needs additional research to clarify the relative importance of these two alternative explanations. This points to a general

need for research to clarify under what pharmacologic and environmental conditions tolerance develops to the reinforcing effects of

drugs. It seems obvious that if conditions could be arranged so that

drug dosage was not continually escalated, many of the social and medical problems associated with drug abuse could be avoided. Stated

another way, by studying the variables that give rise to the dosage

escalation characterizing drug abuse, it may be possible to develop

procedures for aiding drug users to maintain their drug use at lower

levels. Such a therapeutic goal is perhaps admissible at this time

since it is obvious that the goal of total drug abstinence is probably

not obtainable for the vast majority of drug abusers.

I have stated elsewhere that I believe that drug abuse involves not

only the self-administration of a drug, but also the demonstration

that such drug taking has deleterious consequences (Schuster and Johanson 1974). This means that drugs must be evaluated not only for

their reinforcing effects but for their physiological and behavioral

toxicity as well. It is clear that tolerance does develop to many

of the toxic effects of abused drugs. For example, what might be a

behaviorally incapacitating dose of marihuana to the nontolerant

individual might actually enhance certain performances of the highly

tolerant individual. One must be very careful therefore in defining

the drug history of experimental subjects when assessing a drug’s possible toxicity. Further, this complicates legal and social policies

regarding acceptable levels of drug use. Ultimately it would seem

appropriate to base legal decisions as to acceptable levels of drug

use on the basis of functional tests rather than on arbitrary blood

levels.

A final issue concerns the relationship of tolerance to drug dependence . The WHO (WHO Tech. Report 1964) has stated that drug dependence

includes three distinct components: tolerance, physical dependence,

and compulsive abuse (psychic craving). Different classes of abused

drugs show these three components in differing proportions. Opiates,

for example, produce all three components whereas with drugs such as

the psychomotor stimulants, the physical dependence component is minimal if not completely absent. It is unclear whether there are common

mechanisms underlying both tolerance and physical dependence. On the

other hand, it is clear that both tolerance and physical dependence

can be separated from a drug’s ability to generate compulsive abuse.

Thus, tolerance may occur with all drugs of abuse, but not all drugs

producing tolerance are subject to abuse. Clearly, more research is

needed to determine the importance of tolerance in the development of

drug dependence and the consequent abuse of drugs. I believe we have

only begun to do the systematic work necessary to define the pharmacologic, organismic, and environmental variables which affect the development of functional tolerance to the behavioral actions of drugs.

As the papers presented in this monograph emphasize, studies of

the repeated administration of drugs must take into consideration the

complex interaction between drug-induced behavioral change and the

consequences of such behavioral change in the organism’s adaptation

to his environment. I believe that behavioral pharmacologists have a

15
great deal to contribute to the understanding of the mechanisms underlying functional tolerance to behaviorally active drugs. Ultimately,

such understanding is essential for the evolvement of rational preventive and therapeutic approaches to the problems of drug abuse.

REFERENCES

Balster, R.L.,and Schuster, C.R. Fixed-.internal schedule of cocaine

reinforcement: Effect of dose and infusion duration.

Behav. 20:119-129. 1973.

J. Exp. Anal.

Campbell, J.C., and Selden, L.S. Performance influence on the development of tolerance to amphetamine. Pharmac. Biochem. Behav. 1:703-

708. 1973.

Deneau, G., Yanagita, T., and Seevers, M.H. Self-administration of

psychoactive substances by the monkey. Psychopharmacologia 16:30-38.

1969.

Downs, A.W.,and Eddy, N.B. The effect of repeated doses of cocaine

on the rat. J. Pharmac. a Therap. 46:199-200. 1932.

-

Ferster, C.B.,and Skinner, B.F. Schedules of Reinforcement. New York:

Appleton-Century Crofts, 1957.

Fischman, M.W.,and Schuster, C.R. Unpublished observation, 1973.

Fischan, M.W., and Schuster, C.R. Tolerance development to chronic

methamphetamine intoxication in the rhesus monkey. Pharmac. Biochem.

Behav. 2:503-508. 1974.

Fischman, M.W., and Schuster, C.R. The effects of long term methamphetamine administration in the rhesus monkey. J. Pharmac. Exp. Therap.

(in press). 1977.

Kalant, H., LeBlanc, A.E:,and Gibbins, R.J. Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmac. Rev. 23:

135-191. 1971.

Post, R.M. Progressive changes in behavior and seizures following

pit cocaine administration: Relationship to kindling and psychosis.

: Ellinwood, E.H.,and Kilbey, M.M., eds. Cocaine and Other Stimulants.

Advances in Behavioral Biology, vol. 21. New York Plenum Press, 1977.

pp.353-372.

Schuster, C.R., and Zimmerman, J. Timing behavior during prolonged

treatment with dl-amphetamine. J. Exp. Anal. Behav. 4:327-330. 1961.

Schuster, C.R., Dockens, W.S., and Woods, J.H. Behavioral variables

affecting the development of amphetamine tolerance. Psychopharmacoloeia 9:170-182. 1966.

Schuster, C.R., and Thompson, T. Self-administration of and behavioral dependence on drugs. Ann. Rev. Pharm. 9:483-510. 1969.

16
Schuster, C.R.. and Johanson. C.E. The use of animal models for the

study of-drug abuse. In: Poplan, R.E., Schmidt, Wolfgang, and Smart,

R. G., eds. Research Advances in Alcohol and Drug Problems, vol. 1.

New York: John Wiley Sons, 1974. pp. 1-31.

Schuster, C.R., and Balster, R.L. The discriminative stimulus properties of drugs. In: Thompson, T., and Dews, P.B., eds. Advances in

Behavioral Pharmacology. New York: Academic Press, 1977. pp. 85-138.

Seiden, L.S., Fischman, M.W., and Schuster, C.R. Changes in brain

catecholamines induced by long-term methamphetamine administration

in rhesus monkeys. Drug and Alcohol Dependence 1:215-219. 1976.

Seiden, L.S.,and Dykstra, L.A. Psychopharmacology: A Biochemical

and Behavioral Approach. New York: Van Nostrand Reinhold Co., 1977.

Shannon, H.E., and Holtzman, S.G. Evaluation of the discriminative

effects of morphine in the rat. J. Pharmacol. Exp. Therap. 198:54-

65. 1976.

Stripling, J.S., and Ellinwood, E.H. Sensitization to cocaine following chronic administration in the rat. In: Ellinwood, E.H.., and Kilbey,

M.M., eds. Cocaine and Other Stimulants. Advances in Behavioral Biology,

vol 21. New York: Plenum Press, 1977. pp. 327-351.

Tatum, A.L ., and Seevers, M.H. Experimental cocaine addiction. J.

Pharmac. Exp. Therap. 36:401-410. 1929.

Thompson, T.I., and Schuster, C.R. Behavioral Pharmacology. Englewood

Cliffs, New Jersey: Prentice-Hall Inc., 1968.

WHO scientific group report. Evaluation of dependence producing drugs.

WHO Tech. Rep. Ser. 287, Geneva. 1964.

AUTHOR

Charles R. Schuster, Ph.D., Professor of Psychiatry, University of

Chicago, Chicago, Illinois 60637

17
I. CONCEPTUALIZATION

Behavioral Tolerance

P. B. Dews, M.D., Ph.D.

Many different mechanisms for the development of tolerance to drugs

have been demonstrated, yet for some well-established examples of

tolerance, no mechanism has been shown. No doubt, additional mechanisms remain to be discovered. It is, therefore, impossible

to infer by exclusion a mechanism in any particular example of tolerance. We are here to discuss a particular mechanism of tolerance:

behavioral tolerance. Behavioral tolerance must be identified by

positive criteria, not by exclusion. Further, as the various mechanisms of development of tolerance are not usually exclusive, we must expect that more than one mechanism will be involved in the development

of tolerance to a drug, even in a single individual at a particular

time. A mechanism that has been shown to operate may make only a

trivial contribution to the total tolerance in a particular instance.

It is, therefore, necessary to measure the contribution of a particular mechanism; for, if the quantitative contribution is not assessed,

the major contributors to tolerance may be overlooked. Behavioral

tolerance has been discussed only in recent years and relatively few

workers have studied it quantitatively. It is the purpose of this

essay to contribute to the search for criteria for behavioral tolerance that can be applied in the laboratory and clinic and that lead

to quantitative assessments. The presentation will be largely theoretical and forward looking, and will rely heavily on analogies.

Quantitative criteria will be sought that will be hard to achieve,

and, indeed, comparable precision rarely has been achieved in physiological and biochemical studies. That most physiological and biochemical studies on tolerance do not fulfill precise quantitative criteria

is no reason why studies on behavioral tolerance should not seek to

do better. The establishment of strict criteria may be useful in suggesting the area of doubt remaining to be resolved in a particular line

of investigation; for example, the strict criteria articulated by Paton

(1958) for identification of neurohumora1 transmitters may have helped

to reduce premature claims for transmitter roles for substances found

in the CNS.

18
Tolerance has been defined as a reduction in the intensity of the effect of a dose of a drug, or the requirement of a larger dose for the

original intensity, when the drug has been previously present in a subject. It is preferable, however, to define tolerance as a shift to the

right of the dose-effect curve of a drug following appropriate exposure

to the drug. This definition emphasizes the importance of exploring

dose-effect relations and leads naturally to measurement of the degree

of tolerance as the shift in the curve. Pharmacologists have long

realized that it is more useful to measure changes in dose-effect

curve and not just changes in effect. The shift-to-the-right definition of tolerance also leads to analogies to drug antagonisms that

may be useful heuristically. Tolerance is antagonism to the effects

of a drug as a result of exposure to the drug itself or to a relative,

in which case the effect is called cross-tolerance. Tolerance may

be considered as reflexive (in the sense of a reflexive verb) selfantagonism.

We are led to ask whether there are varieties of tolerance corresponding to the varieties of antagonisms. Is there surmountable tolerance

in which the full range of effects of the drug can still be achieved,

but at consistently higher doses Tolerance to many of the effects ?

of morphine appears to be of this type. Is there unsurmountable tolerance, in which the full effect of the drug in the nontolerant subject can no longer be achieved at any dose, no matter how large? Tolerance to indirect effects of drugs, the drug liberating pharmacologically active substances from pre-existing body stores, must become

unsurmountable if the stores can be depleted. Is there irreversible

tolerance in which the effects of a drug in a subject are permanently

changed? The tolerance to some behavioral effects of drugs may be

of this type: in initial exposures the effects of the drug are enhanced by novelty that is permanently lost in the drug-experienced

subject (Dews 1962, p. 438). Negative tolerance clearly occurs in

the form of sensitization to the effects of a drug by prior exposure,

corresponding to potentiation in the realm of antagonism.

DEFINITIONS

Tolerance may be defined as the reduction in the effect of a constraint on a biological system as a result of exposure to the constraint. Tolerance develops to a variety of physical circumstances

such as heat, cold, and delivery of electric shocks. Tolerance develops to exercise and the effects of many brain lesions. Tolerance

is a very common biological phenomenon. The changed effect of a

drug is called pharmacological tolerance. Three types of pharmacological tolerance can be recognized by the processes they involve:

dispositional, physiological, and behavioral. Dispositional tolerance is conceptually the easiest to understand: as a result of

exposure to a drug, the physicochemical processes handling the drug

in the body are so modified that reduced concentrations of the drug

reach the receptive cells, whose modification produces the pharmacological effects of the drug.

19
The most familiar mechanism of dispositional tolerance is increased

rate of metabolism of the drug following repeated administration, as

by the induction of higher activity of metabolizing enzymes, typically in cells other than those responsible for the pharmacological effects of the drug. It follows that tolerance to all the effects of

the drug will occur, evidenced by a reduction in effect corresponding

to a movement left along the dose-effect curve by an amount determined

by the reduction in concentration of the drug. Because of the differing slopes and positions of dose-effect curves for different effects of even the same drug, the proportional reduction in the various

effects of the drug will not generally be the same even with pure

dispositional tolerance. Dispositional tolerance rarely produces a

more than 2- or 3-fold decrease in sensitivity, i.e., an 0.5 log unit

shift of the dose-effect curve to the right.

Physiological tolerance is a change in the receptive cells, or in

cells functionally related to them, such that the effects of a dose

of the drug are reduced, even though the receptive cells are subjected to the same concentration of the drug. The changes must be in the

specific cells related to the pharmacological effects of the drug.

Physiological tolerance may lead to a shift in the dose-effect by

one log (10) unit or more to the right. Rarely is much more known

about the mechanism.

Behavioral tolerance to a drug is a change in the effect of the drug

due to alteration of environmental constraints. In common parlance,

subjects learn to cope with the effects of the drug, but “learn” is

an undesirable word as it seems to point to a specific process, a

gratuitous and meaningless extension.

The distinction between the three types of tolerance is based on the

kind of mechanism involved, but the type of tolerance may be recognized without knowing the specific mechanism. Dispositional tolerance

may be diagnosed by knowledge of drug levels, without any information

on how the levels came to be changed in the tolerant subject. Physiological tolerance may be identified by the reduced responsiveness

of isolated tissue from a tolerant subject, also without any information on how the cells have changed their susceptibility. Recognition of type is generally much easier than elucidating mechanism and

is usually a prerequisite for the latter.

As with all relatively simple definitions, our definitions of types

of pharmacological tolerance should not be considered exhaustive.

New types may well be discovered. Indeed, it is easy to think of

possible mechanisms of tolerance that would not fit easily into any

of the three types. Suppose the reduction in the peripheral blood

flow caused by a vasoconstrictor is progressively attenuated because

the heart, unaffected directly by the drug, hypertrophies and generates higher arterial pressures. Such a mechanism of tolerance is

hardly covered by the definitions. Conversely, the definitions cover

some trivial cases of “tolerance.” Schuster points out that for a

drug with an inverted U-shaped dose-effect curve, in the absence of

any change in sensitivity, cumulation can move the effect to the

20
upper descending limb of the dose-effect curve, simulating tolerance.

Rather than elaborating the definitions in a futile attempt to make

them perfectly apposite to preconceptions, let us stay with brief,

simple definitions and add the limiting and aberrant cases as codicils. Such a course is surely better heuristically than defining

behavioral tolerance as tolerance to the behavioral effects of a

drug, which merely specifies the obvious dependent variable and provokes no further thought or experiment.

BEHAVIORAL TOLERANCE

Behavioral tolerance, then, is tolerance due to behavioral mechanisms.

Generally, behavioral tolerance is thought of only when the behavioral

effects of a drug change, but behavioral tolerance may develop to nonbehavioral effects of a drug. For example, a pigeon may continue to

work under FR 50 following a dose of pentobarbital that puts a nonworking pigeon to sleep and abolishes its righting reflexes. Behavioral tolerance to the nonbehavioral effects of pentobarbital in

producing sleep and abolishing righting reflexes may be developed,

therefore, by bringing a subject under the control of a behavioral

schedule. (If it be objected that sleep and righting reflexes may

be classified as behavior, we may predict confidently that the cardiovascular and respiratory effects of pentobarbital under the above

circumstances will be greatly influenced by the behavioral tolerance.)

Most of the tolerance to physiological and biochemical effects by

behavioral mechanisms is probably indirect, however, as in the example.

Obviously, tolerance to the behavioral effects of a drug may be dispositional and physiological as well as behavioral. The different

types are not exclusive and usually all occur simultaneously, so it

is important to measure the contributions. The rest of the discussion

will be devoted to behavioral tolerance to behavioral effects of

drugs.

Study of tolerance necessitates repeated measurements on the same

subject . If the behavior measured is of a kind that changes with

repeated measurements even in the absence of a drug, the assessment

of the development of tolerance to the effect of a drug would be so

hampered as to be usually unfeasible. In practice, we must seek behavioral activities that are quantitatively repeatable many times,

whenever consistent conditions are reimposed. The behavioral activities in relation to their environmental controls during sessions

must be in a steady state that persists predictably through successive

experimental sessions. For example, subjects under many schedules

of reinforcement emit similar patterns of responding and numbers of

responses in similar sessions repeated over long periods of time;

rhesus monkeys under mult FR FI yielded similar patterns and rates

over hundreds of sessions over a period of years (Dews 1977)) and

there are many other examples in the literature. Also, the effects

of doses of most drugs, judiciously spaced to avoid tolerance, on

schedule-controlled responding are qualitatively and quantitatively

similar on repeated administration. Unless it has been shown that

21
under some circumstances the effects of a dose of a drug are replicable in a subject, it is difficult to see how tolerance can be

identified and distinguished from metastability of the behavior itself, leading to irreversible change following a single exposure to

a variety of more or less nonspecific influences.

Repeatable patterns of behavior and repeatable effects of drugs on

the patterns indicate that the drug effect is a modulation of the

governing relations between schedule and consequent pattern of responding. With doses of drug insufficient to abolish behavior, the

patterns of responding continue to have a recognizable relation to

the controlling schedule; for example, under a variety of drugs,

clear differences in responding under FR and under FI of a multiple

schedule persist, though both patterns may be drastically changed

from control patterns. It is as though the schedule continued to

exert functional control under the drug, but that the drug had, in

effect, changed the parameter values of the functional relationship.

When the drug disappears, the parameters return to their prevailing

values. The development of behavioral tolerance would be a lessening

in the change of parameter with repeated doses of the drug.

One of the difficulties in studying tolerance to a drug is that, as

indicated before, the several types are usually operating simultaneously and jointly in the development of tolerance: mechanisms

of physiological, dispositional, and behavioral types, and often

more than one mechanism within each type. It may be useful in identifying specifically behavioral mechanisms in behavioral tolerance

to examine behavioral tolerance to agencies other than drugs. Consider a subject responding consistently in repeated sessions under

a particular schedule. If an additional salient, but irrelevant,

stimulus is added, the patterns of responding can be modified, as

with a drug. Repeated sessions with the new stimulus will lead to

a progressive return to the patterns of responding occurring before

the introduction of that stimulus. The progressive reduction in the

effect of the stimulus may be considered as behavioral tolerance to

the stimulus. The progressive reestablishment of original patterns

of responding in discrimination-reversal situations, for example,

when stimuli of a multiple schedule are interchanged, is behavioral

tolerance, although, of course, it has not been discussed in these

terms. The advantage of studying such situations to illuminate some

of the features of behavioral tolerance to drugs is that the direct

effects of the stimuli do not change with the development of tolerance.

If we use visual stimuli, the effects of the stimuli on the retina and

the resultant discharges in the optic nerves do not change as a stimulus comes to control, e.g., FR rather than FI patterns of behavior.

The same is true with auditory stimuli. The evidence for the preceding statements is that with the exception of a few very special circumstances such as visual deprivation in early life, neurophysiologists obtain consistent discharge patterns from eye and ear to specific stimuli from subject to subject without regard to the behavioral

history of the subject. Behavioral tolerance to a stimulus can be

studied with assurance that the direct impact of the stimulus is

22
constant. The situation is therefore clearer than for study of

behavioral tolerance to a drug, where the development of behavioral

tolerance is accompanied by the development of dispositional and

physiological tolerances.

Accepting that the behavioral mechanisms involved in behavioral tolerance to a stimulus are the same as those involved in behavioral

tolerance to a drug, study of tolerance to a stimulus can provide

valuable quantitative information on the rate of development of

behavioral tolerance. If the effects of a drug can be even very

roughly mimicked by manipulation of salient stimuli, then the amount

and rate of development of behavioral tolerance to the stimulus can

be used as an estimate of the contribution of behavioral tolerance

to the development of tolerance to the drug. There are three possibilities. First, the develoment of tolerance to the drug may be

greater than the development of behavioral tolerance to the stimulus. We would conclude that there was a significant contribution

from other mechanisms of tolerance developing along with the behavioral tolerance, the extent of the last being estimated from the

development of behavioral tolerance to the stimulus. Second, the

development of tolerance to the drug may be the same as the development of behavioral tolerance to the stimulus. We would conclude

that the develolpment of tolerance to the drug was primarily due to

behavioral mechanisms. Third, the development of tolerance to the

drug may be less than the developent of behavioral tolerance to the

stimulus . We would conclude that some aspects of the effects of the

drug were impairing the development of behavioral tolerance more than

dispositional and physiological mechanisms were enhancing tolerance.

For example, a drug interfering with motor coordination as well as

schedule-controlled responding may show little development of behavioral tolerance, because the drug impairs motor execution of the performance and so prevents the normalizing effect of the schedule on

the patterns of responding.

As is usual in pharmacology, indeed, in biology, the arguments of the

previous paragraph are by no means definitive and conclusive. For

example, impairment of the development of behavioral tolerance to

some effects of a drug by other effects of the drug may occur even

when the development of tolerance to the drug exceeds behavioral

tolerance, so that the contribution of dispositional and physiological mechanisms would be underestimated. Such refinements of estimates,

however, must surely await until an initial attack has measured the

contributions of the various mechanisms to a first order of approximation.

Let us consider another scheme for the measurement of behavioral

tolerance to drugs. It is characteristic of schedule-controlled

patterns of responding, at steady-state, that the control does not

diminish appreciably with the mere passage of time out of the situation. A subject showing stable patterns of responding under, say,

mult FR FI may be left without exposure to the schedule for days,

23
weeks, or even months, and then when re-exposed will give, from the

first, patterns of responding indistinguishable from those before

the recess. A subject with stable patterns under mult FR FI may be

subjected to sessions only once per week or once per two weeks and

will continue to respond during the sessions as it does when sessions

are daily, or, as is most common, on five days per week. It is

possible to have a subject work in daily sessions on an entirely

different schedule and still not interfere with responding in interpolated sessions under mult FR FI, provided, of course, that care

is taken not to confound stimuli. The property of durability is not

peculiar to mult FR FI; it is seen with most schedules that have

been studied; mult FR FI is chosen as an example because it is one

of the most widely studied schedules in behavioral pharmacology. In

the development of dispositional and physiological tolerance, however,

the frequency of exhibition of the drug is a crucial variable; it

is generally supposed that the more frequent the administration, the

greater and faster the development of tolerance. Indeed, the

optimum procedure for dispositional and physiological tolerance may

be to keep the subject continuously under the influence of the drug,

the target cells continuously bathed. If a subject undergoes a daily

session of schedule-controlled responding, and if repeated aclministrations of a dose of a drug at one-or two-week intervals yield consistent effects, it is reasonable to assume that the development of

dispositional and physiological tolerance is minimal at that frequency of administration. The subject could then be exposed to the schedule only once per week, or once per two weeks, but always under the

influence of the drug, the drug not being given otherwise. If tolerance to the effects of the drug develops under this regimen, a clear

case would exist for identifying all of the tolerance as behavioral.

Interesting variants of the scheme are apparent.

Since the beginning of behavioral pharmacology, there have been two

general experimental designs. Some workers have exposed subjects

to daily sessions, giving drugs on some days and leaving other days

as control days. Other workers have exposed subjects to double sessions daily, the first session being always a control session and the

second session being sometimes preceded by administration of a drug.

In light of experience, it is unlikely that either design has a decisive general advantage over the other, and they are used interchangeably. With respect to study of tolerance, the difference in

the design may make an important difference. Take a drug with a

moderate duration of action, say 1/2 time of about 4 hours? to whose

behavioral effects tolerance develops when the drug is given daily

before a session. If the double session design is used, the control

session will start about 20 hours after the previous day’s administration of the drug, so that only about 6% of the drug will remain,

and performance in the control session would presumably be normal.

Sessions under the drug would alternate with normal sessions. Under

the single session design, all responding would take place under

the influence of the drug. The development of behavioral tolerance

would be expected to be more pronounced under the latter regimen.

Further, when administration of the drug is discontinued, performance

in the first session without drugs would be expected to be abnormal

24
under the single session design, where all of the previous several

sessions had been performed under drug; under the double session

regimen, however, there is no reason to expect disturbance even in

the first postdrug session, since normal sessions have continued

to occur. The general approach offers the advantage that the contribution of behavioral mechanisms to tolerance is assessed during

continuing sessions rather than only during occasional probes or once

in the course of the experiment. As before, responding in the first

session after drug cessation should be abnormal under the single

session design, even if enough time is allowed to permit complete

dissipation of the physiological and biochemical aftermath of repeated drug administrations.

SUMMARY

Behavioral tolerance is defined as tolerance due to behavioral mechanisms. The study of behavioral tolerance to behavioral effects of

drugs requires, in the present state of knowledge, objective and

quantitative means of recording behavior. Behavioral activities that

do not lend themselves to such recording should probably be left

aside in the study of tolerance until the more general quantitative

features of tolerance have been measured in quantifiable systems.

The behavior selected should occur reproducibly in many successive

daily sessions. Many varieties of schedule-controlled patterns of

responding fulfill the preceding criteria! and it is likely that

study of schedule-controlled responding will play a central role

in elucidation of behavioral tolerance in the foreseeable future.

Drug and behavior should also be chosen that yield reproducible

effects of the drug when dosing is suitably spaced.

In a suitable system, the contribution of behavioral tolerance to

a drug tolerance may be estimated by:

1. measuring behavioral tolerance to changes in the environment

that grossly mimic the effect of the drug,

2. measuring tolerance development under conditions that permit

behavioral tolerance, but minimize other forms of tolerance.

These two criteria are insufficient. Our confidence in our estimate

of a contribution of behavioral tolerance depends on the number of

independent ways in which the estimate can be made and the closeness

in agreement of values arrived at in the different ways. Additional

criteria are needed. Understanding of behavioral tolerance may come

slowly, but interesting quantitative behavioral pharmacology will

be accumulating along the way.

25
REFERENCES

Dews, P. B. Psychopharmacology. In: Bachrack, A. J., ed.

Experimental Foundations of Clinical Psychology. New York: Basic

Books, 1962. pp. 423-441.

Dews, P. B. Studies on responding under fixed-interval schedules

of reinforcement: The scalloped pattern of the cumulative record.

Journal of Experiental Analysis of Behavior, 1977, in press.

Paton, W. D. M. Central and synaptic transmission in the nervous

system (pharmacological aspects). Annual Review of Physiology,

21:431-470, 1958.

AUTHOR

P. B. Dews, M.D., Ph.D., Laboratory of Psychobiology, Harvard

Medical School, Boston, Massachusetts 02115

26
II. NARCOTICS

A Pavlovian Conditioning Analysis

of Morphine Tolerance1

Shepard Siegel, Ph.D.

INTRODUCTION

Many of the effects of a variety of drugs, including morphine, decrease

in magnitude over the course of successive administrations, the phenomenon being termed tolerance. Most theories of tolerance stress the

physiological consequences of repeated pharmacological stimulation.

There is considerable evidence, however, that the display of tolerance

is highly dependent upon the organisms' experience with the drug

administration environment as well as the drug. The role of such

environmental signals of the drug in the development of tolerance has

been emphasized in an account of morphine tolerance which stresses

Pavlovian conditioning principles (Siegel 1975b; 1976, 1977b). This

paper describes this conditioning theory of tolerance and summarizes

data which support the theory.

DRUG ADMINISTRATION PAVLOVIAN CONDITIONING, AND DRUG TOLERANCE

A prototypical learning design is that developed by Pavlov (1927) who,

in fact, suggested that the usual drug administration procedure was

operationally similar to his conditioning situation (Pavlov 1927).

The basic conditioning preparation used by Pavlov involves

the use of TV cues. The first of these, the "conditional stimulus"

is said to be "neutral"; it elicits little relevant activity prior to

its pairing with the second stimulus, the unconditional stimulus. As

the name implies, the unconditional stimulus is selected because it

elicits relevant activities from the outset--unconditionally--prior to

any pairings. In Pavlov's well-known conditioning work, the conditional Stimulus was some conveniently manipulated exteroceptive stimulus

(bell, light, etc.), and the unconditional stimulus was either food or

orally injected dilute acid, both of which elicited a conveniently

monitored salivary response. In the case of drug administration, the

conditional stimili. are those procedures, cues, or rituals reliably

predicting the systemic stimulation induced by the drug, with the

actual central effects of the drug constituting the uoconditional

stimulus. The development of the association between these stimuli

may be revealed if the subject, following a history of administration

of the drug, is presented with the usual drug administration procedure

27
not followed by the usual pharmacological. consequences--rather, for

such a conditional response test session, a placebo is administered.

The Compensatory Pharmacological Conditional Response

Following Pavlov's demonstration that responses to drugs can be conditioned, there has been a considerable amount of research concerning

such pharmacological learning (see review by Siegel, 1977a). Although

many forms of conditional drug responses can be conceptualized, and

have been reported, an especially common type of pharmacological conditional response is opposite in direction to many of the effects of

the pharmacological unconditional stimilus. Table 1 (next page) summarizes a number of investigations which have reported such conditional responses opposite to the unconditional effects of the drug.

The Compensatory Pharmcological ConditionalResponse and Drug Tolerance

As suggested by Bykov (1959), conditional drug responses'

evidenced in anticipation of the actual pharmacological assault should

be expected to interact with the drug-induced unconditional response.

and thus pharmacological learning may be evidenced by the modulation

of the unconditional effects of the drug as it is repeatedly presented

in the context of the same situational cues. Since the drug conditional response is often opposite in direction to the drug unconditional.

response, the effect of the drug would be expected to became reduced

by this compensatory conditional response evidenced in anticipation of

the drug's central effects. Because the association between the drug

administration procedure and the systemic effects of the drug is

strengthened by repeated pairings, the drug's effect would be expected

to become increasingly cancelled as the drug-compensatory conditional

response grows stronger. Such a decreased effect of a drug, as a

function of successive experiences with the drug, defines tolerance.

The Morphine Compensatory Conditional Response and Morphine Tolerance

Of special relevance to the conditioning analysis of morphine tolerance

are several. demonstrations that the conditional response following

training with morphine consists of a variety of morphine-compensatory

responses. As indicated in Table 1, animals with a history of morphine

administration (with its analgesic, hyperthemic, and bradycardic

effects), when administered a placebo, display hyperalgesia (Siegel

1975b), hypothermia (Siegel, submitted), and tachyardia (Rush, Pearson,

& Lang 1970). Since organisms evidence such responses opposite to

those induced by morphine confronted with the usual predrug cues,

but without actual administration of the drug, it would be expected that

when morphine is presented in conjunction with the usual predrug cues,

these compensatory conditional responses would attenuate the

unconditional responses, thereby decreasing the observed response to

the drug over the can-se of successive administrations.

COMPARISON OF THE CONDITIONING THEORY WITH OTHER INTERPRETATIONS OF

TOLERANCE

The conditioning interpretation of tolerance may be contrasted with

formulations of the phenomenon which do not acknowledge a role for

28
TABLE 1

COMPENSATORY CONDITIONAL PHARMACOLOGICAL RESPONSES

Unconditional

Stimulus

epinephrine

epinephrine

epinephrine

glucose

insulin

nicotine

atropine

chlorpromazine

amphetamine

dinitrophenol

histamine

methyl dopa

lithium

chloride

nalorphine

morphine

morphine

morphine

Unconditional

Response

tachycardia

gastric secretion

hyperglycemia

hypoglycemia

hypoglycemia

hypoglycemia

antisialosis

activity

 02 consumption

to consumption,

hyperthemia

hypothermia

blood pressure

Conditional

Response

bradycardia

gastric secretion

hypoglycemia

hyperglycmia

hyperglycemia

hyperglycemia

hypersalivation

activity

O2 consumption

O2 consumption

hypothermia

hyperthermia

blood pressure

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

drinking

tachycardia

bradycardia

hyperthermia

analgesia

drinking

bradycardia

tachycardia

hypothermia

hyperalgesia

(l3)

(14)

(15)

(16)

(17)

a

(1) Russek & Pina (1962); Subkov & Zilov (1937). (2) Guha, et al.

(1974). (3) Russek & Pina (1962). (4) Mityushov (1954); Deutsch

(1974); LeMagnen (1975). (5) Siegel (1972a, 1975a). (6) Lundberg &

Thyselius-Lundberg (1931). (7) Korol, et al. (1966); Lang, et al.

(1966, 1969); Mulinos & Lieb (1929); Wikler (1948). (8) Pihl & Altman (1971). (9) Obal (1966). (10) Obal (1966). (11) Obal, et al.

(1965). (12) korol & McLaughlin (1976). (13) Domjan & Gillan (in

press). (14) Goldberg & Schuster (1967, 1970). (15) Rush, et al.

(1970). (16) Siegel (submitted). (17) Siegel (197%).

Referencea

29
associative processes. These alternative theories usually postulate

physiological changes, induced by early drug administrations, which

functionally reduce the effects of later drug administrations. Such

systemic alterations may involve opiate receptors in the brain (e.g.,

Collier 1965; Snyder & Matthysse 1975), or peripheral changes which

hinder the drug from gaining access to central receptors (e.g., Cochin

1971; Mule & Woods 1969). These physiological theories have been

extensively reviewed elsewhere (see Hug 1972, Kuschinsky 1977, Takemori 1975).

Some nonassociative interpretations of tolerance! like the conditioning

theory, stress the role of homeostatic counter adjustments to the pharmacological stimulation: As the drug is repeatedly administered, these

"autonomic hyperreactions" (Himmelsbach 1943) or "opponent processes"

(Solomon & Corbit 1974) elicited by the drug become stronger as they are

repeatedly exercised, acting increasingly to attenuate the effects of

the drug (for a review of many such theories, see Collier 1972).

These counteradjustment models, like those models which more particularly specify the nature of the systemic drug-induced alterations, do

not incorporate a learning process in the acquisition of tolerance.

In summary, all these traditional interpretations of tolerance are nonassociative. That is, they assert that tolerance results simply from

repeated pharmacological stimulation, and specify no role for drugassociated environmental stimuli in the display of tolerance. In

contrast, the conditioning interpretation of tolerance indicates that

the development of tolerance depends on repeated pairings of environmental cues signalling the drug with the systemic effect of the drug,

and not merely the frequency of pharmacological stimulation -

A Note on Associative vs. Nonassociative Theories of Tolerance

For purposes of exposition, a conditioning theory of tolerance is

distinguished from the more traditional, nonassociative theories. In

fact, both associative mechanisms and systemic processes unrelated to

associative mechanisms are undoubtedly involved in tolerance. Clearly,

processes unrelated to learning are relevant to interpreting tolerance

observed when the drug is not repeatedly presented (e.g., pellet implantation studies, Way, Loh, & Shen 1969), or when tolerance is

observed in the offspring of rats prenatally treated with opiates

(O'Callaghan & Holtzman 1976, 1977), or when tolerance is observed in

isolated tissue (e.g., Paton 1957; Takemori 1962). However, it is

equally as clear that many tolerance phenomena appear inexplicable

without incorporating a learning mechanism in interpretations of tolerance and that until recently the contribution of learning to tolerance

has been largely ignored by investigators in the area. The research

reported in this paper was designed to clarify the role of conditioning

in tolerance, but not to suggest that pharmacological phenomena

can best be understood merely with an appreciation of Pavlovian principles.

EVIDENCE FOR THE CONDITIONING THEORY OF TOLERANCE

We have completed a substantial amount of research which provides evidence that association between the drug administration ritual and

the systemic effects of the drug plays an important role in the

30
acquisition of tolerance. The complete reports of most of these experiments have been published, and only the major findings will be briefly

summarized here.

General Methods

Certain procedures were common to all the experiments summarized

in this section. The subjects were experimentally naive, male, albino

rats. All injections were made subcutaneously in the dorsal surface of

the neck. The drug dose was 5mg/kg (of a 5 mg/ml solution) of morphine

sulfate. All placebo injections consisted of an equivalent volume of

physiological saline (i.e., 1 ml/kg).

In some investigations, the analgesic effect of the drug was assessed

with the hot plate technique (Fennessy & Lee 1975) which involves the

determination of the rat's latency to lick a paw following placement

on a warm (54.2" C) surface (with analgesic responses indicated by

relatively long paw-lick latencies). In other investigations, analgesia level was assessed with a cammercially available version of the

Ramdall-Selitto paw-pressure analgesiometer (Randall & Selitto 1957).

To use the analgesiometer, the rat is positioned so that it is free

to withdraw its paw from a source of gradually and constantly increasing pressure, with the amount of pressure applied before the pawwithdrawal response occurs providing a measure of pain sensitivity

(with analgesic responses indicated by relatively high paw-withdrawal

thresholds).

The dose of morphine used in these experiments elevates, body temperature

in the rat, the magnitude of this hyperthermic response successively

decreasing with successive drug administrations (Gunme 1960, Hermann

1942; Winter 6 Flataker 1953). In same experiments, the role of

conditioning in such pyretic tolerance was investigated. 21 these

studies, colonic temperature was assessed with an electronic thermometer 30 sec after the probe was inserted 4 cm into the rat's rectum.

In these experiments, unless otherwise indicated, the usual drug

administration procedure involved transporting the rat, in its home

cage, from the colony room to a different room which, in different

experiments, contained either the hot plate, analgesiometer, or temperature assessment apparatus. A constant background of white noise waS

maintained in this room. The rat was injected in this distinctive

environment, and, in sane experiments, the drug's effect was determined

on a single occasion, usually one-half hr after the injection. In

other experiments, the time course of the drug's effect was determined

by sequential assesments on many occasions after administration. The

interval between injections differed in different experiments, but was

never less than 24 hr.

The Situation Specificity of Tolerance

Although there are many nonassociative interpretations of tolerance,

they are all similar in stipulating that tolerance results from systemic changes induced by repeated pharmacological stimulation However,

there are many demonstrations that tolerance does not result simply

from the organism suffering repeated pharmacological stimulation. It

does result from repeated administration of the drug in the context of

31
environmental. cues which reliably signal the impending chemical stimulation. A remarkable series of experiments by Mitchell and his colleagues have demonstrated that rats (Adams, Yeh, Woods, & Mitchell

1969, Ferguson, Adams, &Mitchell 1969, Gebhart &Mitchell 1971, 1972;

Gebhart, Sherman, & Mitchell 1971, 1972, Kayan, Ferguson, & Mitchell

1973; Kayan &Mitchell 1969, 1972; Kayan, Woods, &Mitchell 1969,

1971) and humans (Ferguson &Mitchell 1969) respond in the expected

tolerant manner to the analgesic effect of the last of a series of

morphine injections only if this final injection is presented in the

same environment as the prior injections in the series. These findings, although not readily interpretable by theories of tolerance which

do not acknowledge a role for drug-associated environmental cues in the

acquisition of tolerance, are expected on the basis of the conditioning

theory of tolerance. According to this conditioning theory, cues that

reliably predict the systemic effect of the drug should be crucial to

the development of tolerance because they enable the subject to make

timely compensatory responses in anticipation of the central responses

elicited by the drug.

We have completed a number of studies (Siegel 197fb, 1976, submitted,

in preparation) which confirm and extend these previous reports indicating that the display of morphine tolerance is greater in the environment in which the drug has been previously administered than in an

alternative environment. The details of the designs of these investigations from our laboratory differ somewhat from experiment to experiment, but they all incorporated two groups, both of which received

morphine a sufficient number of times for tolerance to develop, with

the effect of the drug being assessed following the Last administration.

For one group, this final administration and evaluation of the drug's

effect took place in the same environment as that in which the previous

injections occurred. For the second group, this tolerance test took

place in a different environment than that in which the previous injections occurred. The results of a number of such experiments are summarized in Figure (next page). These experiments have consistently

demonstrated that animals tested following drug administration in the

same environment in which they had previously experienced the drug

respond less (i.e., are more tolerant) than animals tested following

drug administration in a different environment from that which they

had an opportunity to associate with the drug. The difference between

these two conditions, labeled SAME and DIFFERENT in Figure 1, were, in

each experiment, statistically significant.2

Figure IA indicates the results of one of these experiments (Siegel

1975b, Experiment IA) in which independent groups of rats were tested

for the analgesic properties of morphine either in the same environment

in which they had previously received the drug, or in a different environment. Rats in the group labeled SAME were injected with morphine on

four occasions in the distinctive room, with hot-plate responsivity

determined for the first time 30 min following the fourth administration of the drug. The latency to respond to the heat stimulation in

this group, which was tested for the effects of the fourth drug administration in the context of the same environmental cues as those present

at the time of the three prior administrations, was contrasted with

that displayed by rats in the group labeled DIFFERENT, which received

the three pretest drug administrations in a different environment, the

colony room. As can be seen in Figure lA, Group SAME was more sensitive

32
FIGURE 1

Summary of results of experiments demonstrating that rats

display greates morphine tolerance to the final injection of a series

if this final injection is administered in the same environment as the

prior injections (SAME) than if the final injection is administered in

a different environment (DIFFERENT ) . Figure IA illustrates hot-plate

response latencies reported by Siegel (1975b, Experiment IA), with

groups designated SAME and DIFFERENT corresponding to Groups M-CP and

M-CAGE, respectively, in the original experiment. Figure IB illustrates hot-plate response latencies reported by Siegel (1976), with

groups designated SAME and DIFFERENT corresponding to groups trained

with a nonfunctional hot plate and nonfunctional paw-pressure analgesiometer, respectively. Figure 1C illustrates analgesiometer paw-withdrawal thresholds reported by Siegel (1976), with groups designated SAME

and DIFFERENT corresponding to groups trained with a nonfunctional

analgesiomter and nonfunctional hot plate, respectively. Figure ID

illustrates hot-plate response latency time-effect curves, constructed

with independent groups at each temporal interval (Siegel, in preparation), Figure 1E illustrates thermal modifications reported by Siegel

(submitted), with groups designated SAME and DIFFERENT corresponding

to Groups Mor-ROOM/Sal-CAGE and Mar-CAGE/Sal-EWM, respectively, in

the original experiment.

33
to the heat stimulation (i.e., more tolerant to the analgesic effect

of the drug) than Group DIFFERENT.

Figure 1B displays the results of another experiment (Siegel, 1976)

which similarly demonstrated that, following eight morphine injections,

rats responded on the hot plate following a subsequent injection of the

drug more rapidly if this test injection was administered in the same

environment as the previous injections, rather than in a different

environment.

Figure 1C presents the results obtained from additional groups included

in Siegel's (1976) study, for which pain sensitivity was assessed with

the paw pressure analgesiometer. Once again, rats with a similar history of morphine stimulation do not respond in a similar manner to the

final test injection Group SAME subjects were more sensitive to the

pressure stimulation (i.e., n-ore tolerant) than Group DIFFERENT subjects.

In a further experiment, the time course of the analgesic response to

morphine was assessed (Siegel, in preparation). Independent groups of

rats (6 rats per group) were tested on the hot plate at various intervals of time following their sixth morphine injection. That is, timeeffect curves were constructed using independent groups at each assessment interval (rather than testing each subject repeatedly). The

results are displayed in Figure lD. As may be seen in Figure ID, rats

displayed much more tolerance to the analgesic effect of morphine the

sixth time it was administered if such administration occurred in the

same environment as that in which they were injected on the five prior

occasions than if this sixth injectionoccurred in a different environment.

The results of the expertits summarized in Figures IA-D demonstrated

that environmental cues are crucial for the display of tolerance to

the analgesic effect of morphine. This pain-sensitivity measure of

opiate action (althogh the most common in investigations of tolerance)

uses an indirect behavioral criterion of pharmacological activity, and

it has been suggested that it may be an uncertain manifestation of the

drug's effect (Goldstein, Arnow, & Kalman, 1974). Thus, an

additional experiment was conducted to determine if environmental cues

are also important in the display of hyperthermic tolerance (Siegel,

submitted, Experiment IA), The design of this experiment was somewhat

different from that of the analgesia experiments. During the pretest

phase of the experiment, tolerance waS induced in two groups of rats

by injecting them with morphine on 10 occasions, one injection every

On those alternate days when morphine was not administered,

both groups of rats were injected with physiological saline. Morphine

and physiological saline were systematically administered in either of

two different environments, with the two groups differing only with

respect to the environmental cues associated with each injected substance. One group received its morphine injections in the distinctive

room and its saline injections in the colony room. The second group

received its morphine injections in the colony room and its saline

injections in the distinctive roan For both groups, following each

injection in the distinctive room, the rat remained in this room for

two hr, with colonic temperature assessed immediately after the injection and thereafter at 10-min intervals. Following this tolerance

development phase of the experiment, rats in both groups were

34
administered morphine in the distinctive roan, followed by colonic

temperature assessment. It should be emphasized that prior to this

final session, both groups had equalexposuretothetestenvironment

and temperature assessment procedure For one group, however, this

final test session consisted of the usual pre-morphine environmental

cues signalling the usual pharmacological consequences (Group SAME).

In contrast, for the second group, morphine was administered in the

context of cues which, in the past, signalled physiological saline

rather than the opiate (Group DIFFERENT). The time course of the mean

temperature alteration following this final injection in the distinctive room for each group is shown in Figure I.E. As is obvious in

Figure IE, the pyretic effect of the drug was much more pronounced in

Group DIFFERENT than in Group SAME. In fact, Group DIFFERENT showed

no evidence of pyretic tolerance, the hyperthermic response following

this eleventh injection of morphine for Group DIFFERENT did not differ

significantly from that which would be expected the first time rats

receive the drug.

In all the experiments summarized in this section, prior to the final

tolerance test session, both Groups SAME and DIFFERENT suffered the

same morphine-induced systemic effects, equally as often, and at the

same intervals. The rats in these groups should have been subject to

the same metabolic, cellular, or immunifacient modifications that,

according to the various nonassociative theories, mediate tolerance.

Thus, it would be expected, according to any of these traditional

theories of tolerance, that the two groups should not differ in the

acquisition of tolerance. In every experiment, it was found that the

group which received the drug in a distinctly different environment

for the pre-test sessions evidenced little if any indication of tolerance on the test session, suggesting that reliable environmental signals of the drug are important in the development of tolerance. These

results are expected on the basis of the conditioning analysis of

tolerance, but not of the alternative formulations.

Extinction of Morphine Tolerance

A unique prediction of the conditioning account of morphine tolerance

is that tolerance should be subject to the decremental effects of extinction. That is, if morphine tolerance occurs because environmental

cues signalling the central effect of the drug elicit a compensatory

conditional response, acting to cancel the effect of the opiate, presenting the administration cues without the drug to the tolerant organisn should extinguish these learned responses, and thus cause some

recovery of the response to morphine. In other words, according to

the conditioning theory of tolerance, repeated placebo sessions should

be an effective procedure for attenuating established tolerance.

The results of a number of experiments have, in fact, demonstrated that

morphine tolerance is subject to extinction (Siegel 1975b, Experiment

3; Siegel 1977b-, Experiments 1 and 2, Siegel, submitted, Experiment

2). Although there were numerous procedural differences between the

experiments, all incorporated two groups, both of which initially

received a series of daily morphine injections sufficient to induce

tolerance. This constituted the tolerance acquisition phase of each

experiment. Some days later, subjects received at least one further

injection of morphine. This final experience with the drug constituted

the tolerance test phase of each experiment. The two groups differed

35
only with respect to their treatment during the interval between the

tolerance acquisition phase and the tolerance test phase. One group

received daily placebo sessions, i.e., they were treated in the same

manner as on morphine sessions, except the substance injected was

physiological saline rather than the opiate (hereinafter referred to

as Group EXT, i.e., extinction). The response of Group EXT to the drug

during the tolerance test indicated the effects of repeated presentations of the morphine administration procedure, in the absence of the

drug, on tolerance acquired during the tolerance acquisition phase

Rats in the second group were simply left undisturbed in their home

cages during the period between tolerance acquisition and tolerance

testing (hereinafter referred to as Group REST). The response of subjects in Group RED to the drug during the tolerance test provided a

measure of any alteration in tolerance attributable simply to the interval that intervened between the tolerance acquisition phase and the

tolerance test phase.

According to the conditioning interpretation of tolerance, presenting

drug-associated environmental conditional stimuli without the drug is

an extinctionprocedure, and thus the group receiving such treatment

subsequent to tolerance acquisition (Group EXT) would be expected to

display less tolerance on the tolerance test than would the group with

no such extinction experience (Group REST). Results of four experiments demonstrating that such extinction does, in fact, occur, are

summarized in Figure 2 (next page). In all experiments, it was found

that extinction attenuated tolerance established during the tolerance

acquisition phase of the experiment.

Figure 2A illustrates results reported by Siegel (1975b, Experiment 3).

In this experiment, rats in Groups REST and EXT were each initially

given three, daily, morphine-hot plate analgesia assessment sessions

in the distinctive room, which was sufficient for a substantial amount

of tolerance to the analgesic effect of the drug to develop (there

being no difference between the two groups in the acquisition of analgesic tolerance). Group EXT rats were then given nine daily placebo

sessions, and Group REST rats Were left undisturbed for nine days. On

the tolerance test session, which occurred on the day after the ninth

placebo session (Group EXT) or the ninth rest day (Group REST), all

subjects me again injected with morphine. As is obvious in Figure

2A, on this test session, morphine had a me pronounced analgesic

effect in Group ExT than in Group REST. (The difference between Groups

EXT and REST was statistically significant in this and other experiments summarized in Figure 2.)

Prior to the morphine test session, both groups suffered the systemic

effects of morphine equally as often, at the same intervals, and with

the same analgesic effect. According to the nonassociative interpretations of tolerance, both groups should display equal tolerance when

presenting the morphine administration ritual unacconpanied by the

again injected with the drug on the test session. However 

central effects of the opiate to Group EXT, tolerance subsequently observed in this group was substantially attenuated Such attenuation

of tolerance was not due simply the nine-day delay between the end

of tolerance acquisition and the tolerance test, since this delay did

not affect the tolerance of Group REST (in agreement with other reports

that morphine analgesic tolerance dissipates little simply with the

36
FIGURE 2

Summary of results of experiments demonstrating that morphine

tolerance can be extinguished. In each experiment, all subjects

were first made tolerant to morphine, and then given a series of either

placebo sessions (EXT) or a rest interval (REST) prior to a morphine

tolerance test session, with only the results obtained on this tolerance test session illustrated for each experiment. Figure 2A illustrates hot-plate response latencies reported by Siegel (1975b, Experiment 3). Figures 2B and 2C illustrate analgesiometer paw-withdrawal

thresholds reported by Siegel (1977b, Experiments 1 and 2, respectively) . Figure 2D illustrates thermal modifications reported by Siegel

(submitted, Experiment '2).

37
passage of time [e.g., Cochin & Kornetsky 1964, Kayan & Mitchell

19721).

Inasmch as no nonassociative interpretation of tolerance would predict

that tolerance should be subject to extinction, it was thought desirable to assess the reliability of this confirmation of a unique prediction of the conditioning theory of tolerance with a different analgesia

assesment situation. The design of this subsequent experiment (Siege1

1977b, Experiment 1) was similar to that of the earlier hot-plate experiment by Siegel (1975b, Experiment 3), with the following exceptions:

Analgesia level was assessed with the paw-pressure analgesiomter; the

tolerance acquisition phase of the experiment consisted of six sessions;

and subjects received either 12 placebo sessions (Group EXT) or a 12-

day rest interval (Group REST) between tolerance acquisition and tolerance testing. The results obtained on the tolerance test session are

shown in Figure 2B. It required significantly more pressure to elicit

a paw-Withdrawal response in Group EXT rats than in Group REST rats.

Once again, Group EXT responded to morphine with a higher level of

analgesia (i.e., more tolerance) than Group REST, despite the fact that

the two groups did not differ in any manner with respect to their experience with the opiate prior to the test session.

The results of the two experiments described above indicated that presentations of the morphine administration procedure to morphine tolerant rats deleteriously affected the display of tolerance. In both

experiments, an attempt was made to make the placebo-initiated extinction sessions as similar as possible to the drug administration sessions, including the application of nociceptive stimulation. Thus,

only the group subjected to extinction (Group EXT) had any experience

in making the analgesia-indicant response--either paw licking (Figure

2A) or paw withdrawal (Figure 2B)--whilenot drugged. A further

experiment was conducted (Siegel, 1977b, Experiment 2) to determine

whether extinction is an effective procedure for attenuating established

tolerance even if subjects do not practice the analgesia-indicant response during the extinction sessions. In addition, this experiment

differed from the previous tolerance-extinction experiments in two

other major respects: (a) the time course of the opiate-induced analgesia was assessed (in the previous experiments, the analgesic effect

of each administration was assessed on only a single occasion, .5 hr

after injection), and (b) the effect of extinction on single dose tolerance was evaluated (previous work has demonstrated that only a single

experience with morphine is sufficient to subsequently reduce the analgesic effect of a second administration [Ferguson, et al. 1969; Kornetsky & Bain 19681). During the tolerance acquisition phase of this

further extinction experiment, subjects in Groups EXT and REST were

injected with morphine on only a single occasion, and evidenced similar

analgesic tin-e-effect curves. Group REST subjects were then left undisturbed for four days, while Group EXT subjects received four daily

placebo sessions, but without analgesia assessment. On these placebo

sessions, Group EXT rats were positioned in the analgesiometer after

each of the post-injection assessment intervals, but the apparatus was

nonfunctional and no pressure was applied to the paw. Five days following their tolerance acquisition injection of morphine, all subjects

received their tolerance test session. Thus, prior to this second

morphine session, both groups had but a single experience with opiate

stimulation and analgesia assessment.

38
The time course of the analgesic effect of the drug on the tolerance

test session for both groups is shown in Figure 2C. Examination of the

time-effect curves reveals that Croup EXT was less sensitive to the

pressure stimulation than Group REST, and evidenced peak responsivity

to the drug closer to the tin-e of administration than Croup REST--both

indicative of less analgesic tolerance (see Siegel, 1977b, Experiment

2). The results of this experiment, in agreement with the previously

described experiments, demonstrated that morphine tolerance is subject

to extinction, supporting the conditioning analysis of tolerance.

Additionally, the results of this experiment indicated that such extinction of morphine tolerance can be observed after only a single

administration of the drug, and is not attributable to any additional

practice that extinguished subjects have in responding to the aversive

stimulation used to evaluate the effect of the drug.

The results of experiments summarized in Figures 2A-C demonstrated that

tolerance to the analgesic effect of morphine can be extinguished. A

final experiment in this series was designed to determine whether tolerance to the py-retic effect of morphine similarly could be extinguished

(Siegel, submitted, Experiment 2). During the tolerance acquisition

phase of this experiment, subjects in Groups REST and EXT were each

administered morphine for 12 daily sessions, with the colonic temperature of each subject being determined at 15-min intervals following

each injection. Both groups evidenced a similar course of tolerance

acquisition. Croup EXT subjects then received 12 daily placebo sessions (which were conducted in the same manner as morphine sessions,

except that the substance injected was physiological saline) As WAS the

case in the previously described experiments, Group REST was left undisturbed during this period. Finally, all rats received a tolerance

test session, which was initiated with an injection of morphine.

To evaluate the extent to which extinction can attenuate tolerance, the

design of this hyperthermic tolerance experiment included a group which

received morphine for the first time during tolerance testing (Group

CONTROL).3 To the extent that extinction is an effective procedure

for attenuating established pyretic tolerance, Croup EXT should, on

the tolerance test, evidence a drug-induced hyperthermia resembling

that seen in Group CONTROL. The thermic effects of the drug on the

tolerance test session, for each group, are shown in Figure 2D. By

comparing Croups REST and EXT, it is clear that extinction decreased

hyperthermic tolerance. Indeed, the hyperthermic tolerance of Croup

EXT was so reduced that the pyretic effect of morphine was similar to

that obtained in Group CONTROL, which received the drug for the very

first time during the tolerance test. Thus, in this experiment, extinction not only was an effective procedure for attenuating tolerance--

in fact, the procedure eliminated tolerance.

It would appear to be well-established that tolerance can be extinguished. Indeed, under sane circumstances, repeated presentations of the

drug administration environment in the absence of the drug to the

tolerant subject can completely abolish tolerance. Evidence for the extinction of tolerance is robust, having been demonstrated in four experiments encompassing a range of procedural differences and parametric

manipulations. These findings that tolerance is subject to extinction

(like the previously presented findings on the situation-specificity of

tolerance) appear inexplicable by traditional interpretations of

39
tolerance which stress only the effects of repeated pharmacological

stimulation, and ignore the importance of cues present at the time of

such stimulation. However, the finding that tolerance can be extinguished is readily interpretable by the conditioning model of tolerance.

Partial Reinforcement of Morphine Tolerance

Results discussed previously demonstrated that extinction, a procedure

which decrementally affects established conditional responses, similarly

affects established analgesic and pyretic tolerance, thus supporting the

conditioning analysis of tolerance. If tolerance is a manifestation of

a conditioning process, it would be further expected that manipulations

of the putative conditional stimulus (i.e., environmental. cues present

at the time of drug administration) known to be effective in retarding

acquisition of conditional responses would similarly retard the acquisition of morphine tolerance. One such procedure that is effective in

retarding conditional response acquisition is partial reinforcement.

if the unconditional stimulus is paired with the conditional stimulus

on less than 100% of the trials, conditional response acquisition is

generally poor, relative to a situation in which every conditional

stimulus is paired with the unconditional stimulus (see Beecroft 1966).

Although most studies of partial reinforcement effects

in classical conditioning have compared 100% to 50% reinforcement

schedules, there is evidence that acquisition rate declines as the percentage of reinforced conditional stimuli decreases, even when the

number of reinforced trials is equated in the various reinforcement

schedule conditions (i.e., both partially and continuously reinforced

groups receive the same number of paired presentations of conditional

and unconditional stimuli, with the partially reinforced group receiving additional conditional stimlus-alone trials interspersed between

these paired trials).

The implication of the partial reinforcement literature for the conditioning theory of tolerance is clear: A group in which only a portion

of the presentations of the drug administration cues are actually

followed by morphine (i.e., a partial reinforcement group) should be

slower to acquire tolerance than a group which never has exposure to

environmental cues signalling the drug without actually receiving the

drug (i.e., a continuous reinforcement group), even when the two groups

are equated with respect to all pharmacological parameters.

We have completed experiments concerned with the effects of partial

reinforcement on both analgesic (Siegel 1977b_, Experiment 4) and

pyretic (Siegel, submitted, Experiment 3) tolerance In both experiments, rats were administered morphine a sufficient number of times

for tolerance to be evidenced, with the interval between morphine sessions irregularly varied between two and five days. In each experiment,

one group was continuously reinforced (Group CRF). For Group CRF all

presentations of the drug administration procedure were accompanied by

the drug, subjects in this group simply being left undisturbed in their

home cages on the days between morphine sessions. A second group in

each experiment was partially reinforced (Group PRF). For Group PRF,

only a portion (25%) of the presentations of the drug administration

procedures were accompanied by the drug. Subjects in this group received the drug on the same days as subjects in Group CRY, but on each

of the days between drug sessions they received placebo sessions (that

40
is, they were treated in the same manner as on morphine sessions, except

the substance injected was physiological saline rather than the opiate).

Thus, in each experiment, rats in Group CRF and PRF received the same

dose of the drug, equally as often, and at the same intervals. The two

groups differed only with respect to the reliability of environmental

cues as signals for the drug. Group CRF subjects always experienced

these cues in conjunction with the drug, and never without the drug.

In contrast, Group PRF subjects had extensive experience with these

cues, without the drug, between drug sessions.

The results of the two partial reinforcement experiments are summarized

in Figure 3 (next page). Figure 3A displays the mean response latency

on the hot plate, 30 min following each morphine injection, for both

goups in the analgesic tolerance experiment (Siegel, 1977b_, Experiment

. As indicated in Figure 3A, both groups displayed analgesic tolerance, that is, decreasing response latency to the thermal stimulation

as a function of repeated morphine sessions. However, as may be seen

in Figure 3A, tolerance was acquired more rapidly by subjects in Group

CKF than by subjects in Group PRF. This difference, which is statistically significant (mixed design analysis of variance, p's <.Ol), demonstrates that partial reinforcement retards the development of morphine

analgesic tolerance, much as it has been demonstrated to retard learning

in more traditional conditioning preparations.

The deleterious effect of partial reinforcement on tolerance was also

demonstrated in the investigation of pyretic tolerance (Siegel, submitted, Experiment 3). The results obtained in that experiment are

summarized in Figure 3B, which displays the mean colonic temperature

two hr following each morphine injection for groups which either did

or did not have placebo sessions interspersed between these morphine

sessions (Groups PRF and CRF, respectively).4 Again, both groups evidenced tolerance to the hyperthermic effects of morphine, but this

tolerance developed significantly more rapidly in Group CRF than in

Group PRF.

It should be emphasized that in both partial reinforcement experiments,

Groups CRF and PRF do not differ with respect to pharmacological history, yet they do differ in speed of tolerance acquisition. These

experiments clearly demonstrate that the development of tolerance can

be affected simply by manipulation of the reliability of environmental

cues as signals for morphine. The findings, although not explicable

by any interpretation of tolerance which ignores these cues, are to be

expected on the basis of the conditioning model of tolerance.

Latent Inhibition of Morphine Tolerance

The results of the experiments described in the previous section indicated that one procedure that is effective in retarding the acquisition

of conditional responses, partial reinforcement, is also effective in

retarding the development of morphine tolerance, thus supporting the

conditioning analysis of tolerance. Another procedure which is known

to have a deleterious effect on conditional response formation is preconditioning exposure to the conditional stimulus. It has been reported that in many conditioning preparations, with both human and a

variety of infrahuman subjects, presentations of the conditional

stimulus prior to the start of acquisition serve to decrease the

41
FIGURE 3

Summary of results of experiments demonstrating that the

acquisition of morphine tolerance is retarded in a group in which only

25% of the presentations of the drug administration procedure are accompanied by morphine (PRF), compared to a group in which all presentations

of the drug administration procedure are accompanied by morphine (CRF).

Figure 3A illustrates hot-plate response latencies reported by Siegel

(1977b, Experiment 4). Figure 3B illustrates therma1 effects reported

by Siege1 (submitted, Experiment 3).

MORPHINE SESSIONS

MORPHINE SESSIONS

42
effectiveness of that stimulus when it is subsequently paired with an

unconditional stimulus during conditioning. The deleterious effect of

conditional stimulus preexposure has been termed "latent inhibition"

(Lubow & Moore 1959). Although there is some controversy concerning

the mechanism of latent inhibition (see reviews by Lubow, 1973, Siegel

1972b), the theoretical interpretation of the phenomenon is irrelevant

for its exploitation as a technique to assess the conditioning theory

of morphine tolerance. According to this theory, inasmch as tolerance

results from an association between the predrug environmental conditional. stimulus and the pharmacological unconditional stimulus, the course

of tolerance acquisition should be affected by the relative novelty of

environmental cues present at the time of drug administration. Thus,

on the basis of the conditioning theory of tolerance, animals with extensive experience with the administration procedure prior to its actual

pairing with morphine should be relatively retarded in the acquisition

of tolerance, compared with animals with mininmal prior experience with

these environmental cues, despite the fact that both groups suffer the

systemic effects of the same dose of the opiate, given the same number

of times, at the same intervals.

We have reported the results of an experiment designed to assess whether

the latent inhibition procedure does, in fact, retard the acquisition

of analgesic tolerance (Siegel 1977b, Experiment 3). In this experiment, one group of rats was extensively preexposed to the drug administration cues, in the absence of the drug, before these cues were actually followed by morphine. Rats in this group (Group 18P) received 18

daily placebo sessions prior to seven daily morphine sessions. Rats in

a second group received only a single preexposure to the administration

procedure prior to this procedure actually signalling the drug (Group

1P). Rats in Group 1P received a placebo session the day before the

start of the seven daily morphine sessions.

The mean response latencies of Groups 18P and IP on the hot plate following each morphine injectionare shown in Figure 4 (next page). As

can be seen in Figure 4, both groups evidenced similar, highresponse

latencies following the first morphine administration, which is a

manifestation of the initial analgesic effect of the drug. Response

latencies of both groups rapidly decreased on subsequent drug sessions

(i.e., analgesic tolerance developed), but this decrease was significantly more rapid [F(1,20)=6.25,p=.02] for Group IP than for Group 18P.

On the basis of any of the systemic, nonassociative theories of tolerance, it would be expected that Groups IP and l8P should become equally

tolerant to the analgesic effect of morphine. The two groups displayed

equivalent levels of analgesia the first time they received the drug,

and both groups had equivalent experience with the systemic effects of

the drug. However, contrary to this expectation of nonassociative

interpretations of tolerance, tolerance was more marked in Group 1P

than in Group 18P. This finding that predrug experience with the

administration procedure retards the acquisition of tolerance (i.e.,

that tolerance is subject to latent inhibition) supports yet another

unique prediction of the conditioning model of tolerance, and is not

explicable by alternative theories of tolerance which do not enphasize

the role of drug-associated environmental cues in the development of

tolerance.

43
FIGURE 4

Mean response latency on the hot plate following each of

seven morphine injections for groups receiving either 18 preexposures

(18p) or 1 preexposure (1P) to the drug administration procedure prior

to morphine administration (from Siegel 1977b, Experiment 3).

1 2 3 4 5 6 7

MORPHINE SESSIONS

44
LEARNING AND TOLERANCE : RESEARCH FROM OTHER LABORATORIES

The results of a number of experiments conducted in my laboratory have

been summarized, all supporting the Pavlovian conditioning analysis of

morphine tolerance. These investigations have all demonstrated that

tolerance (at least in part) is a manifestation of an association

between the drug administration ritual and the systemic effects of the

drug. Drug preparatory conditional responses, evidenced in anticipation

of the actual pharmacological assault, attenuate the pharmcological

insult. It should be noted that other investigators, while not committing themselves to a specific associative model of tolerance, have also

presented evidence implicating learning or memory processes in the

development of morphine tolerance.

Retention of Tolerance

Evidence suggesting that associative processes may be involved in

tolerance is provided by experiments indicating that tolerance dissipates little with the passage of time (see Cochin & Kornetsky 1964;

Kayan &Mitchell 1972). Indeed, it has been reported that four

opiate addicts display profound tolerance to the analgesic effect of

morphine as long as eight years after their last experience with the

drug (Andrews 1943). Gochin (1970) has suggested that such persistence of tolerance in the absence of any experience with the opiate is

not interpretable by many systemic theories of tolerance. However,

this great retention of tolerance would be expected on the basis of a

learning analysis of tolerance, since learned responses are highly resistant to decrement merely as a result of the passage of time (see

Kimble 1961, p. 281). Indeed, Cochin (1972) suggested that since

tolerance occurs with very long intervals between drug administrations,

"a reaction analogous to memory" (p. 265) may be important in the

phenomenon.

Metabolic Intervention and Tolerance

There is evidence that a variety of suppressors of protein synthesis,

such as puromycin and cycloheximide, retard the acquisition of certain

learned responses (see review by Nakajima, 1976). These drugs also

retard the development of morphine tolerance (see review by Ginsburg

& cox, 1972). Cohen, Keats, Krivoy, and Ungar (1965) suggested that

there may be a parallel between learning and tolerance since metabolic

inhibitors have similar effects on both processes.

It has been reported that the ability of metabolic inhibitors to retard

learning is antagonized by the pituitary peptide, desglycinamide9-

lysine vasopressin (e.g., Lande, Flexner, & Flexner 1972). Furthermore, this vasopressin facilitates sane types of learning (e.g., lande,

Witter, & DeWied 1971).

demonstrated that desglycinamide9-1ysine vasopressin facilitated the

Recently, Krivoy, Zimmerman, and Lande (1974)

acquisition of morphine analgesic tolerance, again demonstrating a

similarity in the effect of metabolic agents on learning and tolerance.

Consolidation and Tolerance

Learning can be retarded by a variety of cerebrally insulting events

presented shortly after the learning experience, such as electrocnvul45
sive shock (ECS) or electrical stimulation of certain brain regions,

such as the frontal cortex (see Jarvik 1970; McGaugh & Herz 1972).

Recently reported results from two laboratories, obtained in experiments specifically designed to examine the analogy between tolerance

and learning, both indicate that ECS retards the development of tolerance to the analgesic effect of morphine (Stolerman, Bunker, Johnson

Jarvik, Krivoy, Zimmermann 1976; Kesner, Priano, & Dewitt 1976).5

Similarly, Kesner, et al. (1976) further demonstrated that stimulation

of the frontal cortex following each morphine administration disrupts

the acquisition of tolerance, and they concluded:

.the data from both the ES and discrete brain stimulation

experiments provide additional support for a possible parallel between conventional learning and tolerance to drugs

(Kesner, et al. 1976, p. 1081).

In summary, investigations from a number of laboratories have demonstrated that the acquisition of tolerance shares many similarities

with more conventional learning preparations: Both tolerance and

learning are retained over long periods of time, and both are similarly

disrupted by ECS, frontal cortical stimulation, and metabolic inhibitors (and both are facilitated by antagonists of metabolic inhibitors).

These findings generally support the view that learning plays a role

in tolerance and are fully consistent with the conditioning theory of

tolerance.

SUMMARY

It has been demonstrated that many conditional responses to a variety

of drugs are opposite in direction to the unconditional effects of the

drug, and the conditioning analysis of morphine tolerance emphasizes

the fact that subjects with a history of morphine administration display morphine-campensatory conditional responses when confronted with

the usual administration procedure but without the drug. Thus, when

the drug is presented in the context of the usual administration cues,

these conditional morphine-compensatory responses would be expected to

attenuate the drug-induced unconditional responses, thereby decreasing

the observed response to the drug. Research has been summarized which

supports this compensatory conditioning model of tolerance by demonstrating that the display of tolerance is specific to the environment in

which the drug has been previously administered. Further evidence

supporting this theory of tolerance has been provided by studies establishing that extinction, partial reinforcement, and latent inhibition--

non-pharmacological manipulations known to be effective in generally

affecting the display of conditional responses--similarly affect the

display of morphine tolerance. Additional research has suggested many

parallels between learning and morphine tolerance. Both processes

exhibit great retention, both are disrupted by electroconvulsive shock

and frontal cortical stimulation, both are retarded by inhibitors of

protein synthesis, and both are facilitated by antagonists of these

metabolic inhibitors.

46
FOOTNOTES

1This paper was prepared for a National Institute on Drug Abuse Symposiun on Behavioral Tolerance, June 23-24, 1977. Research by the

author smmarized in this paper was supported by NIDA Grant DA-01200.

2In addition to groups labeled SAME and DIFFERENT _

in Figure 1, each of

the summarized experiments included additional treatment conditions

which, for simplicity, are omitted from the figure. The two groups

that are displayed for each of the analgesia experiments (Figures IAID) were similarly treated in that, in each case, no subject had any

practice in performing the analgesia-indicant response until the final

assessment of the drug's effect. The design of the hyperthermic tolerance experiment (Figure lE) was somewhat different, and is described

in the text.

3The data labeled CONTROL in Figure 2D represent the man of readings

for two groups, both of which received morphine for the first time

during the tolerance test, and both of which responded to the drug

similarly. One of these groups received the same schedule of pretest

injections as Group BEST, and the other group received the same schedule of pretest injections as Group EXT; but, in each case, all pretest injections consisted of physiological saline.

4

In the hyperthermic tolerance experiment, the time course of the temperature alteration on all sessions was determined. For simplicity,

Figure 3B displays the temperature measured 120 min following each of

the 10 morphine injections. The more complete time-effect data may

be found in the original report of the experiment (Siegel, submitted).

5

I t should be noted that the authors of one experiment suggested that

their results indicated that post-administration ECS did not affect

the development of analgesic tolerance (Ferguson, Adams, & Mitchell

1969). However, examination of their tolerance acquisition data

indicates that they, too, obtained an ECS-induced tolerance retardation effect, but the statistical significance of the trend cannot be

evaluated from the data presented in the published paper.

41
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AUTHOR

Shepard Siegel, Ph.D., Professor of Psychology, McMaster University

Hamilton, Ontario, Canada L8S4Kl

53
II. NARCOTICS

Narcotic Tolerance and

Operant Behavior

James H. Woods, Ph.D., and John Carney, Ph.D.

This paper describes the production and measurement of narcotic

tolerance as It is reflected in operant behavior. The long-term

goals of the project are to describe the variables that control

the development and extent of narcotic tolerance; to describe

how narcotic tolerance affects different types of operant behavior

and vice versa; and, further, to document the types of narcotic

tolerance that may exist, as defined by different inducing agents.

Additionally, we are interested In particular behavioral consequences of tolerance development, e.g., changes in rate and pattern of narcotic-reinforced responding. Although It is commonly

assumed that changes in narcotic self-injection reflect increased

tolerance development, to our knowledge no direct evidence

bearing on this issue has been offered.

We have devoted most of our attention toward simple characterization of narcotic tolerance. Nevortheless, we have been influenced by evidence that suggests that tolerance to narcoticinduced behavioral changes may be of both a metabolic and nonmetabolic nature (e.g., Goldstein et al. 1973). Moreover, we

share the suppositions proposed by a number of participants that

dose-effect expressions of tolerance are good measurement tools,

and that operant behavior iS a good starting point for the analysis of behavioral tolerance. Because of the variety of behavioral circumstances under which we make observations of narcotic tolerance, operant behavior is the only cohesive descriptive system available to us. We will draw particular attention

to aspects of our findings on narcotic tolerance where it appears

to reflect behavioral mechanisms above and beyond the types of

narcotic tolerance noted above.

Narcotics affect a variety of operant behaviors, including behaviors not closely related to painful events (e.g., Dews 1973).

Dose-effect relations and relative potency measures of agonists

and narcotic antagonism may be obtained with operant behavior

in a variety of species (e.g., McMillan 1973), suggesting the

suitability of measuring tolerance using this endpoint. There

is the suggestion that examples of narcotic tolerance observed

54
may be characterized as a shift to the right in dose-effect curve

of the narcotic (McMillan and Morse 1967). In the following experiments, the generality and degree of narcotic tolerance were

assessed in a variety of ways.

NARCOTIC TOLERANCE AND FOOD-REINFORCED PERFORMANCE

Pigeons

In an experiment with pigeons in which key-peck responses were

maintained by occasional food presentations, we gave weekly

administrations of morphine to obtain dose-effect relations that

would serve as a referent for subsequent tolerance development.

Individual cumulative records of performance are shown in

Figure 1 for one of the birds from the experiment. Each bird’s

key peck performance was maintained by 4 sec periods of food

access following the first response after five minutes (fixed

interval 5 [FI 5]) in the presence of a red key light, or following 30 responses (fixed ratio 30 [FR 30]) in the presence of a

blue key light. These schedule conditions alternated following

either reinforcement, after 1 min periods of nonresponding under

FR 30, or 1 min periods of nonresponding after 5 minutes had

elapsed in the FI. Responding was maintained at a lower rate

in the FI, and responding gradually increased in rate during the

interval (Figure la). Following food delivery, fixed-ratio

responding ocurred at a rapid rate until food was delivered

again. Morphine at 5.6 mg/kg reduced responding in both components of the schedule (Figure lb) and almost completely eliminated the behavior at 32 mg/kg (Figure lc) . We then delivered

the drug daily in gradually increasing doses over the course of

six months. At this point, occasional substitutions of larger

and smaller doses of morphine were administered; the effects of

32.0, 56.0, and 320 mg/kg are shown in the d-f segments of

Figure 1. Clearly, there is loss of sensitivity to morphine in

this individual case that suggests a lo-fold change. There do

not appear to be other qualitative changes in performance that

accompany tolerance development.

The grouped performances following maintenance for over 50 days

at 32.0 mg/kg/day showed an approximately 6- to 10-fold shift

to the right of dose-effect curves on response rates for morphine in FI and FR components (Figure 2). Before chronic morphine, a 3.2 mg/kg dose decreased response rates to approximately 45% of control; after daily maintenance at 32.0 mg/kg/day,

however, doses of 17.8 and 32.1) mg/kg were required to produce

about the same decrease in response rates. Similarly, before

daily morphine maintenance, a 32.0 mg/kg dose almost completely

suppressed responding. After daily maintenance at 32.0 mg/kg/

day, however, a test dose of 320 mg/kg was required to cause

about the same degree of response suppression.

55
NONTOLERANT

FIGURE 1

TOLERANT (320 mg/kg /day)

30 MINUTES

Cumulative records of a pigeon’s performance on a multiple fixed-interval 5 min,

fixed-ratio 30 schedule of food presentation. Individual responses step the recorder pen up;

diagonal deflections indicate food delivery. The fixed-interval and fixed-ratio components

alternate and the recorder pen resets automatically after the completion of the fixed-ratio

component . Records a, b, and c are examples of the effects of the pretreatments of saline or

morphine in the doses shown when the morphine was delivered at weekly intervals. Records d, e,

and f are from a later stage of the experiment in which 32 mg/kg morphine was delivered daily

prior to the session and still larger doses were given as probes. This bird developed slightly

more tolerance than is presented in subsequent grouped data (from Carney et al. 1977; in press).
FIGURE 2

MORPHINE DOSE (MG/KG)

Effects of morphine test doses and saline (S) on FI

and FR response rates and FT quarter-life before chronic morphine

(open symbols) and after daily maintenance at 32.0 mg/kg/day

(closed symbols). Control values were calculated from 5 noninjection sessions before morphine testing. Each point represents the mean (f S.E.) of nine observations in the nontolerant

conditions and 18 observations in the tolerant condition. Morphine and saline were administered intramuscularly immediately

before the session (from Carney et al. 1977).

57
In both nontolerant and tolerant pigeons, morphine test doses

caused dose-related decreases in FI quarter-life. However, in

contrast to FI and FR response rates, the dose-effect curve

for FI quarter-life was shifted to the right by about 30-fold

after daily administration of 32 mg/kg for 50 days. Decreases

in FI quarter-life usually represented a tendency for responding

to become relatively evenly distributed within FI components, even/

though the actual number of responses emitted may have been

reduced substantially.

Thus, the amount of tolerance that develops to the rate-decreasing effects of morphine is substantial and is even greater for

the measure of temporal pattern of responding in the interval.

This differential tolerance suggests a behavioral mechanism,

and it would be interesting to examine temporal patterns of

responding on other multiple schedules involving temporal variables in order to generalize this result.

We then examined, in these tolerant birds, the sensitivity to

narcotics in which stereoisomers are available. With the morphinans, levorphanol and dextrorphan, only the levorotatory form

has a full range of narcotic activity, while dextrorphan lacks

many of the actions of narcotics and is thought not to bind to

narcotic receptors (e.g., Goldstein et al. 1971). Levorphanol

(Figure 3) and dextrorphan (Figure 4) reduce food-maintained

key-pecking, with levorphanol being more potent in the case of

nontolerant birds. Chronic morphine administration conferred a

marked loss of sensitivity to levorphanol but considerably less,

if any, tolerance to dextrorphan. Thus, stereospecific tolerance may be conferred by morphine even in situations in which

the nonnarcotic has a comparable behavioral activity.

Rhesus Monkeys

We have carried out similar experiments with rhesus monkeys in

behavioral situations in which FR 30 responding was maintained

by the delivery of 300-mg banana-flavored food pellets. The

same paradigm of tolerance assessment was used in that doseeffect relations were obtained before and during chronic administration of morphine. Cross tolerance was assessed by examining changes in sensitivity to levomethorphan and dextromethorphan. Figure 5 shows the extent of tolerance observed under

conditions in which 3.2 mg/kg morphine was administered at 8-

hour intervals. There was a large shift to the right in the

morphine and levomethorphan dose-rate functions without any

change in dextromethorphan’s effects on FR responding.

Operant behavior has served us well in describing changes in

sensitivity to narcotics and assessing the pharmacological specificity of this effect. A variety of drugs may affect foodreinforced operant behavior, and this fact was taken advantage

of in these situations to obtain comparable effects of the

stereoisomers. Another important advantage of operant behavior

during chronic drug administration is that of being able

58
FIGURE 3

MG/KG

The effects of Ievorphanol on rates of FI responding,

quarter-life values and rates of FR responding in nontolerant

(open symbols) and morphine tolerant (closed symbols) pigeons.

Each point represents the mean (* S.E.)of at least five observations at each dose (from Carney et al. 1977).

59
FIGURE 4

The effects of dextrorphan on rates of FI responding,

quarter-life values and rates of FR responding In nontolerant

(open circles) and morphine tolerant (closed circles) pigeons.

Each point represents the mean (± S.E.) of at least 5 observations

of each dose (from Carney et al. 1977).

60
FIGURE 5

DOSE (mg/kg)

Effects of morphine, levomethorphan and dextromethorphan on fixed-ratio food-reinforced

responding in rhesus monkeys before (open symbols) and durin,g (closed symbols) the chronic

administration of 3.2 mg/kg morphine every 8 hours. Each data point represents 3-12 observations.

Brackets indicate 1 standard error (from Carney and Woods 1977).
to assess control performance in the absence of drug. In our

case, at some times absence of drug yielded behavior that did

not differ in rate in any important way from predrug rates.

Thus, rates of responding in the presence and absence of tolerance can be comparable, and dose-effect relations may be

expressed as shifts from a common starting point.

The extent of narcotic tolerance in the monkey and pigeon was

roughly comparable in that there was a 6- to lo-fold increase

in the dose-effect relations. These experiments thus provided

a good test of the empirical significance of the definition of

tolerance in the two species.

NARCOTIC DEPRIVATION: PIGEON AND RHESUS MONKEY

One way of examining other consequences of tolerance development

is to deprive the organism of the narcotic. When the pigeons

were deprived of morphine, they had been maintained on morphine

for about 18 weeks. Saline was substituted for the morphine for

ten days. During this time, there was a transient fall in body

weight; maximum weight loss occurred 2 days after the last morphine InJection (Figure 6). Thus weight loss required an Increase in daily postsession feeding in an attempt to maintain

the 80% deprivation weights. Body weight and amount of grain

fed returned to nontolerant control values by the end of the

ten-day withdrawal period. Rates of food-reinforced responding

generally increased over the ten-day period. After ten days,

fixed-interval response rates returned to slightly less than

the nontolerant control level. Fixed-ratio response rates not

only returned to the nontolerant control level, but increased

to 153% of control rate by the end of 10 days.

Thus, morphine deprivation in the pigeon did not result in changes in schedule-controlled responding consistent with the expression of an abstinence syndrome. Similar lack of response

disruption by withdrawal in narcotic-tolerant pigeons was reported by Heifetz and McMillan (1971) following 26 days of 5.6

mg/kg/day of methadone or morphine. Morphine deprivation

produced a transient weight loss which is consistent with

other species and has been taken as an abstinence sign.

The rhesus monkey does not withstand morphine deprivation as

readily. If the monkey is deprived of two of the three daily

3.2 mg/kg injections of morphine, the food-reinforced performances are completely suppressed and may be reinstated with a

morphine injection Carney and Woods 1977).

These findings taken together with the tolerance definition

(a shift in dose-effect relationship) suggest that factors

other than a simple equivalent shift of a dose-effect relation

are necessary to predict correlates of tolerance development.

Any number of factors need to be tracked down in order to

supplement the definition in an appropriate way.

62
FIGURE 6

Days of Morphine Deprivation

Effects of morphine deprivation on FI and FR response

rates and FI quarter-life (left) and on body weight and amount

of grain fed to maintain 80% food-deprivation weights (right).

Data for the nontolerant (B) and morphine tolerant (M: 3210 mg/kg/

day) conditions are provided for comparison. Prior to morphine

deprivation, birds were maintained at 32.0 mg/kg/day. Each point

represents the mean (±1 S.E.) of nine observations (from Carney

et al. 1977).

63
TYPES OF NARCOTIC TOLERANCE

Martin and his colleagues (1976) have postulated multiple types

of narcotic receptors on the basis of the effects of particular

prototype agents that, while antagonized by naloxone, have

marked differences in their effects upon various behavioral

measures in the chronic spinal dog. Mark Llewellyn, at the

University of Michigan, has explored the possibility of developing tolerance to ketocyclazocine in the rhesus monkey. Both

morphine and ketocyclazocinc reduce multiple FI 5 FR 30 schedule performances maintained by food presentations. Chronic

administration of morphine and ketocyclazocine produced comparable 3-fold shifts to the right in their dose-effect relations. When tested for cross tolerance, however, there was no

decrease in sensitivity to morphine of monkeys receiving

ketocyclazocine and vice versa. If any change occurred, a

slight supersensitivity developed to ketocyclazocine in the

monkeys receiving chronic morphine. In this experiment,

when we have produced comparable degrees of tolerance to both

morphine and ketocyclazocine, drug deprivation leads to marked

disruption of food-reinforced responding in the case of morphine, but not with ketocyclazocine.

These data lend support via species and behavioral generality

to Martin’s conjectures concerning a different type of receptor for compounds of the ketocyclazocine type. They also

suggest that cross tolerance tests with narcotics and operant

behavior may be an important investigational tool for distinguishing different types of narcotics.

NARCOTIC TOLERANCE AND NARCOTIC-REINFORCED RESPONDING

We have recently adapted the behavioral situations described

above to encompass narcotic-reinforced responding (Carney

1976). The situation is a multiple FR 30 schedule of food

and codeine delivery. Before the monkey is given access to

intravenous codeine for self-injection, a set of dose-effect

curves is obtained with FR responding maintained by food presentation. Subsequently, codeine self-injection is added

under different cue-light conditions but under the same FR

schedule. Drug-reinforced responding is continued for over

a month until stable, and then dose-effect relations are obtained again. Decreased drug sensitivity on food-reinforced responding with narcotics would indicate tolerance development;

however, we have been able to maintain codeine-reinforced responding at high rates for over a month without obtaining a

shift in sensitivity upon food-reinforced responding. Thus,

it is possible to sustain narcotic-reinforced responding without inducing significant tolerance development. If the dose of

codeine is increased markedly, we can induce tolerance. Under

these conditions of tolerance induction, we have not found a

64
corresponding change in pattern of codeine-reinforced responding. We are confident of the dissociation of tolerance and

sustained rates and patterns of narcotic-reinforced responding.

We have no direct evidence that tolerance influences narcotic

drug self-Injection

SUMMARY

Narcotic tolerance was measured as a shift to the right in

dose-effect relations on operant behavior following repeated

administration of drug. Tolerance has been observed with

operant responding in both pigeons and rhesus monkeys. The

amount of tolerance observed with food-reinforced responding

is related both to the amount of morphine administered and to

the nature of the drug-induced change In operant responding.

Pharmacological specificity of the narcotic tolerance has been

confirmed by equivalent loss of sensitivity to other narcotics

without concomitant changes in sensitivity to nonnarcotic

stereoisomers. Tolerant birds do not show disturbed operant

behavior when narcotic administration is terminated abruptly.

Tolerance has been induced by narcotic self-injection and

Its effects measured on rates and patterns of food- and

narcotic-reinforced responding. Tolerance does not necessarily confer changes in narcotic-reinforced responding. Moreover, narcotic-reinforced responding may be initiated and

maintained for periods of over one month without conferring

tolerance.

REFERENCES

Carney, J .M. Selective modulation of codeine-reinforced

responding in rhesus monkeys. Unpublished Ph.D. dissertation, Department of Pharmacology, University of Michigan, 1976.

Carney, J .M. and Woods, J.H. Changes in sensitivity to

the behavioral effects of narcotic agonists and antagonlsts in morphine -dependent rhesus monkeys . Submitted to

J- Pharmacol. Exp. Therap., 1977.

Carney, J.M., Downs, D.A., and Woods, J.H. Tolerance to

effects of morphine on schedule-controlled behavior in

pigeons. Submitted to J- Phamracol. Exp. Therap., 1977.

Dews, P. What is analgesia? In: Braude, M. et al., eds.

Narcotic Antagonists. Adv. Biochem. Psychopharm., vol. 8.

New York: Raven Press, 1973. pp. 235-243.

65
Downs, D.A., Carney, J.M. and Woods, J.H. Cross tolerance to behavioral effects of narcotics in pigeons.

Submitted to J. Pharmacol. Exp. Therap., 1977.

Goldstein, A., Judson, B.A. and Sheehan, P. Cellular

and metabolic tolerance to an opioid narcotic. Brit. J.

Pharmacol., 47:138-140, 1973.

Goldstein, A., Lowney, L.I., and Pal, B.K. Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse

brain. Proc. Nat. Acad. Sci 68:1742-1747, 1971.

Heifetz, S.A. and McMillan, D.E. Development of behavioral tolerance to morphine and methadone using the

schedule-controlled behavior of the pigeon. Psychopharmacologia, 19:40-52, 1971.

Martin, W.R., Eades, C.G., Thompson, J.A., Huppler,

R.E., and Gilbert, P.E. The effects of morphine- and

nalorphine-like drugs in the nondependent and morphinedependent chronic spinal dog. J- Pharmacol. Exp

Therap., 197:517-532, 1976.

McMillan, D.E. Effects of narcotics and narcotic antagonists on operant behavior. In: Braude, M. et al., eds.

Narcotic Antagonists. Adv. Biochem. Psychopharm vol 8.

New: Raven Press, 1973. pp. 345-360

McMillan, D.E. and Morse, W.H. Some effects of morphine and morphine antagonists on schedule-controlled

behavior.

1967.

J. Pharmacol. Exp. Therap., 157:175-184,

AUTHORS

James H. Woods, Ph.D., Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109

John Carney, Ph.D., Department of Pharmacology, University

of Oklahoma Medical School, Oklahoma City, Oklahoma 73190

66
II. NARCOTICS

Conditioning Effects of Narcotics

in Humans

Charles P. O’Brien, M.D., Ph.D., Thomas Testa, Ph.D.,

Joseph Ternes, Ph.D., and Robert Greenstein, M.D.

Observations from classical conditioning studies in human narcotic

addicts suggest ways in which behavioral tolerance may be involved

in human addiction. Narcotic addicts experience sequential drugrelated states usually called “highs”

drawal, craving) , . Such changes are identifiable by self-reports and by measurable physiological changes.

These states are obviously influenced by pharmacological factors

(dose, time since last dose, route of administration, etc.), but

there is also increasing evidence that they are influenced by learning factors. When environmental stimuli are consistently paired

with drug-related states, the stimuli alone may acquire the ability

to produce these states or to modify them. The subject’s adaptational responses to these states may also be learned. Modification

of drug-related states by learning is, of course, related to the

phenomenon of tolerance.

CONDITIONED WITHDRAWAL

We have been studying behavioral and autonomic changes in drugrelated states and the effects of learning on these changes. The

first state we examined experimentally was that of withdrawal.

Animal studies [Goldberg 1970) and clinical evidence (Wikler 1973a)

indicated that withdrawal can be conditioned. We obtained systematic self-report data from the clinic (O’Brien 197%) and then produced withdrawal as a conditioned response in the laboratory

(O’Brien et al. 1975a; O’Brien et al. 1977). SubJects were volunteers, maintained on a steady dose of methadone. Use of confoundine drugs was excluded by daily urine tests. The unconditioned

response (UR) was naloxone-precipitated withdrawal. This consisted

of brief, dose-related behavioral, subjective, and autonomic signs

of narcotic abstinence. It was paired with a complex conditioning

stimulus (tone/odor CS) . After 7-10 conditioning trials, a conditioned response (CR) was evident which generalized to the test room

and frequently had its onset before the discrete CS. The CR was similar to the UR and in the same direction. The withdrawal consisted

67
of subjective components (craving, nausea, cramps), behavioral components (yawning, blinking, restlessness, touching of eyes, rubbing

of abdomen) , and autonomic components (decreased skin temperature,

tearing of the eyes, increased heart rate and respiration, changes

in skin resistance and electrogastrogram). Thus a state similar to

drug withdrawal was produced by a CS in human subjects under laboratory-controlled conditions.

Concerning conditioning in the natural environment, there is anecdotal evidence that addicts may begin yawning and tearing while

discussing drugs during group therapy. We have also reported withdrawal behavior in addicts shown video tapes of drug-administration

rituals (O’Brien et al. 1974). Teasdale reported changes in mood

scales when addicts were exposed to drug-related slides (Teasdale

1973). The most consistent physiological evidence that we have

found to date for a naturally conditioned withdrawal response is a

study in which the “cook up” ritual serves as a CS (O’Brien et al.

1977b). Drug-free (detoxified) addicts who perform this ritual

develop withdrawal responses (pupillary dilatation, decreased skin

temperature) prior to receiving any drug. The CS seems to be a

complex of the sight of a bag of heroin, the odor of the “cooker ,"

and the anticipation of a self-injection. Nonaddicts exposed to

the same stimuli showed a novelty response which did not persist

the way the addict response did. Thus we have evidence that in some

circumstances the withdrawal or drug-negative state can occur as a

conditioned phenomenon.

CONDITIONED AGONIST EFFECTS

We have also examined the drug-positive state in detoxified human

addicts. When the subject is permitted to go through pre-injection

rituals in the laboratory and then inject a narcotic, a sequence of

subjective, behavioral, and autonomic changes occurs. bring

the pre-injection phase, withdrawal or drug-negative responses

usually occur. During the post-injection phase, the withdrawal responses are reversed, and the drug-positive responses occur. The

subject reports relief of craving and withdrawal and the presence

of pleasant or euphoric feelings. Autonomic responses include

pupillary constriction, increased skin temperature, and slowing of

respirations and gut contractions. Of course, the intensity and

duration of the drug-positive effects depend on the dose and previous drug experience of the subject. We have also found that intensity and duration are influenced by pre-injection rituals and

expectation of the subject.

The subjective effects of a narcotic are most influenced by these

nonpharmacological factors, but in some subjects even the autonomic

changes respond to expectation. A test dose of narcotic tends to

produce greater drug-positive effects when self-injected along with

rituals than when given over the same time interval through an intravenous infusion with no drug expectation signals to the subject.

The conditioning of drug-positive responses is further exemplified

by the effects of placebo injections. if a detoxified addict is

68
permitted to self-inject with rituals either narcotic (4 mg hydromorphone) or saline under double-blind conditions, the saline injection will be followed by a small drug-positive effect. This

will extinguish in most subjects after one or two trials, especially

if the subject has the opportunity to compare the effects of saline

and narcotic (cognitive influence).

Addicts who are placed on a narcotic antagonist (cyclazocine or

naltrexone) and then allowed to self-inject show an interesting

series of responses. Most of those receiving saline extinguish

drug-positive responses (high) within 1-3 trials and then show only

drug-negative responses (withdrawal) after subsequent injections.

Those who self-inject a narcotic show drug-positive responses for a

greater number of trials, in spite of the antagonist, but in most

cases extinction is complete within 8-10 trials. (There were some

notable exceptions, with a few subjects showing euphoric responses

for 20-25 trials even with saline injections. It is not clear

whether this relates to prior conditioning history or individual

variation.) After extinction of drug-positive responses, only drugnegative (withdrawal) responses remain, and these may be persistent

and intense. The drug-positive responses probably persist longer

when narcotic is injected in the presence of antagonist than when

saline is injected, because some of the pharmacological effects of

the narcotic are not completely blocked. The cyclazocine or naltrexone acts as a competitive antagonist of narcotic effects, but

some narcotic enteroceptive cues apparently still occur. This

explanation is supported by the fact that drug-positive effects

persist longer when patients self-inject a narcotic while receiving

cyclazocine than while receiving naltrexone. Naltrexone, since it

has few side effects, can be used in a higher dose and thus can

provide an agonist/antagonist ratio more favorable to the antagonist.

Our work with humans, therefore, suggests that both drug-positive

and drug-negative effects can be learned. We have interpreted

these findings within the framework of Solomon’s opponent-process

theory (Solomon and Corbit 1974). The findings are also compatible

with Wikler’s description of conditioned counteradaptive effects

(Wikler 1973b) and Siegel’s discussion of tolerance as a conditioned

phenomenon (Siegel 1975). While Wikler and Siegel deal mainly with

conditioning which reduces drug effects (drug-negative phenomena),

we also have evidence of conditioned drug-positive effects. The

opponent process framework provides a convenient means of describing

the interaction between conditioned drug-positive and conditioned

drug-negative effects. Briefly stated, it is postulated that a

consistent set of rituals reliably signals the appearance of opiates

in the body. The adaptive responses provoked by the impact of the

drug on homeostatic mechanisms act to oppose the drug effects.

These drug-negative responses, after repeated pairings with the

antecedent rituals, can be elicited by the rituals alone. This

learning of drug-negative responses is facilitated by the fact that

the addict frequently is already in a pharmacological state of withdrawal as a result of metabolism of the previous dose by the time

he performs the rituals. Thus there are two pathways for the reinforcement of drug-negative responses.

69
The learned drug-positive effects tend to be briefer and less reliable than drug-negative effects and more easily extinguished.

These can be manifested in self-reports of “high” or euphoria and

in such autonomic changes as pupillary constriction, decrease in

respiratory rate, or increase in skin temperature. These learned

responses are similar to what has been called the placebo effect

and the “needle freak” phenomenon. Their onset follows selfinjection, and they tend to augment rather than reduce the effects

of the drug. These effects appear to be more influenced by expectation or cognitive factors than are conditioned drug-negative

effects. This may help to explain why addicts continue to report

pleasure from street “heroin” which contains minimal, if any,

narcotic (O’Brien 1975b).

Our work with conditioned drug states in humans, though still

preliminary, suggests that learning does play a role. It is too

soon to state how important that role may be or whether the findings

will have a direct application to the clinical management of drug

dependent people.

REFERENCES

Goldberg, S.R. Relapse to opioid dependence: The role of conditioning . Adv. Ment. Sci., 2:170-197, 1970.

O’Brien, C.P., Chaddock, B., Woody, G., and Greenstein, R. Systematic extinction of narcotic drug use using narcotic antagonists.

Proceedings of the NAS/NRC Committee on Problems of Drug Dependence,

Washington, D. C. : National Academy of Sciences, 1974. pp. 216-222.

O’Brien, C.P., O’Brien, T.J., Mintz, J., and Brady, J.P.

Conditioning of narcotic abstinence symptoms in human subjects.

Drug and Alcohol Dependence, 1:115-123, 1975a.

O’Brien, C.P. Experimental analysis of conditioning factors in

human narcotic addiction. Pharmacological Reviews, 27:533-543,

1975b.

O’Brien, C.P., Testa, T., O’Brien, T.J., Brady, J.P., and Wells, B.

Conditioned narcotic withdrawal in humans. Science, 195:1000-1002,

1977a.

O’Brien, C.P., Temes, J., Testa, T., and Greenstein, R. Naturally

conditioned narcotic withdrawal responses. (Manuscript in preparation) , 1977b.

Siegel, S. Evidence from rats that morphine tolerance is a learned

response. Journal of Comparative and Physiological Psychology,

89:498-506, 1975.

Solomon, R.L., and Corbit, J.D. An opponent-process theory of

motivation: Temporal dynamics of affect. Psychological Review,

81:119-146, 1974.

70
Teasdale, J. Conditioned abstinence in narcotic addicts. Int. J.

Addict., 8:273-292, 1973.

Wikler, A. Dynamics of drug dependence, implication of a conditioning theory for research and treatment. Arch. Gen. Psychiatry, 28:

611-616, 1973a.

Wikler, A. Conditioning of successive adaptive responses to the

initial effects of drugs. Conditional Reflex, 8:193-210, 1973b.

ACKNOWLEDGMENT

Preparation of this report was supported by Research Grants

DA 00586 and DA 001218 from the National Institute on Drug Abuse.

AUTHORS

Charles P. O'Brien, M.D., Ph.D.

Thomas Testa, Ph.D.

Joseph Temes, Ph.D.

Robert Greenstein, M.D.

Department of Psychiatry, University of Pennsylvania and

Philadelphia Veterans Hospital, Philadelphia, Pennsylvania 19104

71
III. ETHANOL

Tolerance as a Behavioral

Phenomenon:

Evidence from Two Experimental

Paradigms

A. E. Le Blanc, Ph.D., C. X. Poulos, Ph.D., and

H. D. Cappell, Ph.D.

INTRODUCTION

The purpose of this conference is to define and assess the importance of the phenomenon that has come to be known as “behavioral

tolerance.” Our contribution to this task will be based on two

lines of research that have been continuing in the laboratories of

the Addiction Research Foundation over the course of many years.

During the development of this research, it has become evident to

us, as to others, that no comprehensive account of tolerance can

ignore behavioral concepts. This is so whether the object of study

is drug-induced motor impairment or aversive conditioning by psychoactive drugs.

What Are the Descriptive Requirements of Tolerance?

Before an alteration in drug response can be characterized as tolerance, two requirements must be met:

(a) A drug effect will diminish in magnitude with repeated exposure

to a fixed dose.

(b) A drug effect diminished in magnitude by repeated exposure to

a fixed dose can be reinstated by an increase in dose.

These requirements imply nothing in particular about mechanisms

of tolerance. They merely establish criteria to be applied in

order to characterize a reduction in a drug effect as tolerance.

It is often the case that investigators invoke the concept of tolerance even when only the first of the above requirements has been

met. Usually, this is not a problem because enough is known about

the pharmacology of drugs of interest that other characterizations

of reduced response can be eliminated. However, reduction of response may be a reflection of tachyphylaxis resulting from depletion

of a response mechanism, rather than genuine adaptation (cf. Kalant

et al. 1971a). Where tachyphylaxis is involved, the second requirement for the existence of tolerance could not be met.

72
In the ideal case the production of tolerance should result in a

parallel shift in the dose-response curve for the effect under

investigation (Kalant et al. 1971a). This would be indicative

of a shift in threshold of the dose required to produce the effect.

It is not often the case that this ideal is achieved in actual

research. In any event, this criterion is only applicable in the

relatively simple case of linearity of dose-response function. A

parallel shift of a nonmonotonic relationship may be more difficult to demonstrate. The notion of parallel shift is important

for reasons of interpretation, since the nature of the alteration

of the dose-response curve may be an important clue as to the

mechanism of adaptation involved (Kalant et al. 1971a).

Behavioral Tolerance versus Other Kinds: A Preliminary View

The ideation and experimentation that led to the formulating of

the concept of behavioral tolerance developed in part as a reaction to more physiologically or pharmacologically based conceptions.

(Although “metabolic” tolerance is included as a physiological

notion, we are not concerned with it here, especially since it

seems not to be important in the studies we are discussing. Our

meaning of physiological tolerance refers to changes in sensitivity of receptors at which a drug is presumed to act centrally.)

This distinction has been considered in detail by a research group

(Kalant et aL 1971a) with no inflexible allegiance to either conception. “Physiological” tolerance was defined as “a compensatory

or homeostatic change in the neurons affected by the drug, which

renders them less sensitive to it.” The implication of such a

definition is that tolerance is a necessary consequence of continued contact between a drug and the receptors upon which it acts,

unmodulated by conditions other than pharmacological ones such as

dose and duration of exposure. What is obviously wrong with such

a conception is that it fails to account for numerous examples

of adaptation to a drug that are modulated by nonpharmacological

variables; perhaps more importantly, it fails to account for the

comparative absence of adaptation in instances in which the

pharmacological exposure per se was not adequate to evoke an adaptive response (e.g., Carlton & Wolgin 1971; Schuster et al. 1966).

The final conclusion of Kalant’s review was that there is in fact no

qualitative difference between “physiological” and “learned” (the

word used in the review) or ‘behavioral” (the word adopted for

this conference) tolerance. Rather, Kalant et al.argued, behavioral variables contribute to the rate of development of tolerance

by modulating the rate of a physiological process common to all

manifestations of tolerance. To quote:

. . . . it appears that the “learned tolerance” is essentially the same as “physiological tolerance’ except that

it is acquired somewhat more rapidly. (p.158)

This was not meant to trivialize behavioral factors in tolerance,

but only to emphasize the hypothesis that, fundamentally, some

common mechanism is at work in various manifestations of the adaptation to the behavioral disruptions produced by drugs. As an

73
expression of this conclusion Kalant et al.coined the phrase

“behaviorally augmented tolerance” in order to emphasize a fundamental similarity rather than a fundamental difference in varieties

of tolerance. It may well be the case that a distinction between

behavioral and physiological tolerance is unnecessary in considering an ultimate mechanism of tolerance. Yet it seems also to be

the case that any such mechanism is not fully engaged merely by

the presence of a drug at a receptor site, independently of other

events. The purpose of this paper is to ruminate about what

some of these “other events” might be, and to arrive at a conception of tolerance that does no violence to pharmacology, psychology,

or fact.

EVIDENCE FROM STUDIES OF MOTOR IMPAIRMENT OF RELATIONSHIPS BETWEEN

TOLERANCE AND OTHER FORMS OF ADAPTATION

A reliable consequence of the administration of alcohol and other

CNS depressants is motor Impairment. Such impairment can be effectively quantified in rats by means of a test requiring an animal

to walk a moving treadmill (Gibbins et al. 1968). Alcohol and

barbiturates impair the ability to perform this response, and the

method is highly sensitive to small variations in dose. In this

test, tolerance is evident as reduced impairment of performance

as a result of chronic exposure to a drug. Much of the work reported

in this section employed the treadmill test, although occasionally

other behavioral tests of impairment have been used. To anticipate

somewhat, the thrust of this section is an attempt to draw parallels

between tolerance and other forms of adaptation, such as learning.

Interestingly, another participant in this conference (Siegel 1975)

has viewed the existence of such parallels as an alternative to

a purely physiological conception of tolerance to the analgesic

effect of morphine. The search for alternatives should not be seen

as a dismissal of the relevance of physiology and pharmacology;

rather it represents the addition of a novel dimension that is

clearly needed to account for certain features of tolerance. We

will describe the findings with a minimum of detail since most are

available in the published literature and have been reviewed elsewhere recently (Le Blanc &, Cappell 1977).

Cortical Ablations and Tolerance

One strategy for demonstrating a parallel between tolerance and

general adaptive processes is to compare the impact of an experimental manipulation designed to interfere with them. The parallels

here come from work on ablations of the frontal cortex. An intact

frontal cortex appears to be essential in several species for the

acquisition of behavior requiring a delay of response or a sensory

discrimination in order to receive reward (cf. Grossman 1967).

Thus, frontal cortical ablations may interfere with learning. Moreover, lesions of the frontal cortex have been shown to impair the

physiological adaptation to thermally elicited tachycardia that

is evident in normal animals (Glaser 1966). If tolerance has

something in common with these other adaptive phenomena, It should

74
be possible to interfere with its acquisition by means of comparable ablations. Le Blanc et a1.(1976) tested this hypothesis using

alcohol. Using the treadmill test, rats were first made tolerant

to the motor impairment produced by alcohol. The animals were allowed

to recover from tolerance for a month before being assigned to

groups selected for bilateral frontal polar lesions, sham operations,

or no operation. Following recovery from surgery, the reacquisition of tolerance was studied under conditions identical to those

of initial acquisition. Although all groups were shown to be

capable of acquiring tolerance before surgery, only the controls

did afterward; the lesioned animals displayed virtually no reacquisition of tolerance. A smaller pilot study yielded similar

results with lesions to the occipital cortex.

These results in themselves offer only modest support for our basic

thesis. However, they do indicate that alcohol tolerance shares

a property in common with complex learning and a physiological

adaptation. Moreover, research on amphetamine (Glick 1973) suggests

that the involvement of the frontal cortex in tolerance development is not peculiar either to alcohol or to motor impairment.

Protein Synthesis and Tolerance

The evidence on the effects of frontal cortical ablations provided

some support for a commonality of process in tolerance development

and the acquisition of new responses. To the extent that protein

synthesis is involved in learning, another opportunity for pursuing the analogy presents itself. Evidence of a role for protein

synthesis in learning is provided in a study by Segal et a1.(1971),

who showed that cycloheximide, an inhibitor of central protein

synthesis, interfered with the retention of discrimination learning

in mice. The effect of cycloheximide on alcohol tolerance was

pursued by Le Blanc et a1.(1976) using a design and procedures very

similar to those adopted in the ablation study; the major difference

was that the effects on reacquisition of tolerance of treatment .

with cycloheximide were at issue. During exposure to the initial

tolerance-inducing regime, cycloheximide treatment was combined

with alcohol in the critical experimental group. On tests of the

reacquisition of tolerance to the impairing effects of ethanol the

performance of controls improved over time by more than 50%, whereas rats treated with cycloheximide acquired virtually no tolerance

whatsoever. Hence, the evidence for our general hypothesis increases,

although it is conceded that this experiment does not rule out

mechanisms of interference with tolerance acquisition not involving

the inhibition of central protein synthesis (e.g., subclinical

convulsions) . The effect of cycloheximide on tolerance is not unique

to alcohol, since cycloheximide has been found to inhibit the

development of tolerance to the analgesic property of morphine in

mice (Loh et al. 1969).

75
Manipulation of Serotonin

A third source of evidence for the tolerance/adaptation parallel

derives from recent data on the role of serotonin in the development of tolerance to ethanol. That depletion of serotonin retards

habituation to non-drug stimuli has been amply demonstrated in

studies of acoustic startle responding (Carlton & Advokat 1973;

Connor et al. 1970; Swonger et al. 1970). In all of these studies,

serotonin level was manipulated by prior treatment with p-chlorophenylalanine (PCPA), an established depletor of serotonin in the

CM. The drug studies (Frankel et al. 1975) employed the movingbelt test to measure tolerance. Both alcohol and pentobarbital

were investigated, but since the results were quite similar,

only the ethanol work will be presented in any detail.

The essential strategy of the study was to expose animals depleted

of serotonin to a schedule of alcohol administration that would

be expected to promote tolerance to the impairing effects of a test

dose. Treatment with pCPA was given daily for 10 days before

chronic exposure to alcohol, and continued for 25 further days

during which experimental animals were also exposed daily to large

doses of alcohol by gavage. Tests of impairment on the treadmill

apparatus were interspersed at intervals during the chronic regime

of treatment. Control animals exposed to ethanol but not pCPA

clearly developed tolerance to the test dose; rats exposed to pCPA

also displayed some tolerance, but the rate of acquisition was

significantly impaired, and the level did not approach that of

controls during the course of the experiment. Much the same

assertion can be made where pentobarbital was concerned.

As with the other data presented in support of our general hypothesis, these findings are by no means free of alternative interpretation. Yet they do seem to enhance the credibility of the

hypothesis by providing supporting data from another general domain

of investigation. Moreover, there is evidence that comparable

manipulations retard the development of tolerance to morphine as

well way et al. 1968; Shen et al. 1970).

Topographical Similarity between Tolerance and Learning

A fourth source of parallels between tolerance and adaptation derives from a topographical similarity in one aspect of tolerance

and learning. One property of learning that is demonstrable by

appealing to both personal experience and the scientific literature

(Kimble 1961) is that responses are reacquired after a period

of disuse with much greater facility than they are initially

mastered. A similar process can be demonstrated in studies of

adaptations of a more fundamental physiological nature; for example,

physiological adaptation to thermal stimuli proceeds more rapidly

to the extent that an organism has a history of adaptation to those

stimuli (Glaser 1966). The parallel was illustrated in a study

by Kalant et al. (1971b), in which repeated cycles of acquisition

of tolerance to alcohol were studied using the treadmill test.

76
Bats were exposed to as many as 4 cycles of aquisition, with 17-

day drug-free intervals between cycles to permit recovery to baseline levels of impairment. The basic finding was that the same

Level of tolerance was achieved during each cycle, but that this

level was attained in fewer and fewer trials over successive cycles

of acquisition. Whereas 13 to 16 days of chronic exposure were

required for maximal tolerance to be attained during an initial

cycle, maximal tolerance was evident with 4 days of treatment during

a fourth cycle.

Effects of Behavioral Manipulations on Tolerance

Although they do not, strictly speaking, provide an example of a

parallel between tolerance and learning, studies in which the acquisition of tolerance has been manipulated by behavioral interventions

are quite pertinent to our approach. Some studies have explicitly

attempted to provide an empirical distinction between ‘behavioral”

and “physiological” tolerance. Physiological tolerance implies a

change in the sensitivity of the neurons directly affected by a

drug, and should be a consequence of mere exposure; this is to be

distinguished from the functional adaptation (i.e., adaptation to

some ultimate behavioral effect of a drug) implied by behavioral

tolerance. Experiments that provided evidence of this distinction

where amphetamine is concerned have been reported by Carlton and

Wolgin (1971) and Schuster et al. (1966). Briefly, these studies

showed that tolerance to effects of amphetamine developed to the

extent that adaptation was of some “benefit” to the drugged animal;

given equivalent pharmacological exposure, tolerance was not observed

when there was no “benefit” to be gained thereby. Our discussion

focuses on a related phenomenon involving alcohol.

In the study that inspired our own research, Chen (1968) compared

groups of rats that first received injections of alcohol either

before or after performance was tested on a maze task in which approach behavior was maintained by food reward. On the critical

test, all rats received their injection before testing. The finding

from this test was that tolerance was evident in the group that

had consistently received alcohol before the test, but not in the

group that was given alcohol prior to the test for the first time.

This outcome seems to indicate clearly that mere exposure to alcohol

was not in itself sufficient to provoke tolerance. Chen concluded

that this was evidence of a qualitative distinction between physiological and behavioral tolerance. However, Le Blanc et al. (1973)

argued that Chen’s manipulation may simply have affected the rate

of tolerance development, and that his results may have depended

on the limited number of exposures to alcohol (4 in all} that he

employed. Clearly, one would draw different conclusions about the

existence of a fundamental difference between behavioral and physiological tolerance if the rate and not the asymptote of a process

were the major difference. Le Blanc et al. (1973) tested their

hypothesis using a design similar to Chen’s, but one which incorporated

many more exposures to alcohol prior to the critical test of tolerance . Consistent with the hypothesis, tolerance was acquired more

77
rapidly if alcohol treatment consistently preceded the behavioral

test, but the same final level of tolerance was achieved if during

acquisition a sufficient number of exposures to the same dose

was given following the behavioral measurement. Le Blanc et al.

(1973) concluded from these data that one need not entertain the

possibility of a separate cellular mechanism for behavioral and

physiological tolerance if behavioral manipulations primarily affect

only the rate of tolerance development. For this reason, they proposed the phrase “behaviorally augmented tolerance” to describe

the interaction between behavioral demand and the rate of tolerance

development, while rejecting the suggestion of fundamentally different mechanisms. Other studies involving opiates (Kayan et al.

1969)) barbiturates (Waslstrom 1968)) and chlorpromazine (Irwin

1963) are consistent with this hypothesis.

In an important extension of this work, it has been found that

behaviorally augmented tolerance is not task-specific (Le Blanc et

al. 1975). First it was shown that behavioral augmentation of

tolerance could be demonstrated on the treadmill test; although

this result was not novel, it extends the generality of the phenomenon. More importantly, it was found that the behavioral augmentation of tolerance was transferred to a maze task on which performance was shown to be entirely independent of treadmill performance

(i.e., there was no transfer of training in no-drug control conditions) . This outcome is of particular Importance because it demonstrates that behaviorally augmented tolerance results in more than

an enhancement of learned compensation for the impairment produced

in a specific behavioral test. Rather, it appears that behavioral

augmentation facilitates\ the development of a fundamental adaptation

at neuronal level that is generalizable to an entirely novel behavioral circumstance. Moreover, it is worth noting that behavioral

augmentation of physical dependence was also shown in this work.

In summary, it appears that it may not be necessary to think of

behavioral and physiological tolerance as independent phenomena

that challenge the possibility of a single neural mechanism of tolerance , This resolution ispossible to the extent that we entertain

a unitary mechanistic theory of adaptation that allows for the

influence of behavioral manipulations on the rate of adaptation.

The fact that behavioral manipulations do have a clear influence

on the rate of adaptation seems to strengthen rather than weaken a

unitary theory, although it does require some revision of any thought

that mere exposure of the CNS to the drug is the only adaptive

stimulus of importance in tolerance development.

SUMMARY

Although our case rests to a large extent on analogy, it is difficult to avoid being impressed by the convergence of all of the foregoing data. It may be possible to dispute the persuasiveness of

any or even all of the experimental illustrations taken individually,

but the mass of evidence taken together is remarkably consistent with

our basic supposition that tolerance and adaptation are quite similar

78
processes. The parallels hold across a diversity of experimental

manipulations and they are not peculiar to any single pharmacological agent. Yet admittedly the argument is still speculative

and must remain so until there is some better understanding of the

unitary neural mechanism of adaptation that we have suggested.

With our basic thesis established, we can now turn to an area of

research that has proceeded somewhat independently from that already

described. On the face of it, it would have been difficult to see

that these lines of research would ever converge, but they have.

EVIDENCE FROM STUDIES OF GUSTATORY AVOIDANCE CONDITIONING

Our first encounters with gustatory avoidance conditioning some

years ago were characterized by a combination of intrigue and

puzzlement. Using doses that were known to be positively reinforceing to rats, we were able to condition avoidance behavior with amphetamine (e.g., Cappell & Le Blanc 1973). When the response of

drinking saccharin was paired with doses of amphetamine that were

not obviously toxic, a phenomenon that looked much like punishment

occurred. At first, this behavioral model was intriguing, in large

part because it generated an outcome that was nonobvious and apparently paradoxical. Of the possible research avenues to follow,

we opted to consider conditioned gustatory avoidance as a model of

control of behavior by a pharmacological stimulus, just as intravenous self-administration is. The study of tolerance to the effects

that exert such control is obviously important, but intravenous

self-administration methods had not been ideally suited for the

purpose. For one thing, it is quite difficult to use the intravenous

model to generate baselines of drug-maintained behavior that obviate

the development of tolerance prior to the acquisition of a stable

baseline. Another problem, although not an insuperable one, is

that the presentation of the reinforcer might affect the behavior

on which it is contingent in such a way as to obscure the measurement of tolerance. Although it has problems of its own, the gustatory conditioning method averts these two.

Since much of this work is already published and the earlier work

is reviewed elsewhere (Cappell & Le Blanc 1975a; in press) we will

deal briefly with the history and later concentrate more fully on

our newer findings. Our first effort in this area (Le Blanc &

Cappell 1974) began with an essentially traditional (i.e., “physiological”) conception of tolerance. Animals were chronically

exposed to regimes of treatment with high and low doses of morphine

or amphetamine. Next, their acquisition of avoidance of saccharin

conditioned by these drugs was studied. Attenuation of the acquisition of avoidance in this procedure could reflect tolerance to

the drug effects that are responsible for avoidance. Pretreatment

with amphetamine at both a high (20 mg/kg) and low dose (4 mg/kg)

greatly attenuated the degree of gustatory avoidance that could be

subsequently conditioned with a dose of 1 mg/kg. These results

were corroborated in an analogous experiment with morphine. Although

there were several alternative explanations for the results, the

best one seemed to be that the pretreatment regimes had produced

79
tolerance to the effects of the drugs that were responsible for

avoidance conditioning (whatever these effects might be).

The next logical series of experiments was also dictated by a traditional contention of tolerance. It was here that the trouble

with such a notion first began to emerge. The reasoning (Cappell

et al. 1975) was that if pretreatments were effective because they

produced pharmacological tolerance, pretreatment with a drug from

one pharmacological class should not affect gustatory conditioning

by a drug from another class. This prediction was found to be

generally true: pretreatments by morphine, amphetamine, or

chlordiazepoxide were effective in attenuating conditioned

avoidance by themselves, but not by each other. The one strange

exception to this was that amphetamine did attenuate conditioning

by morphine, although the reverse was not true. We could find only

scant evidence to account for this on pharmacological grounds, but

the flaw in the tolerance hypothesis still seemed to be outweighed

by its merits. Recently, similar anomalies have been reported by

other laboratories (Braveman 1975; Vogel & Nathan 1976).

Other experiments were designed specifically to further the interpretation of these pretreatment effects as evidence of tolerance

to the unconditioned effects of the drugs. Two parametric studies

(Cappell & Le Blanc 1975b) showed that the rate of acquisition

and loss of the effectiveness of amphetamine pretreatment corresponded to what might be expected if pharmacological tolerance was

at work (Kalant et al. 19719). The effectiveness of pretreatment

increased linearly with the number of pretreatments and was lost

in linear relationship to the duration of withdrawal following a

fixed duration of pretreatment. We also found that the persistence

of the effect of pretreatment with morphine outlasted that of amphetamine (Cappell & Le Blanc 1977). This result seemed very persuasive in view of the evidence, admittedly meagre and controversial,

that tolerance to morphine is uniquely persistent (Cochin & Kometsky

1964).

In the same paper, however(Cappel1 & Le Blanc 1977), another finding

not entirely consistent with a purely physiological conception of

tolerance emerged. We compared the effectiveness of 1.5 “massed”

and “spaced” pretreatments with morphine and amphetamine in attenuating the acquisition of aversive conditioning by themselves. As

far as possible, comparability across the two drugs was attempted

by selecting approximately equipotent doses of the two drugs during

pretreatment ( morphine, 40 mg/kg; amphetamine, 4 mg&kg) and

conditioning (morphine, 10 mg/kg; amphetamine, 1 mg/kg). Despite

the fact that animals in the “spaced” conditions were injected at

intervals of 120 hr compared to 24 hr for the “massed” conditions,

the two schedules of pretreatment were highly and equally effective

regardless of the drug used. Why is this inconsistent with a purely

pharmacological construction of tolerance? According to some empirical evidence and a mathematical model of the kinetics of tolerance acquisition developed in our laboratories (Kalant et al. 197la;

Le Blanc & Cappell 1975), a drug treatment schedule should be more

effective in producing tolerance to the extent that the adaptive

80
response to the pharmacological stimulus can accumulate with minimal opportunity for dissipation over time. From this postulate

we predicted the greater effectiveness of the massed schedule -

incorrectly.

Our prediction was based upon the assumption that there is a

decay of the tolerance produced by a single injection of a drug to

the point that injections spaced at 120 hr will not provoke much

cumulation of tolerance. The loss of the adaptation was assumed

to represent a recovery to normalcy, in this case to nontolerant

status, in the prolonged absence of a continued pharmacological

stimulus to adapt. If this model is not applicable, what kind of

interpretation could predict such “savings” of the effectiveness

of drug administrations spaced at wide intervals? One possibility

that we had considered and rejected earlier (Le Blanc & Cappell

1974) and that has been specifically proposed by Braveman (1975)

to account for pretreatment effects is the operation of an associative process. Although Braveman did propose two versions of the

operation of an associative mechanism, he was necessarily speculative about how they might work. However, even in the absence of

a specific proposal of how such a mechanism might work, in principle

it would seem less vulnerable to decay with the mere passage of

time than a physiological one such as we had been entertaining.

The reason for this is that an active intervention rather than the

mere passage of time seems to be required to offset the effectiveness of an associative mechanism,

Further exploration of an associative basis for these pretreatment

effects involved an excursion into some principles of conditioning

theory. Specifically, pretreatment phenomena were analysed in the

context of Rescorla and Wagner’s (1972) associative-blocking model

of conditioning. First, the operations involved in our typical

experimental paradigm were subjected to scrutiny as a conditioning

procedure per se. Consider first the operations involved in a pretreatment procedure. The animal is repeatedly exposed to a relatively consistent set of cues (i.e., the cues of handling and injection) followed reliably by the pharmacological effects of the

administered drug. Formally, this can be considered as the repeated

Pavlovian pairing of a CS and a KS. During gustatory conditioning,

the animal is exposed to an intended CS (the flavor of saccharin)

followed in 5 minutes by handling, injection, and pharmacological

effects. That is, during conditioning there is an attempt to establish a new associative link between a flavor (CS2) and a pharmacological effect, although such a link between the cues of handling

and injection (CS1) has already been established. According to

an associative-blocking analysis, the prior association of CSl and

the UCS should ‘block” an association between CS2 and the same UCS

because CS1 has in effect preempted the associablllty of the UCS

to other CSs. In an empirical test of this analysis, we specifically attempted to neutralize the association between handling and

injection cues and a drug effect by an explicit nonreinforcement

procedure, and thus to “unblock” the association between flavor and

drug effect. In the interest of brevity, only the results of one

experiment that supported this analysis will be presented, although

81
it should be added that we have successfully replicated and extended

the results recently.

On the basis of our analysis, it is evident that the cues requiring

neutralization are those that most reliably and immediately precede

the drug effect; thus an effective procedure must neutralize the

associative value of handling and injection cues. An obvious way

to do this is by nonreinforcement- that is, by presenting these

cues not followed by a drug effect. In our first experiment designed

to test this conceptualization, we examined the effect of a nonreinforcement procedure on the effectiveness of pretreatment by

amphetamine (7.5 mg/kg for 12 days). The nonreinforcement procedure simply consisted of administering injections of saline 4 times

per day for 4 days prior to the beginning of conditioning trials

and on the 2 days intervening between each conditioning trial.

The conditioning dose was 1.0 mg/kg of amphetamine. The nonreinforcement procedure had the predicted effect. In the group exposed

to the procedure, the usual effect of pretreatment was completely

reversed.

This finding can be approached in at least two ways. First, an

unelaborated interpretation based on the concept of associative

blocking and its reversal suffices on its own. In such an approach,

tolerance need not be mentioned, and the information value of the

nonreinforcement procedure can be emphasized. Thus it may be that

the application of the nonreinforcement procedure tells the rat

that the important association in gustatory conditioning is between

the flavor and the drug effect, rather than between the handling

and injection procedure and the drug effect. Consequently, it

learns to avoid the flavor. However, one cannot help but be impressed by the comparability of our nonreinforcement procedure to

the associative manipulations that Siegel (reported elsewhere in

this monograph) has applied to interfere with analgesic tolerance

to morphine. Both involve nonreinforced presentations of a CS

intended to interfere with a drug effect that is also associated

with the same CS at another point in an experimental procedure.

But Siegel (1975) has suggested, and provided direct evidence for,

a particular mechanism that mediates the effectiveness of his associative manipulations. Specifically, he has argued that his associative procedures bring under stimulus control the occurrence of

a conditioned compensatory response to morphine without which analgesic tolerance will not occur. Could something similar apply to

our own procedures?

In theory, it is possible to specify how such a mechanism might

work. During pretreatment, a compensatory response might be conditioned to the cues of drug administration by the repeated pairing

of these cues with the systemic effects of amphetamine. If this

conditioning were allowed to remain intact, these cues would elicit

a compensatory response when an injection of amphetamine was paired

with the flavor of saccharin during gustatory conditioning. This

compensatory response would summate with the actual drug effect

and diminish its magnitude. All of this should lead to attenuation

82
of flavor avoidance, which is of course the result of pretreatment.

However, if the drug administration procedure were specifically nonreinforced we would expect a reduction in its ability to evoke

the compensatory response. There would be no subtraction from the

actual drug effect when it occurred during gustatory conditioning,

and avoidance of the flavor should be relatively strong. Of course,

this was the effect of our nonreinforcement procedure.

All of this is very plausible in theory. But we cannot avoid the

question of whether there is any empirical basis for these arguments.

Unfortunately, we can only be highly speculative on this point,

but we can specify some of the requirements that any hypothesis of

compensatory response activity would need to meet to be applicable

to our situation. The most obvious is that it would have to apply

in the case of amphetamine, at least to account for our data. We

know of no evidence to suggest that the conditioned form of the

response to amphetamine administration includes a component that is

compensatory. A second requirement is that this hypothetical compensatory response would need to be engaged by a variety of unconditioned stimuli in addition to amphetamine. The reason for this is

that pretreatment effects have been obtained even when pharmacologically dissimilar agents have been used during pretreatment and

conditioning. As we mentioned earlier (Cappell et al. 1973)) pretreatment with amphetamine attenuated conditioned aversion by morphine; in an extreme case of dissimilarity of unconditioned stimuli,

Braveman (1975) found that pretreatment with a number of different

pharmacological agents attenuated the gustatory avoidance that could

be conditioned by rotation on a turntable. If associatively mediated compensatory conditioning is involved in these examples of

“tolerance,” clearly the mechanism must be general rather than UCSspecific. We can identify procedural operations of conditioning

common to the administration of drugs and rotation that can account

in associative terms for successful pretreatment effects using such

discrepant manipulations, but specification of a compensatory mechanism remains quite another matter. Where morphine analgesia is

concerned, a behavioral compensation is a relatively simple matter

to suggest (i.e., analgesia-hyperalgesia) and measure.

One suggestion of a physiological response mechanism that might-be

common to the wide variety of manipulations used in studies of

pretreatment was made recently by Riley et a1.(1976). They reasoned

that the rat’s response to the various pharmacological and other

manipulations used in gustatory conditioning procedures may be commonly mediated at the level of the hypothalamo-pituitary adrenal

axis. In support of this hypothesis they cited a large body of

evidence to show that ACTH may be involved in gustatory avoidance

conditioning by a variety of agents. Moreover, they cited some

evidence purporting to show tolerance in the ACTH response to some

drugs. Obviously, a compensatory theory would require that responses

compensatory to the effects of ACTH occur and are conditionable for

this mechanism to be involved in the mediation of the associative

effects that we have found.

83
Clearly there is no unequivocal evidential basis for making a commitment to ACTH, or for that matter, any particular physiological

mechanism, as the final common path underlying pretreatment effects

that operate within and between drug classes. We mention this mechanism only because it has been specifically proposed, and because

there is at least some evidence in its favor. One might just as

easily focus on a neuro-transmitter mechanism, since as we saw

earlier, tolerance can be affected by the manipulation of transmitters. The mere suggestion of such a mechanism may, however, bring

us full circle to the idea we raised earlier, namely that we can

profitably think of tolerance as a special case of adaptation. Physiological mechanisms are certainly important considerations here.

What a behavioral perspective has to offer is the idea that the

rate and perhaps even the occurrence of such processes is subject

to modification by environmental manipulations, including Pavlovian

conditioning.

The definitional problems created by the use of the word ”tolerance”

emerge clearly where the study of tolerance in the context of gus

tatory conditioning is concerned. At one level, the reduction in

effectiveness of conditioning by pretreatment seems to have all the

earmarks of tolerance; there certainly appears to be some form of

adaptation involved, and, in fact, habituation has been offered as

an alternative to tolerance in accounting for pretreatment effects

(Vogel 6 Nathan 1976). Yet there are obvious anomalies. What is

intriguing about this is that the puzzling outcomes are anomalous

mainly in the context of a strictly pharmacological conception of

tolerance. It seems that we are faced with two choices: we can

say that it must not be tolerance that we are studying, or we can

change our conception of tolerance. It is tempting to prefer the

latter choice.

CONCLUSIONS AND IMPLICATIONS

In addition to its obvious forensic relevance (e.g., in relationship

to traffic safety), the study of drug tolerance is of special practical importance to the extent that it can help to provide an

account of drug consumption. There is ample evidence that increases

in alcohol consumption in populations (Schmidt & Popham 1975) are

associated with increases in adverse consequences to health. Unfortunately, we cannot yet estimate the precise contribution of tolerance per se to drug consumption. We know much more about tolerance

as a consequence of drug consumption than we do about its contribution to etiology. Therefore, whatever importance we assign to

the contribution of behavioral variables to tolerance cannot be

divorced from the importance we assign to tolerance no matter what

our theoretical bias is. Whether we study motor impairment, operant

behavior, analgesia, or taste aversion, one crucial assumption is

that knowledge of adaptation to these consequences of drugs provides

a basis for making inferences about drug-taking behavior itself.

The case is clear that behavioral factors do contribute substantially

to the adaptive response to drugs. The rate of tolerance can be

84
augmented by behavioral manipulations. Moreover, there are circumstances under which tolerance appears to be substantially controlled

by associative conditioning mechanisms. Still, the question of

whether such manipulations ultimately have consequences for drug

consumption remains one for speculation. As important as it is for

us to continue to develop an understanding of the modulation of

tolerance to drug effects by behavioral factors, it seems necessary

to develop a firmer basis for relating this information to the

phenomenon of drug-taking. Our research on gustatory aversion represents an attempt to move in this direction by studying adaptation

to the ability of drugs to control behavior. Obviously, this model

also requires a considerable inferential leap in order to draw

conclusions about drug-taking. Research relating tolerance more

directly to drug-taking behavior must, therefore, be considered as a

high priority.

Another issue that bears consideration is the relationship of tolerance to physical dependence or withdrawal. Physical dependence is

of concern because it can represent a health problem in itself, and

also because it may play a role in the maintenance of drug-taking

(i.e., by self-medication of withdrawal effects). Earlier we noted

that a behavioral manipulation that augmented tolerance had the

effect of augmenting physical dependence as well. Thus it seems

likely that any increase in our understanding of the behavioral and

other factors that affect tolerance may have implications for an

understanding of physical dependence. One of the more interesting

developments in this area is the evidence that Pavlovian conditioning

mechanisms are involved in the adaptive response to drugs. It is

tempting to relate the concept of conditioned compensatory response

not only to tolerance but to physical dependence as well. Such

conditioning has clear implications for relapse to drug use (c.f.,

Wikler 1973). Conditioning may underly the “savings” observed in

repeated cycles of tolerance acquisition (Kalant et al ,1971b), and

it may also provide a mechanism whereby the potential for the elicitation of withdrawal is preserved long after apparent recovery has

taken place. This suggests that “normalization” of the tolerantdependent organism may require a process of active behavioral intervention beyond abstinence per se. Further research on the phenomenon

in animals should be addressed to its generality, since our knowledge

is largely confined to a single drug (morphine), a single response

criterion (analgesia), and relatively low doses. Our work with conditioned gustatory avoidance by amphetamine may be a step toward

generality, but its relevance is not yet established.

To summarize, there is no question that there is a loss in sensitivity to many of the effects of drugs with repeated exposure. Equally

beyond question is that this adaptive process can be manipulated

behaviorally. However, the relative importance of behavioral and

pharmacological or physiological variables in the acquisition of

tolerance is not established. Certainly there is no empirical justification for entirely discarding one type of account in favor of

the other. And finally, whatever view of tolerance we choose to

emphasize, it must always be kept in mind that its etiological significance for drug consumption is still based largely on indirect infe85
rence from effects of drugs (e.g., motor impairment) whose predictive relationship to drug consumption is still presumptive.

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AUTHORS

A. E. Le Blanc, Ph.D., C. X. Poulos, Ph.D., and H. D. Cappell, Ph.D.

Addiction Research Foundation, Toronto, Ontario, Canada MSS2Sl

89
IV. MARIHUANA

Environmental Influences on

Marihuana Tolerance

Brooks Carder, Ph.D.

INTRODUCTION

The concept of behavioral tolerance appears to have evolved

from the observation that tolerance to a drug can develop to

certain behavioral effects of a drug but not to others. Thus

Thompson and Schuster (1968) reported that when rats showed

tolerance to the effects of amphetamine on responding to one schedule

of reinforcement, they did not show tolerance on a second schedule.

They called this phenomenon “behavioral tolerance,” because the

tolerance appeared to be altered by stimulus, response, and reinforcement conditions.

Along this line, we have shown that tolerance to marihuana develops

more rapidly when drug administration is followed by behavioral

testing than when it is not (Carder and Olson 1973). This is another

example of behavioral tolerance in the sense that we will use the

term in this paper. “Behavioral tolerance” applies to those phenomena

in which tolerance development is influenced by environmental variables .

It is important to make some qualifications at this point. Previous

workers have used such terms as “learned tolerance,” “behaviorally

augmented tolerance,” or “psychological tolerance.” These terms

frequently lead to assumptions that: 1) Learning is involved in the

development of this tolerance; 2) Behavioral tolerance is fundamentally different from “physiological tolerance”; 3) Behavioral tolerance involves an adjustment of behavioral control mechanisms rather

than of the biochemical systems which are responsible for the action

and metabolism of the drug. This paper is directed at a critical

examination of these assumptions. It will examine the phenomenon of

behavioral tolerance to marihuana and its principal active constituent

1-A9-tetrahydrocannabinol (THC). It will describe reasons which lead

us to question the role of learning in behavioral tolerance and to

question whether behavioral tolerance is fundamentally different from

other forms of tolerance. Finally, it will discuss some of the

implications of this work for the study of marihuana in humans.

90
THEORIES OF BEHAVIORAL TOLERANCE

The Instrumental Response Model

In spite of the fact that we will ultimately question this view, we

will start where this line of research began, with the hypothesis

that instrumental learning plays a role in the development of behavioral tolerance. In one of the early demonstrations of tolerance

to THC, McMillan, et al. (1970) first trained pigeons to peck a key

for grain on a multiple reinforcement schedule and then gave them

daily increasing intramuscular doses of WC. The first application

of a dose of 1.8 mg THC/kg impaired performance, but by day 25 a dose

of 36 mg/kg left performance unaltered. In this case, the adjustment

was ultimately a behavioral one, an increase in responding under the

drug. One potential mechanism for behavioral adjustments is, of

course, learning. In fact this study could provide an excellent paradigm for tolerance due to learning. Tolerance, or the increase in

responding under the influence of the drug, would be reinforced by

the increase in frequency of food rewards which accompany the

increase in responding.

While we do not wish to engage in an extended discussion of the

definition of learning, it is essential to differentiate conditioning

from other types of behavioral adjustment. Conditioning requires

reinforcement. There are two types of conditioning: instrumental

and Pavlovian. In the case of instrumental (operant) conditioning,

an organism’s response is followed by an event (reinforcer) which increases the future probability of occurrence of that response. Reinforcers are usually events such as the presentation of food to a

hungry organism or the termination of painful electric shock. In the

case of Pavlovian conditioning, a neutral stimulus (conditional

stimulus or CS) is paired with a stimulus which naturally elicits a

response (unconditioned stimulus or US). After one or more pairings,

the CS elicits a response (conditioned response or CR) which it

previously did not. The class of US’s and the class of instrumental

reinforcers overlap considerably.

In 1972, Olson and I (Carder and Olson 1973) decided to investigate

the role of learning in the development of behavioral tolerance to

marihuana. Rats were first trained to lever press for positive

reinforcers. One study employed food and the second, water. In each

study, one group was treated with marihuana extract before each daily

training session. The second group was treated marihuana extract, in the same dosage, after each training session. Initially,

when the drug was given before session, responding decreased. When

the drug-before group demonstrated tolerance to this disruption of

responding, the drug-after group was tested for tolerance by giving

them the drug before a test session. In both studies the drug-after

group showed little or no tolerance. The drug interfered with responding as much as it did in the drug-before group on the first day. Thus

the development of tolerance was facilitated when the subjects had

the opportunity to respond for reinforcers during the period of drug

action as the drug-before group did and the drug-after group did not.

91
There are a number of other studies which have confirmed the role of

practice and/or reinforcement in the development of behavioral

tolerance to marihuana and THC. For example, Grilly et al. (1973)

described the development of tolerance in chimpanzees on a delayed,

matching-to-sample task. Tolerance development was interval specific.

That is, tolerance which developed at one delay interval did not transfer when the interval was increased. Grilly et al. proposed that

the tolerance involved the learning of compensatory responses which

were specific to each particular set of test conditions. This response was reinforced by increases in food which resulted from

improved performance under the drug.

Manning (1974) reported the development of tolerance to the effect

of MC on free-operant avoidance in rats. He noted that tolerance

developed only in those subjects for which the drug-induced depression of responding led to an increase in shock frequency. Of course

only these subjects would receive reinforcement (in the form of a

decrease in shock frequency) for the development of tolerance.

More recently, Manning (1976) administered THC to rats for 12 days,

each time followed by a return to the home cage. When these rats

were tested under the drug on a Differential Reinforcement of Low

Rate (DRL) schedule, they demonstrated no tolerance. When they were

then tested daily under the influence of THC, they developed tolerance at the same rate as rats that had never been exposed to the

drug. This study provides strong confirmation for the finding of

Carder and Olson (1973) that practice under the drug facilitates the

development of tolerance to THC.

In all of these studies, tolerance development may be interpreted as

having had an instrumental value for the subject. In the Carder and

Olson (1973), Grilly et al. (1973) and Manning (1976) studies, subjects obtained more food reinforcers as they developed tolerance.

In Manning’s (1974) study of free-operant avoidance, tolerance

development was reinforced by a decrease in shock frequency. Thus

it is possible to view these demonstrations of behavioral tolerance

as instances in which tolerance developed as a learned instrumental

response.

It should be noted that there are numerous reports that demonstrate

development of tolerance to THC in situations in which no apparent

reinforcement was involved. For example, Ten Ham (1977) reported

that rats given THC developed tolerance to the effect of the drug

on shuttle avoidance and body temperature whether the drug was given

before or after testing. The point remains, however, that in many

cases, environmental conditions during the period of drug action do

exert powerful effects on tolerance development.

The Pavlovian Model

Most investigators seem to have favored an instrumental response model

for behavioral tolerance to THC. However, there are at least two

other models which can account for most, or perhaps all, of the data

which demonstrate behavioral tolerance. The second model we would

like to discuss is a Pavlovian model.

92
Siegel (1975) working with morphine, seems to have been the first

to develop a Pavlovian model of learned tolerance, although his work

derives from earlier work by Adams et al. (1969), Gebhart and Mitchell

(1972), and others. Siegel argued that the administration of morphine

produces an unconditioned response, and that over the course of

several drug administrations a conditioned response of tolerance

develops to the conditioned stimuli associated with intoxication

(Particularly the test chamber). According to this hypothesis, instrumental reinforcement is incidental to tolerance development. What

is important is that during the period of tolerance development the

unconditioned response (UR) which follows drug administration must be

paired with the CS of the test chamber. In the test, the CS of the

test chamber elicits the conditioned response of tolerance. Siegel

showed that rats which received morphine in the home cage failed to

demonstrate tolerance to the drug in a hot-plate analgesia test,

presumably because the UR produced by the drug was never paired with

the CS of the test chamber. Subjects that received daily doses of

the drug, followed by exposure to the hot plate, did develop tolerance, whether the plate was hot or cold. Apparently, instrumental

reinforcement was not involved, since it is difficult to see how

Siegel’s subjects could have been instrumentally reinforced for

developing tolerance.

Siegel’s hypothesis could lead to some very interesting predictions.

We know for example that Pavlovian CR’s can be brought under discriminative stimulus control. Thus a dog that is reliably fed following a tone (CS+), but not following a light (CS-), will develop a

conditioned salivary response to the tone and will not respond to

the light. To bring tolerance under stimulus control, rats could be

dosed with morphine and then placed in a black chamber (CS+). Placebo

injections could be followed by placement in a white chamber (CS-).

The CR of tolerance should appear when subjects are tested in the

black box, but not in the white. Gebhart and Mitchell (1972) have,

in fact, done something like this. They developed tolerance in the

hot plate environment and then demonstrated that removing various

components of the apparatus, thereby changing the CS, attenuated the

tolerance.

The Stress or Arousal Model

Our third hypothesis, which no one seems to have considered yet, is

the notion that stress, or arousal, plays a role in tolerance development. When a subject is dosed with a drug and then placed in an

experimental test environment, it is presented with the opportunity

to associate a CS with the US of the drug and in some cases with the

opportunity to obtain instrumental reinforcement for tolerance

development. It is also placed in a situation which produces relatively more arousal than does the home cage. Perhaps it is this

increase in stress or arousal during the period of intoxication, and

not the opportunity to obtain instrumental reinforcement or the

exposure to potential Pavlovian conditioning situations, which

facilitates the development of tolerance.

93
EXPERIMENTS

This third hypothesis gives rise to an easily testable prediction.

Subjects given a drug and then placed in an arousal-producing

situation, even without opportunities for instrumental reinforcement, should develop tolerance to the drug and demonstrate it in a

test situation which is quite dissimilar to the situation in which

tolerance was developed.

Some pilot studies in our laboratory have addressed this question.

In the fundamental experiments, 6 groups of 4 rats were treated as

follows: Group THC-cage was treated with 5 daily, intraperitoneal

doses of THC an rep aced in the home cage. Group saline-cage was

treated with 5 daily doses of saline and also replaced in the home

cage. Groups THC-box and saline-box were given the same drug treatment as the first “cage” groups, but 30 minutes following drug

administration each rat was placed for 20 minutes in a small experimental chamber. Groups THC-shock and saline-shock also received the

same drug treatments and exposure to the experimental chamber, but

painful electric shocks were presented during the exposure to the

chamber.

On the day following the final day of pretreatment, each rat was dosed

with 5 mg THC/kg and tested for swimming escape. The rat was placed

in the center of a circular tub of water about 90 an in diameter with

a small platform at one edge. The rat could escape by swimming to the

platform and mounting it. Rats that did not mount the platform within

60 seconds were removed and given a score of 60. Rats that were unable to swim and sank were immediately removed and given a score of

60. There was one test trial with no pretraining.

The results of the test are presented in Table 1. An analysis of

variance revealed a significant effect of pretreatment with THC

compared to saline (F=6.19, df=l/18, p<.02) and a significant effect

of the pretreatment environment (home cage, box, shock) (F=7.13,

df=2/18, p<.01). There was not a significant interaction (F=0.84).

Thus, either the application of THC, the application of stress in the

form of handling, exposure to a novel environment, or electric shock

is sufficient to decrease the sensitivity of rats to THC in the

swimming escape task.

TABLE 1. Mean escape time as a function

of pretreatment.

stress pretreatment

drug-pretreatment

The combination of THC and exposure to either the box or to the box

with shock seemed to produce maximal tolerance. Rats tested under

94
saline in the swimming escape task escaped in a mean of 13 seconds.

In rats pretreated with saline, exposure to shock seemed to produce

more tolerance than exposure to the box without shock, although this

was not statistically reliable (t=1.25, df=6, p<.26).

It should be noted that the stress pretreatment does not produce the

appearance of increased tolerance merely by increasing the strength

of the escape response. Rats pretreated with saline and 5 daily

shock sessions, then tested under placebo, escaped in a mean of

21.25 seconds, indicating that, if anything, shock pretreatment impairs swimming escape.

These data provide strong support for the hypothesis that behavioral

tolerance in this situation is not a learned instrumental response,

since there was no opportunity for the subjects to be reinforced for

tolerance development. Nor does Pavlovian conditioning seem to be

involved, since the tolerance was developed in one environment and

demonstrated in another. Rather, this appears to be an example of

the effect of stress on rats’ sensitivity to THC. The presence of

stress during the period of intoxication accelerates the development

of tolerance to THC.

Perhaps the most interesting aspect of our findings is the fact that

stress alone reduced rats’ sensitivity to THC in a subsequent test.

Pats in the saline-shock group, exposed to the experimental chamber

and shocked for 5 daily sessions, escaped faster under THC than did

the saline-cage group (t=3.37, df=6, p<.02). We have termed this

phenomenon, in which exposure to environmental situations without the

application of drugs reduces sensitivity to a drug in a subsequent

test, “behaviorally induced tolerance.”

We have followed up this initial finding of behaviorally induced

tolerance with several studies designed to explore the dimensions of

the phenomenon. The following study demonstrates two very important

characteristics of the phenomenon: 1) It has a duration of effect

of at least several days, and 2) it extends to physiological as well

as behavioral measures of the THC effect.

The temporal characteristics of tolerance to cannabis following chronic

administration have been widely detailed. While tolerance reversal

has not been consistently noted (Davis et al., 1972), Silva and

Carlini (1968) as well as Webster et al. (1973) observed that tolerance

to chronic administration of THC was virtually absent 8-11 days after

cessation of treatment. In the study below we compared the duration

of shock-induced tolerance with the duration of tolerance produced by

repeated THC administration. In this experiment, tolerance was

assessed by monitoring the hypothermic effect of THC rather than

swimming escape.

Sixty rats were randomly assigned to groups I, II, or III for tolerance

testing at different intervals following tolerance development. Each

group was then subdivided as follows: THC-MC (T-T); shock-THC (S-T);

shock-propylene glycol (S-P-G.) ; and propylene glycol-THC (P.G. -T) .

95
Subjects in the T-T condition were given 7 daily intraperitoneal

injections of 5 mg THC/kg and replaced in the home cage. Subjects

in S-T and S-P.G. were given 7 daily injections of propylene glycol

followed by 20-minute exposures to shock in the experimental chamber,

as in the previous study. Subjects in the P.G.-T group were given

7 daily injections of propylene glycol followed by placement in the

home cage. Following pretreatment, all subjects were tested for the

hypothermic effect of THC. Colonic temperature was measured by a

telethermometer via a rectal probe. Pats in group I were tested on

the first day following pretreatment? while rats in groups II and III

were tested at 3 and 10 days respectively. Rats in groups T-T, S-T,

and P.G.-T were given 5 mg THC/kg before the measurement of body

temperature, while the rats in group S-P.G. were given propylene

glycol before the measurement of body temperature.

FIGURE 1

Mean core temperature as a function of

pretreatment and test condition at three

intervals following pretreatment.

Figure 1 presents the mean core temperature for all groups and conditions throughout the experiment. Neither the S-T, T-T, nor S.P.G.

subjects exhibited noticeable hypothermia on the first day following

cessation of pretreatment. In contrast, subjects in P.G.-T demonstrated significant reductions in temperature following THC administration (pc.05). S-T subjects tested 1 or 3 days following cessation of

pretreatment exhibited no hypothermia. By day 10, however, all Pretreatment groups had lost their tolerance and showed a hypothermic

reaction to THC.

Thus, several brief periods of electric shock can induce a tolerance

to the hypothermic effect of THC that persists for at least 3 days.

It is important to note that while our previous demonstration of behaviorally induced tolerance employed a behavioral measure of tolerance, this study demonstrates that past environmental conditions can

alter a physiological effect of THC.

96
DISCUSSION

There have been previous studies that show that past experience can

alter the effect of a drug. The studies that we are aware of, however, including two from our laboratory (Carder and Olson 1972; Olson

and Carder 1974) and the work of File (1973) involve experience with

the situation in which the effects of the drug are ultimately tested.

This experience would be expected to alter the subject’s reaction

to the test situation and, therefore, it is not at all surprising

that this could alter the effect of a drug in the test situation.

The studies described above demonstrate that experiences which involve neither the drug nor the test situation can alter the effect

of THC. It is very difficult to explain these findings on the basis

of transfer of training.

A possible explanation for the influence of stress on THC tolerance

is that the biochemical changes induced by stress and by THC have

certain common elements and that it is these common elements that are

responsible for the transfer, just as tolerance will transfer between

two drugs that have biochemical actions in common. There is considerable evidence, for example, that stress increases catecholamine turnover (Stolk and Barchas 1973). Several biochemical studies (Johnson

et al. 1976; Howes and Osgood 1974; Ho et al. 1972; Ho and Johnson

1976; Maitre et al. 1970; Maitre et al. 1973; Poddar and Gosh 1976;

Schildkraut and Efron 1971; Singh and Das 1976) indicate that THC

increases catecholamine turnover. Recently, behavioral studies

(Carder and Delkel 1976; Singh and Das 1976) have indicated that the

alteration of catecholamine turnover may underlie some of the behavioral effects of THC. Moreover, the studies provide evidence for cross

tolerance between THC and reserpine and tetrabenazine compounds known

to increase catecholamine turnover. Thus lt is possible that increased

catecholamine turnover may provide the common element between stress

and THC that is responsible for behaviorally induced tolerance to THC.

Along this line, Seiden et al. (1975) have proposed that catecholamine

alterations underlie the observed rate-dependent effect of amphetamine.

A dose which can increase low rates of operant responding will decrease

high rates (Dews 1958). Seiden’s notion, like the one presented above,

is that amphetamine produces different effects on different baseline

rates of responding because both the drug and the behavior influence

catecholamine metabolism. Therefore the net effect of the drug must

depend both on the biochemical effect of the drug and the biochemical

effect of the behavior.

It is important to describe how the stress hypothesis can account for

tolerance which has been ascribed to Pavlovian or instrumental learning.

For example, Siegel (1975) found that the application of morphine,

followed by exposure to the test chamber, led to the development of

tolerance to morphine. According to Siegel, this was because the CS

of the test chamber was paired with the UR produced by the drug,

leading to the development of the CR of tolerance. An alternative

explanation is that the test chamber is a more stressful environment

than is the home cage, and that placement in the chamber during intoxication would accelerate tolerance development. A simple test would

involve the placement of subjects in a novel environment other than the

test chamber during the period of tolerance development. If the

97
Pavlovian hypothesis is correct, this should not accelerate tolerance

development. If the stress hypothesis is correct, this should indeed

facilitate tolerance development. In our studies described above,

tolerance developed in an operant test chamber was transferred

to a swimming escape test, a very different situation. This finding

is quite inconsistent with a Pavlovian interpretation.

Those studies such as the Carder and Olson (1973) study, in which

tolerance is developed in an instrumental training situation, are

also subject to explanation by the stress hypothesis. According to

the instrumental learning hypothesis, tolerance develops as a result

of the increased reinforcement which accrues to improved performance

under the drug. According to the stress hypothesis it is the decrease

in reinforcement frequency which accelerates tolerance development.

A test which could discriminate between the two explanations is again

quite simple. Rats would be trained to press a lever to obtain food.

Following THC administration and the consequent reduction in the rate

of responding and reinforcement, the rate of reinforcement could be

kept low no matter what happened to the response rate. This would

prevent the reinforcement of tolerance development and if the instrumental learning hypothesis is correct, tolerance development should

be retarded. If the stress hypothesis is correct, the stress created

by the continued decrease in the frequency of reinforcement should

accelerate the development of tolerance.

CONCLUSIONS

The preceding analysis of environmental influences on marihuana tolerance has implications for both theory and research. We have attempted

to expand the concept of behavioral tolerance. Our data indicate that

in some cases behavioral tolerance is not a simple learned adjustment

which results in a decreased response to a drug. In studying the interaction between environmental factors and tolerance development, we

have found that shocking a rat or exposing it to a novel environment,

with or without THC, can decrease the rat’s response to the drug.

While it is possible that some type of learned adjustment may be involved, it is very difficult to see how there could be a transfer of

training from inescapable shock to swimming escape. The data indicate

that, if anything, the transfer of training is negative.

Another argument against the notion that behavioral tolerance always

involves a learned adjustment is our finding of behaviorally induced

tolerance to the hypothermic effect of THC. It is difficult to see

how learning could lead to an adjustment of mechanisms which control

this hypothermic reaction.

In addition, the duration of effect of behaviorally induced tolerance

seems to approximate the duration of tolerance to THC produced by

repeated THC application: 8-12 days. Learned responses typically

persist much longer than this.

I would suggest the view that in their effects in the central nervous

system there is no essential difference between pharmacologic and

environmental events. The function of the CNS can be altered, either

temporarily or permanently, by either. Of course, tolerance to both

modes of alteration of CNS function has been described. When a rat

98
is placed in a chamber and presented with a particular auditory stimulus, it will react in a number of ways, both physiologically and

behaviorally. Repeated presentations of the stimulus will lead to an

attenuation of this reaction. We call this tolerance which develops

to environmental stimulation ‘habituation.” The attenuation of behavioral and physiological reactions to a drug on repeated application

is called “tolerance.” There is no a priori reason to expect that

the mechanisms of habituation and tolerance should be different. Moreover, the finding that repeated application of shock leads to tolerance

to THC suggests some overlap between the mechanisms.

If this is the case, it would appear that it is impossible to study

tolerance independently of environmental circumstances. Factors such

as handling, adaptation to the apparatus, housing conditions of the

subjects , deprivation schedules , and a host of other experimental

procedures could play a powerful role in tolerance development. It

is essential to begin to assess the contribution of these factors in

order to gain an understanding of tolerance to any drug. Behavioral

tolerance is not a special case. The term simply refers to the contribution of environmental variables. These appear to be no more or

less important than other variables such as route of administration

of the drug, frequency of administration, dosage, etc.

The phenomenon of behaviorally induced tolerance is particularly

exciting because it may provide us with a model with which to conduct

extensive studies of how an organism’s past history can alter its

reactions to an initial application of a drug. One of the fundamental

questions in the field of drug addiction is why some individuals use

drugs and become addicted while others use the same drugs but do not

develop an addictive pattern. It would be attractive to trace the

differing responses to differences in the histories of the individuals.

The existence of animal models could help us to define the important

variables for such work.

An example of how the animal model might be generalized to research

with humans can be developed with the so-called “panic reaction” to

marihuana. This reaction is usually seen in naive users, persons who

have had no opportunity to develop tolerance through repeated use of

the drug. However, the reaction does not occur in all such persons.

It also appears that the use of the drug under stressful circumstances

IS more likely to lead to a panic reaction, although there is no

statistical data on this. Our pilot studies suggest a third variable

that may be important: tolerance to stress. A person who had had a

great deal of stressful experience and had developed a tolerance to

this should be much more resistant to developing a panic reaction than

a person without this tolerance. This hypothesis could be examined

experimentally or evaluated on the basis of existing clinical data.

Of course, marihuana addiction--if such a phenomenon exists--does not

appear to present a significant social problem in this country. Thus

the most important function of our work may be to provide a model for

the study of other drugs. The study of environmental influences on

tolerance to narcotics, alcohol, barbiturates, minor tranquilizers,

and amphetamines is of the greatest potential interest. Such studies

may be fundamental to the development of a scientific understanding

of the etiology of drug addiction.

99
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AUTHOR

Brooks Carder, Ph.D., Synanon Research Institute, P.O. Box 786,

Marshall, California 94940

102
IV. MARIHUANA

Behavioral Tolerance to Marihuana

Douglas P. Ferraro, Ph.D.

In the lexicon of behavioral pharmacology, the term behavioral

tolerance is used in an unfortunately wide variety of ways. In

some instances the term is used to refer to a specific empirical

event which is observed to occur only in a limited context. In

other instances the term is used to refer to a general theoretical

mechanism which is assumed to account for a myriad of drug-induced

phenomena. Given these extremes of usage, it is little wonder that

confusion arises and controversy surrounds the concept of behavioral

tolerance.

It should be noted at the outset that either an empirical or a

theoretical use of the term behavioral tolerance is acceptable in

its own right; neither usage is necessarily more correct or appropriate than the other. But it is necessary that a distinction be

drawn between the two and that in any particular instance the

intended meaning of behavioral tolerance is made certain. Otherwise,

it is difficult to appreciate the arguments of those who embrace

and those who eschew the concept of behavioral tolerance.

It is my intention to draw the distinction between empirical and

theoretical behavioral tolerance, and to do so with specific

reference to the preclinical behavioral pharmacology literature on

marihuana effects in animals. The choice of drug is no more than

a convenient one; the distinction between empirical and theoretical

behavioral tolerance is as readily elaborated and illustrated with

many other pharmacological compounds. Indeed, the distinction is

a conceptual one which emerges regardless of pharmacological class

or behavioral task.

EMPIRICAL BEHAVIORAL TOLERANCE

Empirical Definition of Behavioral Tolerance

A well-framed empirical definition of the concept of behavioral

tolerance has the characteristics of being both operational and

functional. It is operational in that it states the procedures and

103
conditions which are necessary to observe the concept. It is functional in that it states what sorts of observable behavioral changes

constitute the concept. Take as one instance the following empirical

definition of behavioral tolerance to marihuana: Following prior

exposure to a fixed dose of marihuana (operational), a specified

behavioral effect of marihuana diminishes (functional). A second

acceptable example of an empirical definition of behavioral tolerance

to marihuana is: Following repeated administrations of marihuana

(operational), the dose-effect relationship on some specified

behavior shifts to the right (functional).

By way of summary, what it is that makes both of these definitions

acceptable, and what would make still others so, is that they specify

what is necessary in order to observe behavioral tolerance to

marihuana (operationally, to administer marihuana repeatedly), and

what observed behavioral change constitutes behavioral tolerance

(functionally, a diminution in the behavioral effect induced by

marihuana) . Conversely, the empirical definitions imply what

behavioral tolerance is not. For example, repeated administrations

of marihuana do not constitute behavioral tolerance if they

occasion an increase in the drug’s effect on behavior. Likewise,

a diminution of the behavioral effect does not constitute behavioral

tolerance if it is produced by some nonpharmacological factor. This

is not to deny the possibility of the latter two empirical outcomes.

Indeed, they may well be considered as positive instances of some

other empirically defined concepts (say, perhaps, reverse tolerance

and environmental tolerance). But they are not instances of

behavioral tolerance as defined empirically.

Of course, empirically defining behavioral tolerance to marihuana

does not assure that instances of the concept actually exist. As

it turns out, however, behavioral tolerance to marihuana is readily

identified for several unlearned and learned behaviors in a range

of animal species and under a variety of marihuana conditions.

Indeed, in many instances behavioral tolerance to marihuana is

characterized by its rapid development and large magnitude. Among

these instances, recently reported, are : spontaneous activity in mice

(Anderson et al. 1975) ; dominance status in monkeys (Sassenrath and

Chapman 1975); conditioned avoidance learning in rats (Waser et al,

1976); analgesia in dogs (Kaymakcalan et al. 1974) ; and reinforcement

schedule performance in pigeons (Bruce and Ferraro 1975).

Empirically defining behavioral tolerance to marihuana also does

not serve to explain the concept. Empirical definitions in no

way presume or imply anything about the mechanism(s) which underlie

the concept defined. That is, the answer to the question of "why

does behavioral tolerance to marihuana occur?” is in no way even

minimally broached by the empirical definition. This is as it should

be, since the specification of underlying explanatory mechanisms is

a theoretical matter, not an empirical one. Explanation, in the

sense of answering the question Why?“, is a reductive process.

Identification and description, in the sense of answering the questions

“When, where, and under what conditions?“, are inductive processes.

The inductive-reductive distinction will be discussed further.

are might anticipate, however, that empirical and theoretical

approaches to the concept of behavioral tolerance differ radically.

104
Empirical definitions of behavioral tolerance to marihuana are

lacking in still another regard. They do not include any specifics

about the parameters of the operations that enter into defining

the concept. This creates some difficulty for those who are inclined

to describe behavioral tolerance empirically. For example, consider

the operation of repeatedly administering marihuana. It is not

clear from the empirical definition what parameters of this operation

are pertinent to describing behavioral tolerance. Several degrees

of freedom are available: drug dose and route of administration

(Abel et al. 1974; Fried 1976); number of drug administrations and

time interval separating successive drug administrations (e.g.,

Davis and Borgen 1975); drug vehicle and form of the drug (Kosersky

et al. 1974); and so on. Further, one may wonder how many times

marihuana must be administered before invoking the concept of behavioral tolerance to marihuana is justified. If a completely

diminished drug effect on behavior is observed following one

marihuana administration (Domino 1971; McMillan et al. 1971))

should this observation qualify operationally as an instance of

behavioral tolerance to marihuana?

The lack of parameter specificity inherent in empirical definitions

of behavioral tolerance is not peculiar to the operational aspects

of the concept. It applies as well to the functional behavioral

aspects of the concept. For example, it is not clearly specified

by the empirical definition whether the observed diminution in a

marihuana-induced behavioral effect should be gradual or abrupt,

immediate or delayed, partial or complete. There are two points

to be made in this context. The first is the obvious one that it

is not always easy to identify an instance of behavioral tolerance

to marihuana, even when it is empirically defined because of a lack

of parameter specificity inherent in the generic concept. The

second point is that empirical definition, while necessary, is not

sufficient to provide an empirical description of behavioral tolerance

to marihuana.

Empirical Description of Behavioral Tolerance

The empirical description of behavioral tolerance to marihuana is a

cumulative affair. It is only through repeated observations that

the parameter values of the operations and conditions of behavioral

tolerance are progressively elucidated. For example, we now know that

behavioral tolerance to the depressant effects of marihuana on

reinforcement schedule performance is directly related to the number

of marihuana administrations and indirectly related to the treatment

interval (Davis and Borgen 1975). With respect to conditions,

we now have empirical knowledge that the age of the subject at the

time of first exposure to marihuana interacts with later behavioral

tolerance development (Parnes and Fried 1974) and that stress may

augment behavioral tolerance development (Deikel and Carder 1976).

Furthermore, there now exists an extensive listing of those

behavioral effects which do and those which do not diminish with

repeated administrations of marihuana. To the abbreviated list of

confirmed instances of behavioral tolerance to marihuana given above,

we may add other instances where a lack of behavioral tolerance

development to marihuana has been observed. Briefly, a lack of

behavioral tolerance has been found for rodents and monkeys in a

wide variety of situations such as: open field behavior (Sjoden

105
et al. 1973); isolation-induced aggression (Dubinsky et al.

1973); food and water consumption (Gluck and Ferraro 1974);

conditioned shock avoidance (Manning 1976); discrimination learning

(Adams and Barratt 1976); and performance under a schedule of

reinforcement (Snyder et al. 1975).

However, the endpoint of an empirical description of behavioral

tolerance to marihuana is not the simple collation of a vast

array of specific empirical relationships. Instead, the ultimate

goal in this context is the creation of an empirical descriptive

system. Such a descriptive system constitutes interrelated sets

of empirical relationships which, collectively, generate more

implications than each in isolation. Whereas simple empirical

description answers the immediate questions of when, where, and

under what conditions behavioral tolerance to marihuana occurs,

an empirical descriptive system goes beyond the level of present

observation to generalize extant empirical relationships and to

predict unique relationships regarding behavioral tolerance to

marihuana.

An empirical descriptive system is arrived at by a process of

induction from the existing data base. Since there are no formal

rules for induction (going from the specific to the general) not

all behavioral pharmacologists arrive at the same generalizations,

even though they are all eventually tied to the same empirical

observations. One potential difference among the generalizations

is the level of abstractness at which the descriptive system is

cast. Nevertheless, the overall objectives remain to generalize

from known empirical relationships and to predict unique ones.

For example, one may observe that, "The greater the decrement in

performance initially produced by marihuana, the greater the behavioral tolerance." Taken alone this statement implies only that a

correlation exists between some measure of performance decrement and

some measure of behavioral tolerance. Add to it, however, the

statement, "Reinforcement frequency is a direct function of performance level," and it is possible to predict generally that

behavioral tolerance will occur only when marihuana acts initially

to reduce reinforcement frequency. Indeed, just such an induction

was arrived at by Schuster, Dockens, and Woods (1966) in their

study of the determinants of behavioral tolerance to amphetamine.

One does not always have to be as bold as Schuster et al. (1966)

in making predictions from empirical generalizations. Given the

present marihuana example, it is acceptable to make the more

cautious prediction that behavioral tolerance to marihuana is more

likely to occur (or will occur more quickly) when marihuana acts

initially to reduce reinforcement frequency. At the least, the

latter prediction is more certain to achieve empirical verification

than is one couched in absolute terms. Any specific

prediction arrived at inductively may be incorrect. However, the

empirical generalizations from which the prediction is derived

serve abstractly to summarize a number of concrete empirical

relationships and to direct further experimentation.

The one task which descriptive systems do not accomplish is that of

providing explanations in the earlier-described sense of specifying

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the mechanisms underlying behavioral tolerance; they simply do not

account for why behavioral tolerance occurs as it does, This may

be exemplified by quoting the specific empirical generalization

regarding behavioral tolerance to amphetamine which was referred

to above:

Behavior tolerance will develop in those aspects

of the organism’s behavioral repertoire where the

action of the drug is such that it disrupts the

organism’s behavior in meeting the environmental

requirements for reinforcement. (Schuster et al.

1966, p. 181).

No explanatory mechanism is implied here. We are left to ask the

question, “Why should behavioral tolerance develop in such a fashion?”

But if behavioral tolerance does develop in this way, it may not be

necessary to answer the question of why it does so. That is, if we

can specify lawful empirical generalizations for the development of

behavioral tolerance, we may be better advised to proceed to deal

with the implications of these generalizations than to attempt to

produce a theoretical explanation for them. After all, explaining

the generalizations in no way changes the existence of the

generalizations. And once generalizations have been verified

empirically, there are no remaining grounds for confusion or

controversy about them.

Empirical Generalizations About Behavioral Tolerance

As developed in the preceding section? empirical generalizations

regarding behavioral tolerance to marihuana are abstract statements

arrived at inductively from specific empirical relationships. As

such, empirical generalizations have predictive power but no

explanatory power.

In the present section of this chapter, ten empirical generalizations

about behavioral tolerance to marihuana will be offered in which the

referent behavior change involves an operant/instrumental response.

Many of these generalizations have been previously described

elsewhere (Ferraro 1976), Consequently, the generalizations will

be presented succinctly, and only one of two representative references

will be cited for the specific empirical relationships from which

each generalization was induced. It will be obvious that several of

the empirical generalizations are interrelated and interdependent.

This can be simply explained by the fact that all of the generalizations are ultimately tied directly back to a common set of observations.

Generalization 1. Behavioral tolerance to marihuana

is more likely to develop (or will be quicker to

develop) if the drug initially produces adverse

effects on behavior-environment relationships,

such as reductions in reinforcing stimuli or

increases in aversive stimuli (Domino 1971;

McMillan et al. 1970).

Generalization 2. Behavioral tolerance to marihuana

is more likely to continue to develop if drug-induced

adverse effects on behavior-environment relationships

are maintained (Ferraro 1972).

107
Generalization 3. Behavioral tolerance to marihuana is less likely to develop (or will be slower

to develop) if the drug produces behavioral

changes which are not accompanied by adverse

effects on behavior-environment relationships

(Barry and Kubena 1971; Ferraro 1972).

Generalization 4. Behavioral tolerance to marihuana

is less likely to develop if the development of

tolerance itself produces adverse effects on

behavior-environment relationships (Adams and

Barratt 1976; Hirschhom and Rosencrans 1974).

Generalization 5. Behavioral tolerance to marihuana is more likely to develop for some operant/

instrumental responses than for others, or for

some dependent measures of responses than for

others, within the same organism. (Ferraro

and Grisham 1972; Harris et al. 1972).

Generalization 6. Behavioral tolerance to marihuana

is more likely to develop for simple than for

complex operant/instrumental responses (Ferraro

and Grilly 1973; Snyder et al. 1975).

Generalization 7. Behavioral tolerance to marihuana

is more likely to develop the better the referent

operant/instrumental responses are learned (Ferraro

and Grilly 1974; Olson and Carder 1974).

Generalization 8. Behavioral tolerance to marihuana

is more likely to develop the greater the opportunity to perform the referent operant/instrumental

responses under exposure to marihuana (Bruce and

Ferraro 1975; Carder and Olson 1973).

Generalization 9. Behavioral tolerance to marihuana

which develops under one set of environmental

conditions will not transfer completely to another

set of environmental conditions; the degree of transfer

will be directly related to the similarity of the

conditions (Ferraro et al. 1974; Grilly et al.

1973).

Generalization 10. Behavioral tolerance to

marihuana which develops under one set of

environmental conditions will be relatively permanent under those conditions, even if an extended

period of nonexposure to marihuana intervenes

(Ferraro et al. 1974).

Of the ten empirical generalizations presented above, the first

four pertain specifically to the environmental consequences of

behavior, the next four pertain to characteristics of the referent

responses, and the last two pertain to environmental antecedents

of behavior. In other words, in the instance of behavioral

tolerance to marihuana, a dynamic interaction apparently exists

108
between behavior and the environment. Still other empirical generalizations could be presented which pertain specifically to

characteristics of the marihuana treatment (e.g., dose, route of

administration, etc.). Thus, behavioral tolerance to marihuana

may be reasonably well conceptualized as involving drug-behaviorenvironment interactions.

Any abstract generalization may be confirmed or discredited

empirically. In this regard, it is important that the empirical

test of a generalization be carried out within the boundary conditions of the generalization, and that conclusions regarding the

suitability of the empirical generalization be correctly formed.

For example, a simple demonstration that behavioral tolerance

develops to marihuana-induced disruptions in avoidance behavior is not

as supportive of Generalization 1 as is an experiment which shows

that when marihuana produces an increase in shocks under an avoidance

schedule behavioral tolerance occurs, but that when a decrease in

shocks is produced no behavioral tolerance occurs (e.g., Manning

1976). Similarly, evidence that behavioral tolerance to marihuana

occurs in the absence of adverse behavior-environment relationships, or that behavioral tolerance fails to occur in their presence,

does not definitively discredit Generalizations 1-4. All of the

generalizations presented above are relative statements about the

likelihood and extent of tolerance development to marihuana, and

none of them determines the possibility of behavioral tolerance

to marihuana in an absolute sense.

This is an important point which can bear elaboration. Take Generalization 8 as a further example. This generalization states that

behavioral tolerance to marihuana is more likely to occur the greater

the opportunity to respond under the influence of marihuana. This

again is a relative generalization. It does not imply that behavioral

tolerance cannot occur when marihuana is administered outside of

the behavioral situation (Black et al. 1970) or that behavioral

tolerance requires repeated exposures to marihuana (McMillan, et al.

1971). Rather, the generalization predicts that behavioral

tolerance will develop less quickly if marihuana is administered infrequently and outside of the behavioral situation.

Finally, where a generalization is shown to be inadequate by an

empirical test of the predictions made from it, the generalization

can be readily dropped and replaced by a new generalization induced

from the now enlarged pool of empirical information. However,

nothing about this latter process provides an explanation of the

generalization.

THEORETICAL BEHAVIORAL TOLERANCE

Theoretical Explanation of Behavioral Tolerance

Providing an explanation of behavioral tolerance to marihuana in

terms of the mechanisms which underlie it invades the domain of

theory. Theoretical approaches to behavioral tolerance are reductive.

That is, explaining empirical relationships regarding behavioral

tolerance is done by making reference to a different level of discourse than that at which the empirical relationships exist. This

altered level of discourse is reductive in the sense that explanations

109
are made in terms of molecular processes which occur somewhere

inside the organism. These processes may be hypothetical or they

may be empirically based, but they are always reductive; they

represent the processes that underlie the empirical generalizations

which are to be explained.

In the instance of behavioral tolerance to marihuana, one theoretical

(reductive) approach is to explain the observed empirical phenomena

in terms of pharmacodynamic mechanisms (e.g., McMillan et al. 1971;

McMillan and Dewey 1972). In this context any presumed cellular,

metabolic, or drug distributional mechanism is worthy of consideration

(Davis and Borgen 1975; Dewey et al. 1973; McMillan et al. 1973;

Martin et al. 1976).

A second theoretical approach is to account for the empirical generalizations about behavioral tolerance to marihuana in terms of

hypothetical or inferred learning processes (Elsmore, 1972;

Ferraro and Grisham, 1972; Harris et al., 1972). This latter

approach is reductive in that explanatory power is invested in

hypothetical learning mechanisms which are presumably located

within the organism, but which are not observable.

Both pharmacological and learning theories of behavioral tolerance

reside at a distinctly different level of discourse from empirical

generalizations of behavioral tolerance. The latter abstractly

summarize observed empirical relationships, while the former

reductively attempt to explain the latter. Accordingly, the touchstone of a theory of behavioral tolerance is how well it accounts for

the relevant empirical generalizations. Actually, there is no more

appropriate way to judge the relevance, goodness, truth, or righteousness of a theory of behavioral tolerance than to ascertain how

effectively and efficiently it explains the referent empirical

phenomena.

It is important here to recognize that no one type of theoretical

account is more basic or fundamental than any other. For example,

pharmacological theories are not necessarily to be preferred over

learning theories because by some metric they may be asserted to be

more molecular. Likewise, it is not useful to pursue the truth of

one theoretical approach vis-a-vis another. To be sure, if one

theory is unable correctly to explain an empirical generalization,

then that theory is wrong. But this does not mean that the theory

cannot be suitably revised or that an alternative theory must be

preferred.

When controversy arises over whether behavioral tolerance to

marihuana is learned or pharmacological, the controversy is not an

empirical one, nor actually, can it be resolved empirically. The

controversy is about what type of theoretical mechanism can best be

offered to account for some existing empirical phenomenon. Such

controversy is silly, perhaps even nugatory. Either a pharmacological or a learning theory can equally well serve the functions of

explaining lawful empirical relationships and of generating

future research, and neither type can ever be proved to be true.

The behavioral pharmacologist must choose between these approaches

or some combination of these approaches (e.g., Kalant et al. 1971;

McMillan 1976), actually on the basis of personal preference.

110
Behavioral tolerance is empirical: whether its basis is learned or

pharmacological remains a theoretical issue.

Learning Theory of Behavioral Tolerance

Having drawn a distinction between empirical and theoretical

behavioral tolerance, and between learned and pharmacological theories

of behavioral tolerance, I should like now to present one version of

a learning theory of behavioral tolerance to marihuana. This theory,

which was first presented in 1972 (Ferraro 1972) and which has been

since elaborated (Ferraro, et al. 1974; Ferraro 1976), is indebted

conceptually to Dews (1962) and Schuster (Schuster and Zimmerman

1961; Schuster et al. 1966) for their recognition that learning

may explain behavioral tolerance to psychotropic drugs, and to

Loewe for his early observation (1944) that behavioral tolerance

to marihuana is related to the development of compensatory responses.

The present learning theory is intended specifically to explain the

sorts of empirical generalizations presented in a previous section

of this chapter and, in fact, it has rather narrow boundary conditions.

Specifically, the theory is restricted to operant/instrumental

behavior which is maintained by positive or negative reinforcement

conditions.

The following summary account of the theory very closely follows that

recently presented elsewhere (Ferraro 1976).

It is first assumed that an operant/instrumental response is under the

control of antecedent discriminative stimuli, which set the occasion

for the response, and of consequent reinforcing stimuli, which determine the probability of response occurrence. A second assumption is

that the administration of a behaviorally-effective dose of marihuana

can alter responding so as to produce an adverse change in the

relationship between responses and discriminative and reinforcing

stimuli.

Adverse changes in the behavior-environment relationship produced by

marihuana activate compensatory responses to the extent that they

are available in the situation. Compensatory responses have the

status of a hypothetical construct; they are presumed to exist within

the organism but they are not necessarily observable (they are reductive) . Once activated by marihuana-produced adverse changes in the

environment, these hypothetical compensatory responses counteract or

offset the adverse changes; that is, they function to reestablish the

original, more favorable, behavior-environment relationships.

As compensatory responses are repeatedly activated under marihuana,

they are gradually learned or associated to the existing stimulus

situation. Thus, under repeated administrations of marihuana there

is a progressive increase in the strength of learned compensatory

responses and a consequent progressive diminution in the drug-induced

behavioral alterations. Compensatory responses are learned because

they are reinforced by the reductions in the adverse environmental

consequences which the compensatory responses themselves produce.

By way of overview, the rate and extent of behavioral tolerance to

marihuana is hypothesized to be a direct function of the rate and

extent to which compensatory responses are activated and learned in

111
the situation.

Status of The Learning Theory

As with any other theory of behavioral tolerance to marihuana, the

usefulness of the present theory is gauged by its ability to explain

the empirical generalizations relevant to it. Clearly, the truthfulness of the theory cannot be determined empirically since the

central reductive construct of the theory, the compensatory response,

is asserted to be hypothetical. There is no problem here. The

focus of the behavioral pharmacologist’s research attention is more

appropriately directed to engendering empirical relationships than

to certifying hypothetical theoretical constructs. Where empirical

phenomena arise that are not readily explained by the theory, the

theory is revised accordingly, if possible. If this is not possible,

then the usefulness of the theory is compromised to that extent.

As may already have been anticipated, the present learning theory

of behavioral tolerance to marihuana can explain each of the ten

empirical generalizations presented earlier. After all, the theory

was largely created with these generalizations in mind. Nevertheless,

it might be instructive about the theory to discuss briefly how the

theory accounts for a few of these generalizations.

The first four empirical generalizations, which in one way or another

relate behavioral tolerance to adverse behavior-environment relationships produced by marihuana, follow directly from the theoretical

assumption that marihuana-induced adverse environmental consequences

activate compensatory responses so that compensatory responses are

less likely to occur (but still may) in the absence of drug-produced

adversity.

The empirical generalization (Generalization 6) that behavioral

tolerance to marihuana is more likely to develop for simple than for

complex responses is explained theoretically in terms of the relative

availability or effectiveness of compensatory responses. It is

assumed within the theory that compensatory responses are less

available and/or less effective the more complex the referent response

which is affected by marihuana.

Similarly, according to the theory, the opportunity to respond under

the influence of marihuana enhances the development of behavioral

tolerance (Generalization 8) since the opportunity to learn compensatory responses is greater when the drug is administered inside

as opposed to outside of the situation.

Finally, the last two empirical generalizations, which relate

behavioral tolerance to antecedent environmental conditions, follow

naturally enough from the theoretical supposition that compensatory

responses are learned to the environmental stimuli present in the

situation. That is, the occurrence of learned compensatory responses

will exhibit specificity to the stimulus situation in which they are

acquired, although some stimulus generalization could certainly be

anticipated (Generalization 9). Furthermore, considered as learned

behavior, compensatory responses will be relatively permanently

associated to the stimulus situation in which they are initially

acquired, unless, of course, explicit procedures are executed to

112
counteract the learned associations (Generalization 10).

SUMMARY AND CONCLUSIONS

Confusion and controversy sometimes arise regarding the concept of

behavioral tolerance. This occurs, in part, because a distinction

is not always adequately made between empirical and theoretical

behavioral tolerance. Empirical definitions of behavioral tolerance

are both operational and functional. As such, empirical definitions

permit instances of behavioral tolerance to be identified within

limits. However, they do not provide for the description of parmetric relationships regarding behavioral tolerance nor do they explain

behavioral tolerance. These latter two functions are accomplished,

respectively, by descriptive systems and theoretical systems of

behavioral tolerance.

A descriptive system of behavioral tolerance collates individual

empirical relationships regarding the parameters of behavioral

tolerance and from them inductively arrives at an abstract empirical

generalization which generates more implications than each relationship in isolation. In this abstract form, empirical generalizations

represent a first-order basis for making predictions regarding the

extent and rate of occurence of behavioral tolerance.

Most empirical generalizations regarding behavioral tolerance

relate in some manner to antecedent stimuli, response conditions, and

consequent stimuli. The implication here is that behavioral tolerance

is empirically constituted of various drug-environment-behavior

interactions. But since empirical generalizations are arrived at

inductively, there is no assurance regarding their correctness.

Empirical confirmation of the predictions made from empirical

generalizations of behavioral tolerance must be sought within the

boundary conditions which apply to the generalizations.

Theories of behavioral tolerance go beyond empirical descriptive

systems of behavioral tolerance in attempting to explain the concept

in terms of the mechanisms which underlie it. Accordingly, theories

of behavioral tolerance are reductive; they resort to presumed

processes within the organism to explain observed empirical phenomena. Typically, these are processes described either in terms

of pharmacological or learning constructs. Neither type of theory

of behavioral tolerance is more fundamental, relevant, appropriate,

or correct than the other. Either is acceptable to the extent

that the reductive mechanisms it proposes are Capable of explaining the existing empirical generalizations regarding

behavioral tolerance. Behavioral tolerance is empirical. Thus.

it is inappropriate to debate whether behavioral tolerance is

ultimately a learned or a pharmacological process; this remains

a theoretical question.

Theories of behavioral tolerance are not necessary. They do, however,

represent an efficient, second-order basis for making predictions

regarding behavioral tolerance. Accordingly, theories of behavioral

tolerance can be quite useful (even if not always correct). In this

regard, it is possible to account for several empirical generalizations regarding behavioral tolerance to marihuana with a learning

theory which asserts that behavioral tolerance is directly related

113
to the extent to which compensatory responses are activated and

learned under the drug. The important aspect of this learning

theory is not its correctness or incorrectness (it is most likely

incorrect) but its probability of generating future research and

of providing direction regarding the application of behavioral

tolerance phenomena to clinical and therapeutic situations. These

latter probabilities remain to be determined.

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3

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AUTHOR

Douglas P. Ferraro, Ph.D., Professor of Psychology, University

of New Mexico, Albuquerque, New Mexico 87131

117
IV. MARIHUANA

Behavioral Tolerance: Lessons

Learned from Cannabis Research

Reese T. Jones, M.D.

INTRODUCTION

From the beginning of our cannabis research we were impressed that

so-called nonpharmacologic factors were very important in determining

many of the drug’s effects. I suppose, right from the start, we were

studying the phenomenon this conference is about. However, “behavioral tolerance” and “learned tolerance” are terms I have never felt

a great need to use. I’m not sure why. Perhaps it is due to fuzzy

thinking, but I would rather think it is due to a belief that the

mechanisms of behavioral, learned, physiologic, and other kinds of

tolerance are more similar than different. The definition of

tolerance:

(a) Diminished effect with repeated exposure to a given dose

and

(b) Return of original effect or an increased effect following

an increased dose,

assumes nothing about mechanisms. To adopt a terminology like

“behavioral” or “learned” tolerance that assumes mechanisms and that

may mislead the nonspecialist doesn’t seem to be progress to me.

At one point I kept a list of various terms used to describe (and by

some to explain) different types of tolerance. These include

behavioral, psychological, learned, behaviorally augmented, biochemical, metabolic, cellular, tissue, organic, dispositional,

pharmacological, physiologic, central, peripheral, functional,

central nervous system, cross, acquired, innate, reverse, negative,

and real. Except for the relatively rare instances of “metabolic”

tolerance, most of these terms may well be referring to similar

processes and common mechanisms. The evidence for this was covered

in a review some years ago (Kalant, LeBlanc, and Gibbons 1971) and by

other reports in this monograph (LeBlanc, Poulos, and Gappell 1977;

Carder 1977).

In my own research strategy I have avoided trying to make clean distinctions between behavioral, physiologic, and mental phenomena. This

113
is mostly due to a faith that all mental and psychological and behavioral events do, at some level, have physiologic, neurochemical, neuropharmacologic mechanisms in common.

The psychopharmacology of cannabis is such that the behavioral history

of the person using the drug and things like set and setting are perhaps more important than with many other CNS-active drugs. Cannabis

is a drug that tends to be consumed at fairly low doses by most people,

leading to a low level of intoxication. The material available to

most users tends to be of low potency or often of hardly any potency

at all. The smoked route of administration commonly employed allows

easy titration of dose and level of intoxication. Tremendous “adver -

tising’” and social and cultural forces tend to shape experienced

effects, or at least influence the effects reported by users. It is

difficult to think of a drug about whose effects more mythology, fact,

and fantasy have been spread. Cannabis’ pharmacology, particularly

its spectrum of effects, allowing a relatively clear consciousness

during intoxication (relative to autonomic and other physiologic

effects), perhaps makes psychological factors more important than is

the case with CNS depressants like alcohol and barbiturates. The

drug’s relatively short duration of action and relatively infrequent

use (in our culture) tend to make psychological factors more important

and such pharmacologic factors as the “bathing of the neuronal pool”

less important. All this comes together so as to make expectation,

setting, past psychoactive drug experience, personality, associates,

time of day, etc., more important determinants of ultimate drug

effects than if, for example, we were considering the effects of 150 mg

percent blood levels of alcohol or 1 gram doses of LSD (Jones 1971).

That regular smokers of cannabis become more intoxicated when smoking

in a group, or more intoxicated when they can smell and taste the smoke,

or be more subject to feelings of intoxication after smoking placebos

might strike some as having only tangential relevance to behavioral

tolerance. So I will describe some data from recent experiments that

may have more direct relevance to our topic. The first experiment

concerns the effects of practice on marihuana-induced changes in

reaction time. The second has to do with behavioral tolerance evident

in subjects chronically treated with oral doses of tetrahydrocannabinol

(‘MC) in a situation where behavior, behavioral tolerance, cardiovascular physiology, cardiovascular tolerance, and other things get conceptually muddled in my mind.

EFFECTS OF PRACTICE AND LEARNING ON MARIHUANA EFFECTS

The reaction time study grew out of a problem that arose when we began

studies of ‘IX effects over a 4-to 6-week period in hospitalized

volunteers who were tested repeatedly (Jones, Benowitz, and Bachman

1976).

In our earlier outpatient studies, largely involving single or a few

doses of THC or cannabis given to subjects who visited the lab on only

a few occasions, we found what many investigators have--decrements in

reaction time and impaired performance on a variety of perceptual,

motor, cognitive, and other tasks. Dose-related, to be sure, but

fairly predictable.

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In contrast, the hospitalized volunteers were tested repeatedly on a

daily schedule or even with multiple tests during the day, and most

of their waking hours were spent in the lab. The paradigm used with

the hospitalized volunteers involved a week or so of practice on a

task before administration of the THC or cannabis. Thus, they were

well adapted to a test situation, well trained in laboratory rituals,

and, specifically, well practiced on the task before being drugged.

With such a test schedule we found that the previously reliable drug

treatment effects disappeared. Doses of THC that reliably slowed

reaction time or impaired performance on a memory task in the outpatients had no effect in the hospitalized subjects. It looked like

acquired tolerance developing before any drug was given to them.

We decided to see if this unexpected resistance to drug-induced

alterations in behavior was evident in well-practiced outpatient

volunteers. It was. Since a full description of this study has been

published, I’ll only cover a few points here (Peeke, Jones, and Stone

1976). A group of outpatient volunteers practiced on a complex visual

reaction time task on four successive test days before receiving

marihuana, in order to see whether practice alone in a nondrugged state

would alter the response to cannabis. The 34 volunteers all used

marihuana two to three times a week during the few months prior to

the experiment. They were divided into three experimental groups.

Group M-P smoked marihuana (cigarette containing 20 mg WC) during

successive daily test sessions 1 through 4 and then smoked a placebo

cigarette on session 5. Group P-M smoked placebo cigarettes on

sessions 1 through 4 and a marihuana cigarette on session 5. The

third group performed the tasks on five daily test sessions, not

smoking cigarettes on any. All testing was at the time of peak

effects.

A number of tasks were used, but I’ll just describe the results on

the most difficult one--a categorization task where the subject had

to make a judgment as to whether a two-attribute stimulus, varying

as to both form and color, matched a preceding two-attribute stimulus.

It was a fairly difficult task where four judgments were possible:

that is, the Judgment could be (1) same color, same form; (2) same

color, different form; (3) different color, same form; and (4) different color, different form. If a correct response was made, the

stimulus disappeared to be replaced 368 msec later by the next

stimulus requiring another Judgment. The test stimulus about which

the judgment was made became the “preceding” stimulus for the next

trial and thus had to be retained in memory after the response. Thus

the memory trace for a stimulus served in different capacities on two

successive trials. During an experimental session the task was run

for five blocks, each containing 40 trials. In the data in figure 1

tire mean reaction time for each block of trials was computed, yielding

five data points per session for each Judgment.

As judged by the mean reaction times, the task was a fairly difficult

one. Initial reaction times of over one second were common. The

group M-P, who had received no practice before performing the task

under marihuana, showed considerable impairment during the first test

session. The short duration of the impairment was surprising. The

M-P group showed considerable improvement during session 1 (that is,

120
FlGURE 1

Fig 1 Mean reaction time for drug treatment groups for each

block of trials within each session for the Different Color- Different

Form Judgment of the Contingent Categorization task

during their first exposure to marihuana in the laboratory) and by

the end of session 2 (that is, their second laboratory day smoking

marihuana) , their performance was indistinguishable from the performance of the group that had been smoking placebo only. Remember

that each data point in the figure represents 40 trials on the task

for each subject, so that by block three, when the greatest performance gain is seen, the subjects had already received considerable

practice on the task. Despite the disappearance of marihuana effects

on performance, the physiological and subjective responses to the

marihuana diminished only slightly over the four daily sessions.

These included salivary flow, pulse rate, and self reports of intoxication levels. Practice while intoxicated improved performance. The

rate of improvement differed for the M-P and the P-M groups; however,

the final level of performance was comparable for both groups.

The performance of the group who smoked nothing was not different

from the P-M group on the first four sessions nor different from M-P

on the fifth session. Thus, the well-practiced outpatients resembled

our well-practicedinpatients in terms of diminished magnitude of drug

effects. Our hunch is that with practice, particularly on a complex

perceptual task, such things as the importance of attention are

121
gradually reduced and behavior becomes far more automatic. Thus,

the demands of the task may well change and resulting drug effects

diminish. The alternate explanation--a fundamental adaptation at

the neuronal level with practice and consequent drug effect differences--is also plausible and intriguing.

BEHAVIORAL TOLERANCE : IN THE HEART OR IN THE HEAD?

The utility of considering both behavioral and physiologic data when

trying to understand what might seem to be behavioral tolerance I

hope is illustrated in the next example. The data is from our tolerance studies with hospitalized volunteers (Jones, Benowitz, and

Bachman 1976). The dose of tetrahydrocannabinol was 20 mg given

orally every three hours. Our goal in this study was to produce

tolerance as rapidly as possible so as to study drug interactions

in the tolerant and nontolerant state. Hence, the dosage schedule

was selected so that we could maintain a fairly constant tissue

level of cannabinoids, or “continually bathe the neuronal pool,” as

Seevers and Deneau (1963) said a bit more poetically some years ago

when discussing optimal conditions for the appearance of tolerance

and dependence to opiates. It would be handy if we could implant a

pellet of THC or use some similar strategy. This, of course, is

difficult to do in human studies, so the every-three-hour dosage

schedule used in our current studies is a compromise.

The behavioral tolerance that I’ll discuss has to do with behavior

that I’ll term “falling down.” Many of our experimental subjects

frequently become dizzy and some fall down early during the period

of the THC administration. Even though the MC is continued, the

falling down behavior rapidly decreases and disappears, fulfilling

part of the definition of tolerance. It returns if the THC dose is

rapidly increased. The change in behavior is most dramatic. In most

subjects the falling tends to disappear completely within 24 to

48 hours after the THC is begun, indicating rapid development of

tolerance. One might assume that such behavioral tolerance to

falling down is indicative of some sort of so-called “functional”

or “CNS” or other nonmetabolic mechanisms. Although we are looking

hard, we as yet find no evidence for metabolic tolerance sufficient

to account for the phenomenon. However, by following some fairly

simple cardiovascular changes, we can partially account for the

behavioral tolerance and, I hope, to a small extent illustrate the

utility of not distinguishing too sharply between physiological

and behavioral tolerance.

The falling down behavior tends to occur after a subject has just

stood up following a period of being supine or sitting. Of course,

whenever a person stands up from a prone or supine position, drugged

or not, there is a transitory drop in blood pressure. Tetrahydrocannabinol and many other drugs produce fairly dramatic drops in

blood pressure when measured right after standing. When symptoms

appear we call this orthostatic hypotension. These changes are described in a recent report from our laboratory (Benowitz and Jones

1975).

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The pattern of blood pressure change in a typical subject is shown

in figure 2. The change in systolic blood pressure from supine to

quiet standing for one minute is plotted over the one-month course

of the study. me pressures were all measured at 7 a.m. when the

subject first got out of bed. The drops in BP can be dramatic- -for

example, on day 11. The 20 mg doses of oral THC had been begun at

8 p.m. on day lo, so the subject had a total of four 20 mg doses

prior to the BP recording. The BP drops diminished over the next

four days. on day 17 the THC was stopped at 11 p.m., so that the

BP recorded at 7 a.m. on day 18 was 8 hours after the last dose of

THC . Note the increase in BP on day 18. The drug was restarted at

bedtime on day 18 (11 p.m.). Note the apparent decrease in degree

of tolerance at the 7 a.m. recording on day 19.

Some might view the blood pressure changes as being more evidence of

physiologic tolerance than of behavioral tolerance. An orthostatic

BP drop is not ordinarily viewed as behavior even though one must

engage in behavior to evoke it, i.e., stand up. At least standing

BP requires more behavior on the part of the subject than does

supine BP.

The subject in figure 2 showed fairly typical changes in body weight

during the experiment. During the first 5 days on THC he gained 12

pounds. Although one might consider this to be due to the ‘munchies”

or other THC-induced changes in appetite and diet, our data indicates

it is largely, if not entirely, due to an increase in body water,

mainly increased plasma volume (Benowitz and Jones 1975). When a

person experiences episodes of orthostatic hypotension, various

mechanisms are often triggered so as to increase plasma volume (Weil

and Chidsey 1968). In a sense the organism “learns” and adapts to

the BP drops. During THC administration, tolerances does not develop

or develops slowly to the weight gain or increase in plasma volume.

Thus, the behavioral impairment produced by MC (falling down) disappears after a complicated set of homeostatic cardiovascular changes.

The performance of certain behaviors (for example, getting up and

walking around) is probably of great importance in determining

whether the homeostatic cardiovascular changes take place.

We have not yet done the crucial experiment, but I’m fairly certain

how it would come out, so I will speculate a bit. Suppose the behavior I’m interested in (falling down) did not occur during the period

of THC administration. Would the weight gain and tolerance to the

postural BP drops still develop? What if the person never had occasion to stand up while drugged and thus never became dizzy, faint,

and weak, never experienced precipitous BP drops, and subsequently

fell down? Under such conditions I think the tolerance to the hypetension would develop much more slowly, if at all. The rapid tolerance to the orthostatic hypotension (and to falling) in our test situation I think is a good example of behaviorally augmented tolerance.

Others have speculated that: “Stimulus to the development of tolerante.. .would not be the presence of the drug itself, but the degree

of impairment of required neuronal functions which the drug produces

(Frankel et al. 1975)." Those investigators were talking about CNS

neuronal functions, but cardiovascular system measures make the same

123
FIGURE 2

Figure 2. Body weight and change in systolic blood pressure from

supine to standing for one minute. Measures all taken at 7 A.M.

Maximum THC dose was 20 mg every 3 hours. THC began at 8 P.M. on

Day 10 and stopped 8 P.M. on Day 22.
point. If our hospitalized patients were kept in bed in a supine

position for the first few weeks of THC administration, I’m reasonably sure there would be marked hypotension when they then first

stood up, i.e., there would not be the rapid tolerance shown by the

patient in figure 2. In fact, just lying prone for a week without

any THC administration would, of course, be associated with a certain

degree of “acquired” hypotension upon standing. This maybe reflects

the loss of some other sort of “tolerance” (nondrug-related) to

postural BP changes. If the subject was never exposed to an episode

of hypotension, the necessary stimulus for the increase in plasma

volume would not occur and the large gain in body weight would not

follow. Tolerance in our test situation clearly has instrumental

value for the subject but, if no BP drop occurs, such homeostatic

changes would have no instrumental value.

We have not yet done such an experiment, but have observed that subjects who stay in bed when the THC is begun have less weight gain and

more problems with persistent hypotension. Subjects who are successfully encouraged to get up slowly and keep moving despite the hypotension and other symptoms develop tolerance very rapidly (as in the

case of the subject in figure 2).

I have an impression that our subjects tend to demonstrate more rapid

and profound tolerance to many cannabis effects than is the case in

other chronic administration experiments. It may well be that our

particular dose schedule, i.e., around-the-clock administration, in

a sense forces the subjects into an optimal behaviorally augmented

tolerance paradigm. That is, our subjects can’t smoke a number of

marihuana cigarettes and then go to bed, as happens in other studies.

Even though intoxicated, subjects in our experiment are required

frequently to perform and behave. These subjects very rapidly develop

tolerance.

Does all this mean that BP and plasma volume changes are to be considered part of behavioral tolerance? Or are they examples of physiologic tolerance? I’m inclined to agree with those (Kalant, LeBlanc,

and Gibbons 1971) who emphasize the similarities rather than differences in varieties of tolerance.

REFERENCES

Benowitz, N. L.,and Jones, R. T. Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clin. Pharmacol.

Ther. , 18:287-297, 1975.

Carder, B. Environmental influences on marihuana tolerance. This

monograph.

Frankel, D., Khanna, J., LeBlanc, A., and Kalant, H. Effect of

p-chlorophenylalanine on the acquisition of tolerance to ethanol

and pentobarbital. Psychopharmacologia, 44:247-252, 1975.

125
Jones, R. T. Marihuana- induced “high”: Influence of expectation,

setting, and previous drug experience. Pharmacol. Rev., 23:359-

369, 1971.

Jones, R. T. , Benowitz, N. L.,and Bachman, J. Clinical studies

of cannabis tolerance and dependence. Ann. New York Acad. of

sci., 282:221-239, 1976.

Kalant, H., LeBlanc, A. E., and Gibbons, R. J. Tolerance and

dependence on some non-opiate psychotropic drugs. Pharmacol.

Rev. , 23:135-191, 1971.

LeBlanc, A. E., Poulos, C. X., and Cappell, H. D. Tolerance as a

behavioral phencomenon: Evidence from two experimental paradigms.

This conference.

Peeke, S. C., Jones, R. T., and Stone, G. C. Effects of practice

on marihuana induced changes in reaction time. Psychopharmacology,

48: 159-163, 1976.

Seevers, M. H.,and Deneau, G. A. Physiological aspects of tolerance and physical dependence. Review in: Root, W. S., and Hofmann,

F. G., eds. Pharmacology : A Comprehensive Treatise. New York:

Academic Press, 1963. pp. 565-640.

Weil, J. V., and Chidsey, C. A. Plasma volume expansion resulting

from interference with adrenergic function in normal man.

Circulation, 37:54-61, 1968.

AUTHOR

Reese T. Jones, M.D., Department of Psychiatry, University of

California, San Francisco, California 94143

126
V. STIMULANTS

Behavioral Tolerance to Cocaine

William L. Woolverton, Ph.D., and

Charles R. Schuster, Ph.D.

Conflicting reports regarding the development of tolerance to the

effects of cocaine have appeared in the literature. It has been

reported (Jaffe 1975; Kosman and Unna 1969) that human cocaine

addicts can tolerate doses as high as 10 grams per day. However,

whether this tolerance is acquired or simply the result of normal

variability in initial tolerance in the population is unclear.

In the animal laboratory, the consensus is one of increased sensitivity (reverse tolerance) to many of the behavioral effects

of cocaine. As early as 1924, Lewin stated that

as opposed to morphine, animals cannot become

accustomed to cocaine; they even exhibit an

increasing sensibility to the drug (Byck 1974,

p. 245).

Indeed, numerous reports of increased sensitivity to the central

stimulant effects of cocaine in rats (Downs and Eddy 1932; Post

1977; Stripling and Ellinwood 1977),. dogs (Tatum and Seevers

1929) and rhesus monkeys (Tatum and Seevers 1929; Post 1976)

have appeared in the literature. Doses of cocaine which initially produced a mild stimulation induced convulsions and often

death during repeated administration. However, changes in sensitivity to the effects of cocaine on conditioned behaviors in

laboratory animals have not been studied.

With these considerations in mind, we have been studying the

effects of repeated administrations of cocaine in rats in several

behavioral situations. Both tolerance and increased sensitivity

to cocaine have been observed, depending upon the relationship

of time of injection to the experimental session. Further, cross

tolerance between cocaine and d-amphetamine, as well as increased

sensitivity to d-amphetamine, has also been observed. The findings support the hypothesis of Schuster et al. (1966) that behavioral tolerance develops to the effects of a drug that interfere

with the ability of the organism to meet the contingencies of

reinforcement.

127
GENERAL PROCEDURE

Two basic experimental procedures were used to test the effects of

single and repeated administrations of cocaine in rats.

Milk Drinking Procedure. Daily experimental sessions consisted of

15 minutes access to 50 ml of a sweetened condensed milk solution.

At the end of this period, the quantity of milk remaining was

measured to determine milk intake.

Operant Procedure. Rats were trained in a standard operant chamber to press a lever for food delivery on a schedule of reinforcement that required that responses be spaced by at least 20 seconds

(differential reinforcement of low rates 20 seconds: DRL 20”).

The effects of cocaine on lever pressing frequency were measured.

All animals in both procedures experienced 1) initial dose-effect

determinations of cocaine or d-amphetamine, 2) a period of repeated administration of cocaine or d-amphetamine, 3) dose-effect

redetenminations of cocaine or d-amphetamine. These procedures

were carried out in the following manner:

1) Initial Dose-Effect Determinations. Initially all animals

were injected (i.p.) 15 minutes before the session with 1 ml/kg

0.9% saline. When behavior had stabilized (less than 10% variation in mean intake or number of food pellets delivered for at

least 3 consecutive days) a dose of drug was substituted for the

injection of saline before the session. Doses of cocaine (4.0,

8.0, 16 and 32 mg/kg) or d-amphetamine (0.5, 1.0, 2.0, and 4.0

mg/kg) were administered once each in an ascending order in the

milk drinking procedure. Doses of cocaine (4.0, 8.0, 16, and 32

mg/kg) were administered once in an ascending and once in a descending order to rats responding in the operant procedure. dAmphetamine was not tested in the operant procedure.

2) Repeated Administration. A dose of cocaine or d-amphetamine

that reduced milk intake to at least 50% of levels observed following saline injections was chosen for daily administration to

rats in the milk drinking procedure. Similarly, a dose of cocaine

that decreased number of reinforcements to less than 50% of that

observed following saline injections was chosen for daily administration to the rats trained in the operant procedure. Daily

drug administration continued for between 75-110 days. When milk

intake reached a new stable level, dose-effect redeterminations

were begun in the milk intake procedure. In the operant procedure, dose-effect redeterminations were begun on day 61 of repeated administration.

3) Dose-Effect Redeterminations. Dose-effect redeterminations

were conducted in the following manner. On selected days, test

doses of saline, cocaine, or d-amphetamine were substituted for

the usual drug or saline injection. Test doses were given in an

ascending order in the milk drinking procedure and in an ascending and descending order in the operant procedure. There were at

128
least 3 sessions between test doses of drug in which the animal

was injected with the usual daily injection. Thus, it Was possible to measure the effect of each dose of both drugs during the

period of repeated administration of either drug.

RESULTS

Milk Drinking Procedure. In the initial dose-effect determinations,

cocaine and d-amphetamine produced dose-related decreases In milk

intake [Figs, IA, 2A, 3A, & 5). When the two highest doses of

cocaine (16 and 32 mg/kg) or d-amphetamine (2.0 and 4.0 mg/kg)

were given, stereotyped behaviors including sniffing and head

bobbing were observed.

FIGURE 1

Dose Cocaine (mg/kg) Sessions

Left Panel (A). Effects of injections of cocaine on mean milk

intake of rate in Part 1, before (0-r) and during (0-0) a

period of repeated daily injections of cocaine (16 mg/kg). Drug

effects are expressed as percent of non-drug control levels.

Vertical lines represent the standard error of the mean. The

points above S represent the effects of saline injection on intake.

Right Panel (B). Effects of repeated administration of cocaine

(16 mg/kg) or saline on mean milk intake. Drug effects on milk

intake are expressed as percent of non-drug control Levels. Each

data point is the mean of 5 consecutive sessions.

129
FIGURE 2

Left Panel (A). The effects of d-amphetamine on the mean milk

intake of the rate in Group B of Experiment II before (0-O) and

during (O-O) a period of repeated administration of d-amphetamine (2.0) mg/kg) . Drug effects are expressed as percent of nondrug control levels. The points above S represent the effects

of saline injections on intake. vertical lines represent the

standard error of the mean.

Right Panel (B). Effects of repeated administration of d-amphetamine (2.0 mg/kg) on the mean milk intake of the rats in Group

B from day 1 to day 30. Each point is the mean of 5 consecutive

seesions.

The dose of 16 mg/kg cocaine initially reduced milk intake to

about 30% of control levels and was chosen for daily administration. During the first 45 days of repeated cocaine administration milk intake increased from 30% of control levels to about

70% of control levels. Milk intake of rats receiving saline daily

remained at about 100% of control levels throughout this period

(Fig. 1B). In a group of animals receiving cocaine after the

session during this period, milk intake decreased to about 80% of

original control levels (Fig. 3B).

The dose of 2.0 mg/kg d-amphetamine reduced intake initially to

about 30% of control levels. Intake increased during the first

30 days of repeated administration to about 85% of original control levels (Fig. 2B).

130
FIGURE 3

Left Panel (A) ; Effects of cocaine on mean milk intake before

(0-0) and during (0-0) a period of daily injections of cocaine

(16 mg/kg) given after the session. Milk intake is expressed as

percent of control levels. The points above S represent the

effects of saline injections on intake. Vertical lines represent

the standard error of the mean.

Right Panel (B). The effects of repeated administration of cocaine (16 mg/kg) on milk intake of the rats in Part 2. Injections of cocaine were given immediately after the 15 minute access

period. Intake is expressed as percent of control levels.

After tolerance had developed to the disruptive effects of 16 mg/

kg cocaine, the dose-effect function of cocaine was shifted to

the right in animals receiving cocaine daily before the session

(Fig. l.A) (F=16.6, d.f. 3,48, p<.00l) . Furthermore, when the

dose-effect function of cocaine on milk intake was redetermined

in rats receiving d-amphetamine before the session, it was similarly shifted to the right (Fig. 4B) (F=13.2, d.f.=1, 40, p<.00l).

In contrast, when cocaine dose-effect function was redetermined

in rats receiving cocaine daily after the session, a shift to the

left in the function was observed (Fig. 3A) (F=4,97, d.f.=1,40

P<.05).

131
FIGURE 4

Dose d-Amphetamine (mg/kg) Dose Cocaine (mg/kg)

Left Panel (A). Effects of d-amphetamine (0.5 - 4.0 mg/kg) on

milk intake in Group-A before (0-0) and during (0-O)

a period of daily injections of cocaine (16 mg/kg). Drug effects

on intake are expressed as percent of non-Drug control levels.

The points above S represent the effects of saline injections on

intake. Vertical lines represent the standard error of the mean.

Right Panel (B). Effects of cocaine on milk intake of the rate

in Group B before (0-0) and during (0--0) a period of daily

injections of d-amphetamine (2.0 mg/kg). Drug effects are expressed as in the left panel (above).

Following the redetermination of the cocaine dose-effect function

in animals receiving pre-session cocaine, all injections were

stopped. On selected days (4 and 10) after termination of injections, the effect of 16 mg/kg on intake was again determined. On

day 4, the animals were still tolerant to the effects of this

dose on intake. However, on day 10 the effect of 16 mg/kg on intake was the same as that observed in the initial dose-effect

function, indicating that the animals were no longer tolerant

(Table 1).

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TABLE 1

THE EFFECTS OF 16 MG/KG COCAINE ON MILK INTAKE BEFORE,

DURING, AND AFTER THE DAILY COCAINE REGIMEN

Condition Intake (ml)

Initial dose-effect determination 13.6 ± 4.61 (S.E.M.)

Dose-effect redetermination 25.6 ± 1.96 (S.E.M.)

4 days after daily

cocaine administration 27.3 ± 3.13 (S.E.M.)

10 days after daily

cocaine 14.3 ± 5.4 (S.E.M.)

After tolerance had developed to the effects of 2.0 mg/kg d-amphetamine on milk intake, the dose-effect function of d-amphetamine was shifted to the right in animals receiving daily d-amphetamine before the session (Fig. 2A) (F=18.7, d.f.=1, 40, p<00l).

When the dose-effect function of d-amphetamine on intake was redetermined in animals receiving cocaine daily before the session,

a similar shift in the d-amphetamine dose-effect function was observed (Fig. 4A) (F=35,-d.f.=3,48, p<.001). On the other hand,

when the d-amphetamine dose-effect function was redetermined in

animals receiving cocaine after their daily session, a shift to

the left in the function was observed (Fig. 5) (F=30.9, d.f.=1,40,

p<.00l). Thus, whether tolerance or supersensitivity developed

to the effects of cocaine on milk drinking was dependent on the

relationship of the drug administration to the period of access

to milk.

Operant Procedure. In the initial dose-effect determinations

single injections of cocaine resulted in a dose-related increase

in responses per session (Fig. 6A) and a decrease in the number

of reinforcements received (Fig. 7A). The IRT distribution (Fig.

8A) was shifted to the left with increasing dose of cocaine. A

dose of 16 mg/kg was chosen for repeated administration since it

decreased reinforcements by at least 50% in all cases.

133
FIGURE 5

Initial dose-effect determination

Dose-effect redetermination

Dose d-Amphetamine (mg/kg)

Effects of d-amphetamine on mean milk intake before (0-0) and

during (0-O) the period of repeated daily injection of cocaine

(16 mg/kg). Injections of cocaine were given immediately after

the session. Milk intake is expressed as percent of control

levels of intake.

134
FIGURE 6

Dose Cocaine (mg/kg) Sessions

Left Panel (A). Effects of single injections of cocaine on the

mean numver of responses/session for the rats (N=4) responding

on a DRL 20" schedule for food before (0-O) and during (0-O)

a period of daily injection of cocaine (16 mg/kg). The points

above S represent the effects of saline injection on responding.

Vertical lines represent the standard error of the mean.

Right Panel (B). Effects of repeated administration of cocaine

(16 mg/kg) on responses/session for the rats (N==4) responding

on a DRL 20" schedule for food during the period of repeated

administration. Each point is the mean of 5 consecutive sessions.

During the first 60 days of repeated administration, responses

per session decreased from 278.1 (+ 25.2 s.e.m.) for days l-5 to

195 (+ 12.6 s.e.m.) for days 55-60-(Fig. 6B). Furthermore, in the

initial dose-effect determinations, responses per session following 16 mg/kg averaged 336 (+ 34 s.e.m.) while an average of 195

(+ 18.9 s.e.m.) responses per session was observed following this

dose on days 59 and 60. The decrease in responding was maximal

at about day 40 and relatively stable thereafter. The change in

mean number of reinforcements per session over the first 60 days

135
of daily cocaine injections is shown in Fig. 8B. During this period, reinforcements per session increased from 51.1 (+ 6.0 s.e.m.)

for days 1-5 to 59 (+ 5.4 s.e.m.) for days 55-60. Reinforcements

per session for days l-5 is high since this point is an average.

Most importantly, in the initial dose-effect determinations,

reinforcements per session averaged 32.5 (+ 2.5 s.e.m.) while an

average of 57 (+ 9.4 s.e.m.) food pellets was delivered for

sessions 59 and-60. The increase in number of reinforcements per

session was maximal at about day 40 and relatively stable thereafter,

FlGURE 7

Dose Cocaine hg/kg) Sessions

Left Panel (A). Effects of single injections of cocaine on the

mean number of reinforcements per session for the rats (N=4)

responding on a DRL 20” schedule for food before (0-0) and

during (0-O) a period of daily injection of cocaine (16 mg/kg).

The points above S represent the effects of saline injection on

number of reinforcements. Vertical tines represent the standard

error of the mean.

Right Panel (B). Effects of repeated administration of cocaine

(16 mg/kg) on number of reinforcements per session for rats

(N-4) responding on a DRL 20” schedule for food during the period

of repeated administration. Each point in the mean of 5 coneecutive sessions.

136
FIGURE 8

SECONDS

137
Figure 8

Left Panel (A). Effects of single injections of cocaine on the

IRT distributions of the rata responding on a DRL 20" schedule

for food before the repeated administration of cocaine (16 mg/kg).

Each IRT histogram is divided into 2 second bins and contains the

percent of the total responses per session that occurred in that

bin. Each histogram is the mean of two determinations of the

effects of each drug dose in all 4 rats. The IRT distribution

following saline injection (S) is the mean of 10 control sessions.

Doses of cocaine (mg/kg) are indicated on the left side of each

bin. Solid bins are 20" and represent reinforced IRT's.

Right Panel (B). Effects of single injections of cocaine on the

IRT distributions of the rats responding on a DRL 20" schedule

for food during the period of repeated administration of cocaine

(26 mg/kg). Histograms are as described above. Each is the mean

of two redeterminations of the effects of each dose in all 4 rats.

Figure 6A shows the effects of single injections of cocaine (4.0 -

32 mg/kg) on number of responses per session during the redetermination of the dose-effect function. There was no effect of dose

of cocaine on number of responses per session in the redetermination. Relative to the initial dose-effect function, a two-way

analysis of variance revealed a significant interaction between

dose and daily treatment indicating non-parallel dose-effect

curves before and during daily administration. The decrease in

responses per session was significant (p<.0l) at the 16 mg/kg

dose. Changes observed at 4.0, 8.0, and 32 mg/kg were not significant due to high variability in the effects of these doses in

different rats during the redetermination.

A one-way analysis of variance revealed no effect of dose of cocaine on the number of reinforcements per session in the redetermination (Fig. 7A). Relative to the initial dose-effect function,

a two-way analysis of variance revealed a significant effect of

daily treatment and a significant interaction between daily treatment and dose of cocaine (F=4.44, d.f.=1,56, p (.05; F=4.87, d.f.=

3,56, p<.01 respectively) indicating non-parallel shifts in the

dose-effect function during the period of repeated administration.

Further analysis revealed no change in the number of reinforcements per session following injections of saline, 4.0 and 8.0

mg/kg. `However, a significantly greater number of reinforcements

was delivered at 16 and 32 mg/kg during the dose-effect redeterminations, (p<.01 in both cases).

The average IRT distributions for the group during the redetermination of the dose-effect function are shown in Fig. 8. Consistent

with the response and reinforcement data presented above, there is

little noticeable effect of dose of cocaine on the IRT distribution during the redetermination. Relative to the initial doseeffect data, the IRT’s following saline injection were shifted

slightly to the left as were IRT’s following 4.0 mg/kg. Following

8.0 mg/kg, there is some shift in the IRT’s toward the 20-22

second bin, but the percent of IRT’s that were reinforced remained

the same as was observed initially. Following 16 and 32 mg/kg,

138
there was a distinct shift in the IBT distribution to the right

relative to those observed initially, indicating a decrease in

response bursting and a higher percentage of reinforced IRT’s.

SUMMARY

The experiments reported here demonstrated that single injections

of cocaine caused a dose-related disruption of both milk intake and

scheduled controlled behavior of rats. Cocaine increased the

low response rates of animals responding on a DRL 20” schedule.

In this regard, cocaine is similar to all other psychomotor stimulant drugs (Sanger and Blackman 1976). Furthermore, high doses

of the drug (16 - 32 mg/kg) produced stereotyped behaviors that

were similar to those reported for other psychomotor stimulant

drugs (Ellinwood and Balster 1974; Randrup and Munkvad 1970).

Attenuation of the effects of a single dose of’ a drug and a shift

to the right in the dose-effect function during repeated administration are evidence for tolerance to a drug. Pre-session administration of an intermediate dose of cocaine on a daily basis to

animals allowed to drink milk resulted in the development of

tolerance to the disruptive effects of cocaine on milk intake.

This tolerance was lost, however, by the tenth day following the

cessation of daily administration of cocaine. In contrast, when

the same dose of cocaine was administered post-session to animals

allowed to drink milk, increased sensitivity to the disruptive

effects of cocaine was subsequently observed. This increased

sensitivity was shown as well to d-amphetamine. In addition,

cross-tolerance was clearly observed between cocaine and d-amphetamine, suggesting a common mechanism of tolerance to both drugs.

The repeated administration of cocaine to animals trained to lever

press on schedules of reinforcement generating low response rates

resulted in tolerance to the behavioral effects of cocaine that result in a decreased rate of reinforcement.

Thus, tolerance develops to the effects of cocaine that disrupt

milk intake and DRL 20” performance. These data are consistent

with the hypothesis of Schuster et al. (1966) which states that

behavioral tolerance will develop to the effects of a drug that

interfere with the ability of the organism to meet the contingencies of reinforcement. In this respect, cocaine is similar to

many other drugs for which behavioral tolerance has been demonstrated. In view of the numerous reports of increased sensitivity

to the behavioral effects of cocaine (Downs and Eddy 1932; Stripling and Ellinwood 1977; Tatum and Seevers 1929) it is significant that this effect was only observed when cocaine administration did not decrease reinforcement density. It is possible that

increased sensitivity to cocaine is the major pharmacological

effect of repeated administration but that environmental influences (e.g., reinforcement loss) are capable of activating compensatory mechanisms resulting in the development of tolerance.

139
ACKNOWLEDGMENT

This research was supported in part by grants from the National

Institute on Drug Abuse DA-00250-06, DA-00085-06 and DA-00024-07,

Charles R. Schuster, Principal Investigator, and from the National

Institute on Mental Health PHS l-T32, MH-14274.

REFERENCES

Byck, R. The Cocaine Papers (by Sigmund Freud). New York

Publishing Co., 1974.

Downs, A.W., and Eddy, N.B. The effect of repeated doses of

in the rat. J. Pharma. Exp. Ther ., 46:199-200, 1932.

Stonehill

cocaine

Ellinwood, E.H., and Balster, R.A. Rating the behavioral effects of

amphetamine. Eur. J. Pharm., 28:35-41, 1974.

Jaffe, J. Drug addiction and drug abuse. In: Goodman, L.S.,a.nd

Gilman, A., eds. The Pharmacological Basis of Therapeutics. New York:

McMillan Co., 1975.

Kosman, M.E., and Unna, K.R. Effects of chronic administration of

amphetamine and other stimulants on behavior. Clin. Pharma. Ther.,

9:240-254, 1968.

Post, R., Kopanda, R.T., and Black, K.E. Progressive effects of cocaine

on behavior and central amine metabolism in rhesus monkeys: Relationship to kindling and psychosis. Biol. Psychiat., 11:403-417, 1976.

Post, R.M. Progressive changes in behavior and seizures following

chronic cocaine administration: Relationship to kindling and psychosis.

In: Ellinwood, E.H. and Kilbey, M.M., eds. Cocaine and Other Stimulants.

New York: Plenum Press, 1977. pp. 353-372.

Randrup, A., and Munkvad, I. Biochemical, anatomical and psychological

investigations of stereotyped behavior induced by amphetamines. In:

Costa, E. and Garatini, S., eds.

New York: Raven Press, 1970. pp. 695-714

 Amphetamines and Related Compounds.

Sanger, D.J., and Blackman, D.E. Rate dependent effects of drugs: A

review of the literature. Pharmacol. Biochem. Behav., 4:73-83, 1976.

Schuster, C.R., Dockens, W.S., and Woods, J.H. Behavioral variables

affecting the development of amphetamine tolerance. Psychopharmacologia,

9:170-182, 1966.

Stripling, J.S.. and Ellinwood, E.H. Sensitization to cocaine following

chronic administration in the rat. In: Ellinwood, E.H. and Kilbey,

M.M., eds. Cocaine and Other Stimulants. New York: Plenum Press,

1977. pp. 327-352.

Tatum, A.L., and Seevers, M.H. Experimental cocaine addiction. J.

Pharma. Exp. Ther., 36:401-410, 1929.

140
AUTHORS

William L. Woolverton, Ph.D., Department of Pharmacological and

Physiological Sciences, University of Chicago, and

Charles R. Schuster, Ph.D., Professor of Psychiatry, University

of Chicago, Chicago, Illinois 60637

141
VI. DEPRESSANTS

Behavioral and Pharmacological

Components of Phenobarbital

Tolerance

Maisy Tang, Ph.D., and John L. Falk, Ph.D.

While the degree of tolerance development to barbiturates is not as

great as to opioids, it is well documented (Kalant et al. 1971)

and its physiological basis is a combination of both drug metabolic

and central nervous changes (Goldstein, Aronow, and Kalman 1974).

Tolerance can develop to the behavioral effects of a drug: as well

as to its physiological effects. The development of behavioral

tolerance to repeated drug administration could be due to progressive, general, physiological consequences of the drug regimen, or

to a more specific development of behavioral changes that allow

the organism to accommodate to the drugged condition. One method

for distinguishing these possibilities is to compare the development of tolerance to repeated daily drug doses when they are given

prior to sampling behavior versus after such sampling (Campbell and

Seiden 1973; Carlton and Wolgin 1971; Chen 1968; LeBlanc et al.

1973, 1976). The present experiment used this method to evaluate

the behavioral tolerance which develops to the repeated administration of phenobarbital. Both schedule-dependent and scheduleinduced behaviors were examined to determine If these behaviors

would be differentially sensitive either to the degree of behavioral tolerance developed, or to the dosing regimen in relation to the

tolerance developed.

METHOD

Animals. Eight male, albino, Holtzman rats with an initial mean

body weight of 369 g (range: 350-389 g) were used. Except during

the dally 3-hr experimental session, all animals were housed

individually in standard Acme stainless steel cages in a temperature-controlled room with a 12-hr light-dark illumination cycle

(lights on 7 AM-7 PM). Water was continuously available in the

home cage from calibrated Richter-type drinking tubes.

Experimental chamber. Individual chambers consisted of Plexiglas

boxes (25.5 x 25.5 x 30.3 cm) with stainless steel rod floors. An

142
operant lever and a food-pellet magazine were mounted on one side

of each box. On an adjacent side, a metal drinking spout attached

to a calibrated water reservoir was available. Licks on the drinking spout were recorded with a drinkometer.

Naci). The vehicle solution was made from isotonic saline solution

Drugs. Sodium phenobarbital was dissolved in isotonic saline (0.9% .

titrated with 0.1 N sodium hydroxide to match the pH of the sodium

phenobarbital solution (pH 10.0). All doses were given subcutaneously into the loose sldn on the back.

Procedure. Animals were reduced to 80% of their free-feeding body

weights and held at that level for the duration of the experiment

by limiting food rations. They were trained to lever press on a

fixed-ratio 1 schedule (FR 1) which delivered 45-mg Noyes food

pellets and were then shifted to a fixed-interval one min (FI

1 min) schedule. A lever press delivered a pellet only after at

least one min had elapsed since the last pellet delivery. All

other lever presses were ineffective but were recorded. No programmed stimulus informed the animal when such one-min periods

had elapsed. Animals were given 3-hr FT 1 min sessions every day

and then returned to their cages and allowed a food ration supplement (Purina Laboratory chow, pelleted) sufficient to maintain them

at 80% of their initial free-feeding weights. Number of lever

presses, licks on the water spout, and pellets obtained were recorded both on counters and with cumulative recorders (Ralph

Gerbrands Co.). The volume of water consumed during each session

also was measured. When the values of the above measures became

stable from session to session for individual animals, the effects

of phenobarbital doses (20, 40 and 80 mg/kg, specified as the salt)

given 15 min presession were studied. Each dose was given to each

animal twice, first in an ascending and then in a descending order.

At least 5 noninjection sessions separated drug-injection days.

Two vehicle injections were given, one at the beginning and one at

the end of the drug series. Seven days after the second vehicle

injection, the animals were divided into two equal groups (N = 4).

One group received daily phenobarbital injections of 80 mg/kg

15 min presession (Before Group), while the other group received

the same dose 15 min postsession (After Group). These daily

dosing regimens remained in effect for the duration of the experiment except on dose-effect redetermination days when animals from

both groups received their particular dose 15 min presession.

The dose-effect relation redetermination began on the fourteenth

day of the chronic dosing regimen and subsequent doses in the

redetermination series were at least 8 days apart. On inter-days,

the group dosing regimens continued as previously described. The

Before Group was given dose-effect relation redetermination doses

in the order: 120, 160, 100 and 120 mg/kg; the order for the After

Group was 120, 80, 100 and 120 mg/kg. A vehicle injection was

administered to After Group animals 6 days after the last doseeffect determination dose. No corresponding vehicle injection was

given to the Before Group as this would have constituted a withdrawal condition.

143
RESULTS

The initial dose-effect relations and their redeterminations are

shown for both the Before and After Groups in Figure 1.

FIGURE 1

Fig. 1. Initial dose-effect relations for 2 groups (N = 4 each)

for phenobarbital. (mean of an ascending and a descending dose

order for all animals) shown as solid line functions, and mean

dose-effect relation redeterminations following 13 days of daily

80 mg/kg doses given either presession (Before Group) or postsession (After Group).

The solid-line functions on the left side of each quadrant reveal

that prior to exposure to the different repeated-dose regimens

both groups responded in a similar fashion to phenobarbital doses

on all measures. Relative to the mean vehicle-injection levels,

phenobarbital doses had either no effect or a suppressive one on

all measures in the initial dose-effect determination, except for

lever-pressing rate which showed an enhanced rate at 20 mg/kg for

one group and at 40 mg/kg for the other. In contrast to the other

measures, water intake was decreased by the 20 mg/kg dose. Water

144
intake levels for both groups under day-to-day and vehicle-injection conditions were at polydipsic levels characteristic of schedules such as FI 1 min (Falk 1966; 1971).

Both groups developed tolerance to the 80 mg/kg repeated dose regimen, but the tolerance was not complete. Fig. 2 shows that only

"number of reinforcements" (pellets earned) attained its previous

level for both groups.

FIGURE 2

Fig. 2. Mean dally session measures for 2 groups (N = 4 each) given

80 mg/kg phenobarbital dally-injections either presession (Before

Group) or postsession (After Group). Baseline = mean of 6 sessions

preceding start of dally phenobarbital Injections.

The other measures remained below the former baseline level for

both groups, except the "licks/min" measure for the Before Group.

(Mean baseline values shown In Fig. 2 are the means of values for

the sessions preceding the beginning of the repeated-dose regimen).

The functions to the right in each quadrant of Fig. 1 (dashed

lines) reveal that the Before Group had developed greater tolerance

to phenobarbital than the After Group, as shown by the greater

shift to the right of the Before Group's dose-effect relation re145
determination. Tolerance to repeated 80 mg/kg doses, while not

complete for either group (Fig. 2), was equivalent for the two

groups when the presession effect of this 80 mg/kg dose was compared (Fig. 1). However, when larger doses were explored, the

greater tolerance of the Before Group, relative to the After Group,

became evident as a greater shift to the right in the dose-effect

relations. The reliability and lack of any serial-order effect in

the redetermination relations is indicated by the replicability of

the 120 mg/kg points, as this dose was the first and the last dose

given in the series.

DISCUSSION

Both the Before and After repeated-dose regimens produced marked

tolerance to phenobarbital. However, tolerance was incomplete, as

indicated by the incomplete return 'co previous baseline levels of

most of the behavioral indices (cf. Fig. 2). Suppressive effects

of phenobarbital on running in rats revealed a similar failure to

develop complete tolerance under repeated dosing (Schmidt

Both schedule-dependent (lever pressing) and schedule-induced

(polydipsia) behaviors developed tolerance to repeated phenobarbital dosing (cf. Fig. 1). Moreover, both kinds of behavior were

affected in a similar way by the differential effect of the two

dose regimens. The enhanced FI lever-pressing rate produced by

low doses of phenobarbital agrees with similar findings in the

pigeon given low doses of barbiturates under FI schedules (Dews

1955, 1964; Rutledge and Kelleher 1965). Low to intermediate

doses of barbiturates increase water intake in the rat (Jones

1943; O'Kelly and Weiss 1955; Schmidt 1958), but decrease it

under schedule-induction conditions (Falk 1964). The present

study confirms this latter result.

LeBlanc and his associates (LeBlanc et al. 1973, 1976) studied

the acquisition of tolerance to ethanol using a Before and an

After Group design as well. They concluded that both groups developed the same level of tolerance and only differed as to the

rate at which the tolerance developed. In their experimental designs, the repeated-maintenance and testing doses were at the

same level. We too would have come to the same conclusion if our

testing (redetermination) doses had been limited to the maintenance dose (80 mg/kg). In Fig. 1 it is evident that the groups

did not differ at 80 mg/kg in the redetermination phase; both

showed a similar tolerance. But the larger doses revealed the

different tolerance levels of the groups. Other investigators

have used the Before versus After Group design to explore tolerance

to d-amphetamine (Campbell and Seiden 1973; Carlton and Wolgin

1971). It was concluded that the After Groups showed little

evidence of tolerance development. But again a single level of

the test dose was administered rather than a determination and

redetermination of dose-effect relations. Such a procedure might

have unmasked some level of pharmacological tolerance development

in the After Groups.

146
In conclusion, while the major portion of tolerance development to

phenobarbital in this study was explicable in terms of pharmacological exposure to the drug, nevertheless the greater shift to

the right of the Before Group's dose-effect redetermination functions revealed an additional behavioral tolerance component.

ACKNOWLEDGMENT

Supported by Grant DA-1110 from the National Institute on

Drug Abuse.

REFERENCES

Campbell, J.C. and Selden, L.S. Performance influence on the development of tolerance to amphetamine. Pharmac. Biochem. Behav., 1.:

703-708, 1973.

Carlton, P.L. and Wolgin, D.L. Contingent tolerance to the

anorexigenic effects of amphetamine. Physiol. Behav., 7:221-223,

1971.

Chen, C. S. A study of the alcohol-tolerance effect and an lntroduction of a new behavioural technique. Psychopharmcologia, 12:

433-440, 1968.

Dews, P.B. Studies on behavior. I. Differential sensitivity to

pentobarbital of pecking performance In pigeons depending on the

schedule of reward. J. Pharmacol. Exp. Ther., 113:393-401, 1955.

Dews, P.B. A behavioral effect of amobarbital. NaunynSchmiedebergs Arch. Exp. Pathol. Pharmakol., 248:296-307, 1964.

Falk, J.L. Studies on schedule-induced polydipsia. In; Wayner, M.J. ed.

Thirst: Proceedings of the First International Symposium on Thirst

in the Regulation of Body Water. 'New York: Pergamon Press,

1964. pp. 95-116.

Falk, J.L. Schedule-induced polydipsla as a function of fixed

interval length. J. exp. Analysis Behav., 9:37-39, 1966.

Falk, J.L. The nature and determinants of adjunctive behavior.

Physiol. Behav., 6:577-588, 1971.

Goldstein, A., Aronow, L. and Kalman, S.M. Principles of Drug

Action: The Basis of Pharmacology. 2nd ed. New York: John Wiley &

sons, 1974. pp. 569ff.

Jones, M.R. The effect of phenobarbital on food and water intake,

activity level and weight gain in the white rat. J. Comp. Psychol.,

35:1-10, 1943.

Kalant, H., LeBlanc, A.E. and Gibbins, R.J. Tolerance to, and

dependence on, some non-opiate psychotropic drugs. Pharmacol. Rev.,

23:135-191, 1971.

147
LeBlanc, A.E., Gibbins, R.J. and Kalant, H. Behavioral augmentation of tolerance to ethanol In the rat. Psychopharmacologia, 30:

117-122, 1973,

LeBlanc, A.E., Kalant, H. end Gibbins, R.J. Acquisition and loss

of behaviorally augmented tolerance to ethanol in the rat.

Psychopharmacology,48: 153-158, 1976.

O'Kelly, L.I. and Weiss, H.H. The effects of ether and a barbiturate on water regulation in the rat. J. Comp. Physiol. Psychol.,

48:123-125, 1955.

Rutledge, C.O. and Kelleher, R.T. Interactions between the effects

of methsaphetamine and pentobarbital on operant behavior in the

pigeon. Psychopharmacologia, 7:400-408, 1965.

Schmidt, Jr., H. Pentobarbital facilitation of water ingestion in

the albino rat. J. Comp. Physiol. Psychol., 51:26-28, 1958.

Schmidt, Jr., H., Summe, J.P., and Coby, W.F. Phenobarbital withdrawal end behavioral disruption in the rat. Physiol. Behav., 5:

1473-1479, 1970.

AUTHORS

Maisy Tang, Ph.D., and John L. Falk, Ph.D., Department of

Psychology, Rutgers University, New Brunswick, New Jersey 08903

148
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RockviIle. Maryland 20857

DHEW Publication No. (ADM) 78-551

Printed 1977