Behavioral

Pharmacology of

Human

Drug Dependence

U S DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration
PROPERTY OF DEPR

Behavioral Pharmacology

of Human Drug Dependence

Editors:

Travis Thompson, Ph.D.

University of Minnesota

Chris E. Johanson, Ph.D.

The University of Chicago

NIDA Research Monograph 37

July 1981

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National lnstitute on Drug Abuse

Division of Research

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The NIDA Research Monograph 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.

Addiciton Research Foundation

Palo Alto, California

Jerome Jaffe, M.D.

College of Physicians and Surgeons

Columbia University New York

Reese T. Jones, M.D.

Langley Porter Neuropsychiatric Institute

University of California

Son Francisco California

Jack Mendelson, M.D.

Alcohol and Drug Abuse Research Center

Harvard Medical School

McLean Hospital

Belmont Massachusetts

Helen Nowlis, Ph.D.

Office of Drug Education DHHS

Washington DC

Lee Robins, Ph.D.

Washington University School of Medicine

St Louis Missouri

NIDA Research Monograph series

William Pollin, M.D.

DIRECTOR, NIDA

Marvin Snyder, Ph.D.

DIRECTOR, DIVISION OF RESEARCH, NIDA

Robert C. Petersen, Ph.D.

EDITOR-IN-CHIEF

Eleanor W. Waldrop

MANAGING EDITOR

Parklawn Building 5600 Fishers Lone Rockville. Maryland 20857
Behavioral Pharmacology

of Human Drug Dependence
ACKNOWLEDGMENTS

This monograph is based upon papers presented at a technical

review held at Belmont Conference Center, Elkridge, Maryland,

June 29 to July 1, 1980. Koba Associates, Inc., Washington, D.C.,

provided administrative support for the meeting under NIDA Contract No. 271-79-3607.

Drs. Travis Thompson and Chris E. Johanson served on the staff

of the Clinical/Behavioral Branch, NIDA Division of Research,

during the 1979-1980 academic year by agreement under the Intergovernmental Personnel Act of 1970 (IPA) . Dr. John Grabowski

has been serving in a similar capacity since October 1980.

Opinions expressed in the papers are those of the authors and do

not necessarily reflect the opinions or official policy of the

National Institute on Drug Abuse; Alcohol, Drug Abuse, and Mental Health Administration; Public Health Service; or the Department of Health and Human Services.

COPYRIGHT STATUS

The National Institute on Drug Abuse has obtained permission from

the copyright holders to reproduce certain previously published

material as noted in the text. Further reproduction of this

material is prohibited without specific permission of the copyright holders. The table on page 47 is modified from copyrighted

material and therefore may be under copyright. It is used with

the permission of Silver Burdette Company, Morristown, New Jersey.

Before reproducing, readers are advised to determine its copyright

status and/or to secure permission of the copyright holder. All

other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of source is appreciated.

Library of Congress catalog card number 81-600105

DHHS publication number (ADM)81-1137

Printed 1981

NIDA Research Monographs are indexed in the Index Medicus. They

are selectively included in the coverage of Biosciences Information Service, Chemical Abstracts, Current Contents, Psychological

Abstracts, and Psychopharmacology Abstracts.

i v
Foreword

The behavioral description of drug dependence which began with

anecdotal accounts has now progressed to the sophisticated

behavioral analysis so well summarized in this monograph. The

result of a technical review held by the National Institute on

Drug Abuse (NIDA), this book describes a growing body of systematically derived data on the behavioral mechanisms involved in

the use of drugs and their all too frequent abuse. By emphasizing human use, it provides a valuable link between the

neatly arrayed drug use paradigms of the animal laboratory and

those governing street drug use.

By describing some of the remarkable parallels in many forms

of substance abuse--from smoking cigarettes to mainlining

heroin--we hope that this monograph will be both a useful conpendium of what is presently known about the behavioral pharmacology of drug dependence and a spur to additional research.

Many difficult issues inherent in this increasingly sophisticated research area have been addressed by an impressive

diversity of researchers. As our understanding of these

behavioral mechanisms is enhanced, so is the possibility of

more effective prevention and treatment. It is that goal--

ultimately minimizing the extent and cost of dysfunctional

drug use--to which NIDA dedicates its research efforts. We

hope that this book will help to provide the scientifically

based foundation upon which better intervention techniques

must be built.

Robert C. Petersen, Ph.D.

Editor-in-Chief

NIDA Research Monograph Series

v

Preface

The National Institute on Drug Abuse (NIDA) has published in its

Research Monograph series several volumes focusing on the discipline of behavioral pharmacology. These monographs represent only

a sampling of the extensive data base which has developed over the

past two decades. Their content closely parallels the history of

the field, reflecting its foibles as well as its evolution toward

greater sophistication. Clearly, many important questions remain,

and investigators will not find it difficult to identify areas

requiring further research, as is well documented in the pages of

this volume.

Many investigators have been involved in the expansion of our knowledge and understanding of the orderly relationships between drugs

and behavior; a few have made particularly notable contributions in

the field of drug abuse research. Dr. Joseph Brady, for example,

has contributed substantially to the shaping of the discipline

itself and to the careers of several of the investigators represented in this volume. Drs. Norman Krasnegor and Pierre Renault,

while serving at NIDA, devoted persistent and energetic efforts

toward development of an integrated program in behavioral pharmacology of drug dependence. Their work and that of many other

individuals has been reflected in this monograph series and in the

philosophical and technological evolution of the field.

Behavioral pharmacology has evolved into a mature discipline. Drs.

Thompson and Johanson have provided us with a monograph indicative

of the field's vitality, which both delineates and goes well beyond

efforts of the past.

Progress in behavioral pharmacology as represented in microcosm in

this volume is not a chimera. It is evidenced in two ways. First,

"steps beyond" are evident in the hard data. For example, additional important data on aspects of drug self-administration are

presented. Drug actions and interactions under a greater variety

of circumstances are considered and explicit factors modulating

drug effects are more clearly delineated. Specific data based and

data bound advances such as these are, and should be, the foundation of science.

vii
It is from expansion and integration of the data that a second category of "steps beyond" emanates. In the present volume, the fields

and subfields of psychology, psychiatry, pharmacology, and neurology

are all represented. Thus it is fair to say that the interdisciplinary nature of behavioral pharmacology is now well established.

Rapprochement is clearly increasing. A joining of the conceptual,

methodological, and technological approaches of traditional pharmacological and psychopharmacological perspectives with those of

behavioral pharmacology is evident. Each of the disciplines stands

to gain from interdisciplinary activity, the sharing of traditional

wisdom, and by utilizing innovative techniques--all trends clearly

manifested in this monograph. From this vantage point the volume

presents an integrated conceptual framework for delineating behavioral mechanisms of drug dependence across a range of levels of

analysis.

Within the psychological viewpoints represented, the need for reconciliation of classical and operant psychological perspectives in

analyzing drug use and drug effects has become apparent and has

emerged herein. Similarly the need to account for and measure human

behavioral idiosyncracies such as verbal behavior, an area in which

animal models are limited, is also addressed. It is also evident

that better understanding of the limitations of animal models has

enhanced their usefulness. As a result data from the animal laboratory has increased our understanding of aspects of drug use and has

most certainly disproved Sir William Osler's comment that "the

desire to take medicine is perhaps the greatest feature which distinguishes man from animals." Overall, robust and significant linkages have emerged between basic and applied, and laboratory and

clinical, research.

The efforts to develop statements concerning substance abuse which

are of greater scope and generality are direct consequences of this

coming together of diverse perspectives. However, a word of caution

must prevail. While "seeing the forest" of general statements and

unifying concepts is important, it should be remembered that this

has resulted from inspecting the individual trees. Careful experimental analysis and precise atheoretical data-seeking (couched in

creativity) have, after all, been the methods by which our revelation of the forest has occurred.

The present volume emphasizes "commonalities" in data, descriptions,

and explanations for diverse habitual patterns of behavior. In this

sense behavioral analysis has come full circle. Initially the findings of early nondrug studies were used to shore up our basis for

understanding substance use and abuse. At this juncture, techniques

and conceptual vantage points derived from the study of interrelationships of pharmacological, behavioral, and environmental variables in drug abuse have been turned to advantage in better understanding parallel nondrug phenomena. This evidence best represents

the progress and promise of behavioral pharmacology as a discipline

and points to the need to maintain and nurture its development.

As with earlier volumes in this series, answers are presented while

further questions are raised. This volume certainly reflects

viii
advances in the science of behavioral pharmacology and points to

the ultimate goals of a better understanding of human behavior,

alleviation of disorders characterized by dysfunctional and maladaptive substance use, and improved treatment with behaviorally

active drugs.

John Grabowski, Ph.D.

J. Michael Walsh, Ph.D.

Clinical-Behavioral Branch

Division of Research

National Institute on Drug Abuse

i x

Contents

Foreword

Robert C. Petersen . . . . . . . . . . . . . . . . . . . . v

Preface

John Grabowski and J. Michael Walsh . . . . . . . . . . . vii

INTRODUCTION AND OVERVIEW

Behavioral Mechanisms and Loci of Drug Dependence: An Overview

Travis Thompson . . . . . . . . . . . . . . . . . . . . . . 1

Common Mechanisms in Substance Abuse

Joseph V. Brady . . . . . . . . . . . , . . . . . . . . . . 1 1

Towards a Rapprochement Between Clinical Pharmacology and

Behavioral Pharmacology

Louis Lasagna. . . . . . . . . . . . . . . . . . . . . . .21

Discussion: An Analysis of Commonalities in Substance

Abuse and Habitual Behavior

Peter K. Levison . . . . . . . . . . . . . . . . . . . . . 27

HISTORICAL AND PERSONALITY FACTORS

Personality Factors in Human Drug Self-Administration

Roy W. Pickens and Leonard L. Heston . . . . . . . . . . .45

Personality Factors in Methadone Self-Administration by

Heroin Addicts

George E. Woody, A. Thomas McLellan, Charles P. O'Brien,

and Lester Luborsky . . . . . . . . . . . . . . . . . . . . 6 3

History of Drug Exposure as a Determinant of Drug

Self-Administration

Alice M. Young, Seymore Herling, and James H. Woods . . . .75

Contributions of Reinforcement Schedule Histories to Our

Understanding of Drug Effects in Human Subjects

Harold Weiner . . . . . . . . . . . . . . . . . . . . . . . 90

xi
STIMULUS CONTROL AND DRUG DEPENDENCE

Classically Conditioned Phenomena in Human Opiate Addiction

Charles P. O'Brien, Joseph W. Termes, John Grabowski,

and Ronald Ehrman . . . . . . . . . . . . . . . . . . . . 107

Internal Stimulus Control and Subjective Effects of Drugs

Charles R. Schuster, Marian W. Fischman, and

Chris E. Johanson. . . . . . . . . . . . . . . . . . . . 116

Social Stimulus Factors in Drug Effects in Human Subjects

Maxine L. Stitzer, Roland R. Griffiths, George E. Bigelow,

and Ira A. Liebson . . . . . . . . . . . . . . . . . . . 130

Discussion: Stimulus Control and Drug Dependence

Donald R. Jasinski . . . . . . . . . . . . . . . . . . . 155

COMMONALITIES AND DIFFERENCES AMONG REINFORCERS

Differential Drug Effects as a Function of the Controlling

Consequences

James E. Barrett. . . . . . . . . . . . . . . . . . . . . 159

Predicting the Dependence Liability of Stimulant Drugs

Roland R. Griffiths, Joseph V. Brady, and

George E. Bigelow . . . . . . . . . . . . . . . . . . . . 182

Establishment of Orally Delivered Drugs as Reinforcers for

Rhesus Monkeys: Some Relations to Human Drug Dependence

Richard A. Meisch and Marilyn E. Carroll . . . . . . . . 197

Human Dependence on Tobacco and Opioids: Common Factors

Jack E. Henningfield, Roland R. Griffiths, and

Donald R. Jasinski . . . . . . . . . . . . . . . . . . . 210

Discussion: Commonalities and Differences Among Reinforcers

Chris E. Johanson .................... 235

COMPLEX SCHEDULES AND MAINTENANCE OF DRUG DEPENDENCE

Second-Order Schedules: Extended Sequences of Behavior

Controlled by Brief Environmental Stimuli Associated with

Drug Self-Administration

Steven R. Goldberg and Michael L. Gardner . . . . . . . . 241

The Place of Adjunctive Behavior in Drug Abuse Research

John L. Falk . . . . . . . . . . . . . . . . . . . . . . 271

Discussion: Complex Schedules and Maintenance of Drug

Dependence

James E. Barrett . . . . . . . . . . . . . . . . . . . . 279

Nancy K. Mello . . . . . . . . . . . . . . . . . . . . . 282

Conference Participants . . . . . . . . . . . . . . . . . . . 287

List of NIDA Research Monographs . . . . . . . . . . . . . . . 290

xii
Introduction and Overview
Behavioral Mechanisms and Loci of

Drug Dependence: An Overview

Travis Thompson, Ph.D.

The search for a more thorough understanding of the basic commnon

processes underlying drug dependence has been thwarted by the lack

of a conceptual map of the terrain. Investigators have been in the

position of the crew in Lewis Carroll's The Hunting of the Snark.

The Bellman brought a map purporting to show the elusive Snark's

location: once the voyage was underway, however, the crew discovered the map was completely blank. All too often those of us in

the field of drug dependence find ourselves floating on an uncharted

conceptual sea, zigging and zagging in search of a common causal

process. It would be as naive to suppose that all forms of heart

disease have a common cause. Instead, it is more reasonable to

suppose that, Just as there are similarities in the symptoms in

various forms of heart disease, there are also similarities in the

symptoms in various forms of drug dependence. However, in both

cases one cannot expect the normal controlling mechanisms to have

gone awry in precisely the same ways. It must be assumed that a

relatively limited number of variables, whose weightings differ

among forms of substance abuse, interact to produce the various

states of dependence (see Levison's discussion, this volume).

A second problem facing the field has been the absence of a unit of

analysis and a metric for assessing the control drugs exercise over

the behavior of the user. It wasn't until the mid 1960's that

control over Objectively measurable behavior was suggested as a criterion for assessing dependence-producing properties of drugs.

Finally, we have struggled to develop more Objective ways of assessing behavioral consequences of the drugs which are self-administered, and to provide a consistent framework within which to interpret those effects. Thus, like Janus's two faces, two oppositefacing problems of drug dependence have oriented investigators in

opposite directions. Behavioral pharmacologists have treated drug

self-administration and the study of other behavioral effects of

drugs as only nominally related. People in the drug treatment

community have focused primarily on the adverse conseouences of drug

dependence, with little interest in drug self-administration, per se.

Now the two have finally come face to face (see chapters by Brady

and Lasagna).

1
Drug dependence involves a cluster of processes in which a state is

produced by repeated self-administration of the drug, such that the

drug user will engage in substantial amounts of behavior leading

specifically to further administration of the drug, whicn will continue even when this requires the sacrifice of other important

reinforcers and sources of satisfaction (Kalant et al. 1978). An

understanding of drug dependence requires knowledge of the factors

responsible for development, maintenance, and elimination of drug

self-administration, and of the effects of the self-administered

drug on other ongoing biobehavioral processes. We are interested,

therefore, not only in how a drug comes to serve as a potent reward

exercising extensive behavioral control, but how the drug influences

the subject's ability to meet environmental demands. The aspects of

an animal's or person's behavioral functioning which are altered by

a drug are the drug's locus of action. The processes which account

for the drug's behavioral effects are the mechanisms of action.

BEHAVIORAL MECHANISMS OF DRUG ACTION

In the natural sciences, there is broad agreement concerning what

the term "mechanism" means. For example, the mechanism by which

oxygen is transferred from the atmosphere into the blood stream

involves the differing gradients of partial pressure of oxygen and

carbon dioxide in the alveoli of the lungs and in the bloodstream.

The degree to which oxygen and carbon dioxide are exchanged has to

do with differential pressure gradients. Therefore, in this case we

refer to a general principle of gradients of partial pressure of

gases across a membrance in specifying the mechanism.

In pharmacology, the concept of mechanism of action is intertwined

with that of locus of action. Claude Bernard (1856) conducted

several experiments elucidating these two concepts. In one study,

he examined the site of the paralytic action of curare. Using a

nerve-muscle preparation, Bernard showed that if a muscle was

stimulated directly, the muscle would contract. However, if the

nerve itself was stimulated, even though the nerve continued to

conduct along its axons, the muscle would not contract. Therefore,

Bernard concluded that the site of action of curare must be at the

myoneural junction. In a related experiment, Bernard studied the

mechanism by which carbon monoxide causes asphyxiation. He knew it

was necessary for oxygen to be carried to the tissues by the bloodstream. Moreover, he knew that when an animal was placed under a

bell jar filled with carbon monoxide, the animal was asphyxiated.

In a series of elegant experiments, he demonstrated carbon monoxide

has a differential and selective affinity for hemoglobin, the active

element responsible for distribution of oxygen to the tissues.

Bernard's experiment was critically important for the development of

the concept of mechanism of action, because he demonstrated that

carbon monoxide altered a normal function of hemoglobin which was

responsible for oxygenation of tissues. Thus, the term "mechanism"

in pharmacology. as in other areas of natural sciences. refers to

a description-of a phenomenon in terms of a more general set of

scientific principles.

2
In pharmacology, most of the mechanisms to which we have customarily

referred have been reductionistic. To a degree, this has been a

fortuitous historical development which has become entangled with

unwarranted tenacity in our theoretical fabric. In attempting to

specify the mechanism responsible for the effects of mescaline on

the behavior of certain native Indian tribes who use the drug as

part of religious rites, it is not especially helpful to specify the

receptor sites in the central nervous system activated by the drug.

The mechanisms which account for the drug's effect have to do with

psychological, social, and cultural factors rather than specific

neurochemical factors.

It becomes evident that the choice of level of analysis is dictated

by the system under study and by the degree to which the mechanisms

proposed fit into an established set of lawful relationships. The

existence of a substantial knowledge base with a rich network of

lawful relationships makes it profitable to explore behavioral

mechanisms of drug action. By behavioral mechanism of drug action,

we refer to a description of a drug's effect on a given behavioral

system (1ocus) expressed in terms of some more general set of environmental principles regulating behavior.

Specifying the behavioral mechanism(s) responsible for an observed

effect involves: a) identifying the environmental variables which

typically regulate the behavior in question, and b) characterizing

the manner in which the influence of those variables iS altered by

the drug. In some Instances, the drug assumes the status of a

behavioral variable, per se, rather than modulating an existing

environmental variable. The search for environmental controlling

variables which can be modulated by drugs is aided by a systematic

exploration of antecedent factors, current environmental variables,

and response consequence factors which are known to regulate

behavior. Thus, the three terms in the statement of a behavioral

mechanism are: 1) the drug; 2) the behavioral phenomenon; and

3) a qualitative statement of the relation between the two. The

papers in the present volume are, therefore, organized around these

three classes of mechanisms.

ANTECEDENT VARIABLES

Behavioral mechanisms of drug dependence can involve three classes

of antecedent variables regulating behavior. The Subject's history

provides the first class of variables. Environmental history can

modulate the behavioral locus of a drug's action: for example,

whether punished responding is increased or decreased by amphetamine, or whether response rates increase under fixed interval

schedules following amphetamine administration. Figure 1 illustrates such a reinforcement history effect (see chapter by Weiner).

Environmental history as well as genetic factors can control the

reinforcing efficacy of drugs. Pharmacological history can determine the magnitude of a drug's effect (e.g., tolerance) and the

disruptive effect of discontinuing administration of certain drugs

(withdrawal) (see chapter by Young et al.). In humans, the confluence of historical and genetic dispositional variables is usually

3
Figure 1

d-AMPHETPMINE (mg/kg)

SALINE RESPONSES/MINUTE

Fig. 1. Effects of d-amphetamine on lever-pressing

performance of rats maintained by a FI 15 sec. food

reinforcement schedule. Half of the rats had histories of exposure to Fixed Ration 40 reinforcement

schedules (triangles) and half had comparable exposure to a DRL 11 sec. reinforcement schedule. Each

data point represents the response rate of an individual subject during a single drug session graphed

as a percent of the saline control rate maintained

in the session preceding drug injection. (From:

Urbain, Poling, Millam, and Thompson. d-Amphetamine

and fixed-interval performance: Effects of operant

history. Journal of the Experimental Analysis of

Behavior, 29:385-392, 1978. © 1978, Society for

Experimental Analysis of Behavior. Reprinted by

permission.

4
called personality or psychopathological mechanisms (see chapters by

Pickens and Heston, and Woody et al.).

A second class of antecedent behavioral mechanisms includes various

deprivation conditions. The efficacy of a drug reinforcer depends

in part on the time since last drug administration. Drug deprivation that increases the efficacy of nondrug reinforcers (e.g., food)

can also alter the efficacy of drug reinforcers.

A third class of antecedent behavioral mechanisms involves modulation of behavior by aversive stimulation. The efficacy of some drug

reinforcers derives from the diminution of aversive stimulation the

SubJect brings to the situation.

It may be expected that in the drug user these factors interact in a

complex fashion. However, appropriately designed experiments provide

the opportunity to delineate the relative contribution of these antecedent conditions and thus identify the behavioral mechanisms of

action.

DRUGS MAY BE INVOLVED IN THE PROCESS OF STIMULUS CONTROL

Behavioral mechanisms involving stimulus control include the stimulus properties of drugs and modulation of discriminative control

over behavior by drugs. Stereotyped movements and locomotor activity (e.g., circling) can be elicited by drugs. Drugs administered

to animals and people can also serve as discriminative stimuli,

setting the occasion for responding maintained by other reinforcers.

Such discriminative stimulus properties of drugs are the basis for

classifying drugs by animals and people (usually termed Subjective

effects) (see chapter by Schuster et al.). Drugs can selectively

modulate control by certain environmental cues. For example, A 9 THC

has marked effects on a temporal discrimination while methadone has

little or no effect on the same performance (figure 2). Whether a

drug's effects are evident may depend critically on stimulus complexity. Thus, for example, many simple visual discriminations are

minimally affected, but certain complex discriminations are significantly altered by the same dose of drug.

The role of social stimulus variables in drug effects has been the

Subject of considerable speculation and, more recently, careful

Objective analysis (see Stitzer et al.). That such complex and

subtle stimulus events can serve multiple functions is attested to

by the fact that one and the same stimulus can serve as an unconditioned stimulus for classical conditioning (see chapter by O'Brien

et al.) and as an unconditioned reinforcer for operant behavior (see

chapter by Henningfield et al. and discussion by Jasinski).

BEHAVIORAL LOCUS OF DRUG ACTION

Behaviorally active drugs may alter some behaviors which are topographically distinguishable from others. In understanding effects

of drugs people and animals self-administer, it is useful to know

which behaviors are changed and which are relatively unaffected.

Some effects may be readily apparent. A drug may, in a direct and

5
Figure 2

THC (mg/kg)

Fig. 2. Effects of vehicle control (PVP)

0.06 - 0.50 mg/kg of a 9 THC on percent

of correct choices in a temporal discrimination task 14-second vs. E-second stimuli). The solid line shows percent of

correct choices after a 4-second duration

stimulus has been presented, and the

dashed line shows percent correct choices

on trials after a long duration stimulus

has been presented. (From: Daniel, S.A.,

and Thompson, T. Methadone-induced

attenuation of the effects of A 9 THC on

temporal discrimination in pigeons.

Journal of Pharmacology and Experimental

Therapeutics, 213(21:247-253, 1980.

© 1980, American Society for Pharmacology and Experimental Therapeutics. Reprinted by permission.)

6
obvious fashion, alter the pattern of self-administration. Alternatively the effects may be subtle. Although performance may seem

unaffected across classes of responses, fine grained analysis within

a given response class may reveal some components are affected more

than others. The locus of some effects may be the pattern of intervals between successive responses. Several drugs under an array of

conditions modify the overall rate of responding which is specifically observed as decreases in long inter-response times and

increases in short ones. In this case, the generality of the phenonature of different controlling consequences.

menon, rate dependency or rate constancy, depends in part on the

DRUGS MAY ALTER THE WAY CONSEQUENCES REGULATE BEHAVIOR

The type of motivating event can be a significant determinant of the

effects of a wide variety of drugs on behavior maintained under a

broad range of conditions. This fact does not negate the importance

of other determinants of drug action, nor should it revive notions

that hypothetical underlying states determine a drug's effects. The

differences in drug effects depend on maintaining motivating events

under some conditions. They do not under others, even when the same

events are studied. Performances controlled by dissimilar events

under one schedule can be affected differently by a drug, whereas

under a different schedule with the same maintaining events, these

performances can be affected uniformly (see figure 3 and chapter by

Barrett). These findings argue against the specificity of the

effects of drugs on behavior controlled by a single event.

It appears behavioral mechanisms of drug action involving schedules

can reflect direct and indirect schedule mechanisms. These

mechanisms may modulate contiguity of the response-reinforcer

relation, may alter the number of responses per reinforcer, the

reinforcement density, or reinforcer availability at critical times

when responding weakens. Any of the above mechanisms can be

responsible for systematic changes in schedule-controlled behavior.

DRUGS MAY SERVE AS CONTROLLING CONSEQUENCES REGULATING BEHAVIOR

Two aspects of drug dependence were discussed in our opening remarks:

1) The effects of self-administered drugs on the ability of the

subject to meet normal environmental demands (behavioral mechanisms

and toxic effects involving antecedent factors, stimulus control

variables, and the behavioral locus of drug action have already been

mentioned); and 2) Variables which determine when and to what extent

various drugs can serve as controlling consequences.

Over the past two decades an experimental model of this latter

aspect of drug dependence has developed, using laboratory animals.

Animals are given access to a manipulandum which when operated

results in delivery of a drug. A variety of species have been

studied (e.g., rat, dog, cat, monkey, baboon) using several types of

responses (e.g., lever press, chain pull, panel press) and routes of

administration (e.g., intravenous, oral, intragastric, inhalation).

7
Figure 3

Fig. 3. Hypothetical functions depicting possible relationships between the control rate of responding maintained by different events (open and closed circles) and

the effects of certain drugs. On the basis of experimental data, it is assumed here that the drug produces

differential effects on comparable response rates at

point X and that this represents an intermediate rate

value. The dashed line at 100% represents control, or

nondrug, rates of responding; points above and below

this line represent increases and decreases, respectively,

produced by a drug. None of the relationships shown

reflects an invariant relationship (i.e., have no slope)

between response rate and drug effects. Although an

outcome of this type is possible, it appears to be characteristic of low doses that are not typically behaviorally active, Similar drug effects are obtained when

control rates are high (graph A), low (Graph B), or at

both high and low values (graph D); in graph C similar

effects are obtained when response rates maintained by

one event are low (y) and those maintained by a different event (x) are high. (From: Barrett, J.E., and

Katz, J.L. Drug effects on behaviors maintained by

different events. In: Thompson, T., and Dews, P.B.,

eds. Advances in Behavioral Pharmacology, Vol. III.

© 1981, Academic Press, Inc. Reprinted by permission.)

8
From the beginnings of these studies, animals appeared to selfadminister the same drugs as those abused by humans (see chapter by

Griffiths et al. and discussion by Johanson). Subsequent research

has investigated pharmacological and environmental variables

determining the degree to which and circumstances uner which a given

compound would serve as a reinforcing consequence for the behavior

leading to drug administration (see the Meisch and Carroll chapter

as an illustration).

Most broadly, the behavioral mechanism responsible for compulsive

drug-seeking is the principle of reinforcement. It seems unlikely

that a useful single common reductionistic mechanism can be identified accounting for the reinforcing property of such diverse drugs as

toluene, heroin, ethanol, phencyclidine, tobacco, and cocaine. No

common reductionistic mechanism has ever been found to account for

the efficacy of other reinforcers (e.g., food, water, sexual stimulation, visual stimulation, opportunity for aggression, presentation

of painful shock). It therefore seems improbable that we will be

more successful with drug reinforcers. Thus, we are led to explicate

the concept of drug reinforcement at its own level of analysis,

i.e., to specify as fully as possible the environmental and pharmacological conditions determining the reinforcing efficacy of a drug.

A description of the mechanisms responsible for the reinforcing efficacy of a drug takes the form: The reinforcing efficacy of X is a

function of A, B. C, . . . Z, where A through Z are qualitative variables. The independent variables determining the ability of a drug

to maintain behavior producing drug administration must be explicated

in detail, specifying the quantitative nature of those relationships.

Variables A and B, etc., include such factors as drug dose, hours of

deprivation, and schedule of drug presentation.

THE RELATION OF ANIMAL MODELS TO HUMAN DRUG DEPENDENCE

There is a growing appreciation of the importance of behavioral factors in controlling drug self-administration (Henningfield and et al

chapter). Drug-maintained responding is controlled in the same manner as responding regulated by a variety of other reinforcers. The

illicit use of drugs is a behavioral problem, and the variables controlling it appear to be the same as those controlling any behavior.

By viewing drugs as reinforcers, it is possible to profit from previous studies of the variables affecting the rate, pattern, and persistence of behavior maintained by other stimulus events such as food

and water presentation (Thompson and Pickens 1969, Schuster and

Thompson 1969). Persistent drug-seeking can be produced by the same

reinforcement schedules generating persistent food-seeking. The persistence of these behaviors is often as attributable to the schedule

of drug reinforcement as it iS to inherent properties of the agent

(see Goldberg and Gardner chapter). Though excessive and persistent

drug-seeking is regarded as abnormal, these qualities are generated

by the same variables producing excessive and persistent behaviors

lauded by society (see chapter by Falk and discussions by Barrett

and Mello).

9
The specific papers and discussions contained in this volume are

intended to be an illustrative guide, not an exhaustive literature

review. Collectively, they supply a conceptual map of a very

difficult empirical terrain. We trust the reader will find the

volume prescriptively useful.

REFERENCES

Bernard, C. Notes sur la curarine et ses effets physiologiques.

Bulletin General Therapeutique, 69:23-25, 1856.

Kalant, H.; Engel, J.A., Goldberg, L.; Griffiths, R.R.; Jaffe, J.H.;

Krasnegor, N.A.; Mello, N.K.; Mendelson, J.H.; Thompson, T.; Van

Ree, J.M. Behavioral aspects of addiction group report. In:

Jack Fishman, ed. The Bases of Addiction. Berlin: Abakon Verlagsgesellschaft, 1978. pp. 463-495.

Schuster, C.R., and Thompson, T. Self-administration of and behavioral dependence on drugs. A Rev Pharmacol, 9:483-502, 1969.

Thompson, T., and Pickens, R. Drug self-administration and conditioning. In: Steinberg, ed. Scientific Basis of Drug Dependence.

London: J.A. Churchill, 1969.

AUTHOR

Travis Thompson, Ph.D.

Department of Psychology

University of Minnesota216 Elliott Hall

75 East River Road

Minneapolis, Minnesota 55455

1 0
Common Mechanisms in

Substance Abuse

Joseph V. Brady, Ph.D.

Among the many perplexing aspects of the substance abuse domain,

the topic which provides the title for this essay appears to

present some of the more challenging methodological and conceptual

problems. In recent years, this field of inquiry has been

cultivated assiduously, and the current lively interest in common

factors determining patterns of substance use and abuse is

generously reflected in an expanding literature of multidisciplinary origins (e.g., Maloff and Levison 1980, Krasnegor

1980, Levison, 1977, Griffiths and Bigelow 1978). It is

unfortunately true, however, that dedication and industry, even of

the most intense sort, do not guarantee authentic scientific

achievement. In biology and the social sciences wide gaps

frequently separate experimental operations and interpretive

formulations. Progress in developing systematic and coherent

conceptualizations which serve to integrate and unify interactive

levels of discourse can be painfully slow. Even at the most basic

level, there appear to be no generally acceptable theoretical

formulations which can bring conceptual order to the rapidly

expanding frontiers of inquiry and application in the extended

domain of substance abuse. It seems clear, nonetheless, that the

development of a unifying conceptual framework for encompassing the

commonalities in substance abuse must appeal in the first instance

to an analysis of the data base which focuses upon the behavioral

interactions between organism and environment, both intrapersonal

and social.

Within this behavioral context, the most obvious commonality which

unites the range of phenomena falling within the compass of

substance abuse is the involvement of a self-administration

performance. More traditional views of this process have tended to

emphasize what appeared to be its reactive features with substance

use and/or abuse viewed as a response to some particular set of

conditions or circumstances (e.g., the "you-drove-me-to-drink"

model of alcohol abuse). In addition, the biochemical dimensions

of the problem focusing upon the structure of the molecule and

function of the receptor have dominated the search for mechanisms,

11
common and otherwise. Since the discovery, some two decades ago,

that animals implanted with intravenous catheters would repeatedly

self-inject drugs, however, it has been convincingly shown that

there iS a good correspondence between the range of chemical

compounds self-administered by animals and those abused by humans.

Moreover, the variables of which such drug self-administration are

a function (e.g., dose, response cost, schedule of availability,

environmental conditions, past history) have been found to exert

their influence in a similar fashion independently of the type of

substance maintaining the performance or the species of organism

involved (Griffiths, Bigelow, and Henningfield 1980). The

recognition of these cross-species and cross-drug generalities has

radically changed conceptualizations of substance abuse from a

reactive to a more active process, and has encouraged the kind of

functional analysis of drug-seeking and drug-taking which has

proven productive and useful in other behavioral interactions.

The pursuit of this latter course in search of substance abuse

commonalities would seem to have at least two clear advantages.

First, it. meets the literal requirements for a "mechanism" in the

sense of a collective arrangement of, or relationship between,

parts or components to produce an effect (i.e., adaptation and

adjustment of the living system in a changing environment).

Secondly, it makes contact with an expanding body of knowledge,

based upon observation and experiment, focusing on the interactive

process between organism and environment which defines the unique

domain of behavioral science. Under such circumstances, the search

for common mechanisms in substance abuse within the context of this

existing data base takes on an Investigative focus, and is

advantaged by the strong empirical influence of the experimental

laboratory.

Conceptually, the roots of such behavior-laboratory initiatives can

of course be identified with the fundamentals of environmentalism

which has two main features. The first of these is the conviction

that knowledge comes from experience rather than from innate ideas,

divine revelation, or any of those other obscure sources. And the

second holds that action iS governed by consequences rather than by

instinct, reason, will, cognitions, beliefs, attitudes, or any of

those myriad explanatory fictions which appear to have been created

out of the whole cloth by the magic of human language. Taken

together, these two constructs about human nature define a

philosophy of social optimism which says that if you want persons

to be a certain way or to do certain things, circumstances can be

arranged. The coalescence of these two ideas appears to have taken

place in 19th century England - the names of Locke and Darwin come

to mind - and can be seen to date the emergence of modern

behaviorism. Their influence upon medicine in general and the

problems of substance abuse in particular appears to have developed

much more slowly amidst dominant biochemical and physiological

orientations, but their impact iS now beginning to find expression

in the somewhat explosive emergence of Behavioral Medicine as a

field of scientific and professional endeavor encompassing

virtually all aspects of health and disease (Pomerleau and Brady

1979).

12
The important influence of the experimental laboratory in

establishing the data base which now provides the empirical

foundations for such assertions can be traced to the contributions

of I. P. Pavlov focusing upon the role of environmental

circumstances and behavioral activities in the biochemical and

physiological adaptations and adjustments of the milieu interieur.

Among the many "firsts" with which Pavlov has been credited, his

probable role as the father of behavioral pharmacology has been

acknowledged in a recent historical note by Laties (1979). But of

at least equal importance was the foundation Pavlov's work provided

for conceptualizing behavioral interactions within the framework of

an orderly and systematic body of scientific knowledge based upon

observation and experiment. The contrast between this objective

approach to the analysis of behavior and more traditional (and

lamentably, to some considerable extent, contemporary) appeals to

unobserved and unobservable "mental" processes (in whatever

"cognitive" guise they may appear) is worth emphasizing.

The lessons learned about behavior under such controlled

experimental conditions with individual organisms seem to have been

lost, in large part, on the "psycho" disciplines so long

preoccupied with the average behavior of groups, and the insights

which emerged from the animal behavior laboratory have seldom been

warmly embraced at the clinical level for reasons which appear

somewhat unique to the human condition. Unlike other aspects of

biology (e.g., biochemistry, anatomy, physiology, etc.), where

behavior is concerned, we bipeds at the head of the line harbor

strong chauvinistic dispositions which have nothing to do with

gender, skin pigmentation, or other personal characteristics of the

species. Acceptance of the notion that experimentally analyzing

the behavior of so-called "lower organisms" can meaningfully reveal

anything about our own exalted performance repertoires has been

modest and hard-won in the face of considerable "higher order"

resistance.

But polemics aside, what, in fact, have we learned on the basis of

observations and experiments in the laboratory about the mechanisms

involved in behavioral interactions, and to what extent do they

provide insights with regard to substance abuse commonalities?

Such analysis has revealed two basic modes of organism-environment

interactions. The first appears to be a very fundamental reactive

process rooted in the biochemical and physiological adaptations of

the organism to environmental influences (i.e., the environment

acts upon the organism and the organism reacts). The major

contributions to our understanding of the regularities and

orderliness of the process whereby the influences of such eliciting

environmental stimulus events are broadened through reflex

conditioning are of course associated with Pavlov and are too

well-known to require extensive review. They have, in fact, been

so widely disseminated in popular parlance and quasi-technical

language that this reactive form of "conditioning" has been

somewhat overburdened in well-meaning but misguided attempts to

operationalize the analysis of behavioral interactions in general,

and substance abuse in particular. To the extent, however, that

13
substance-oriented behavioral interactions can be demonstrated to

involve salient eliciting functions and discriminable environmental

stimulus events temporally ordered in associative relationship to

reactive biochemical and/or physiological changes, such Pavlovian

or classical conditioning processes can be presumed operative, and

to that same extent must be considered prime "suspects" in the

search for common mechanisms in substance abuse.

In this regard of course, the early work of Wikler (1965) and the

more contemporary contributions of Siegel (1976), and of course

O'Brien and his colleagues (1977). to be reviewed in a later

section of this volume, firmly establish the potent influence of

such common mechanisms in at least several aspects of conditioned

drug tolerance and withdrawal. And this classical associative

process appears to be as ubiquitous as environmental stimulus

events and their effects upon the milieu interieur, both substance

related and otherwise.

The second basic and generally more active mode characterizing

behavioral transactions focuses on the operations performed by

organisms upon their environments (both internal and external)

rather than on their reflex reactions to such environmental

Influences. Technically, this operant mode has been explicated

within the framework of a 3-term contingency analysis which

delineates the temporal ordering of organismic performances (R),

reinforcing consequences (SR), and the environmental context (SD)

in which the R ->SR relationship occurs. The major contributions

to the experimental analysis of such operant behavior interactions

have been identified with the work of B. F. Skinner, his students

and colleagues (not to mention his disciples!). The dominant

relationship between these component terms emphasizes the

governance of action (i.e., the likelihood of a response) by the

contingently occurring effects of that action (i.e., its

reinforcing "consequences"). Emergent relations between SD

 (i.e.,

environmental context) and R (i.e., response) components are also

specified to the extent that "response-consequence" contingency

relations are dependent upon contextual occasioning (i.e.,

environmental stimulus) events. More complex interrelationships

between these terms have of course been elaborated (e.g., rule or

schedule relations), and along with historical variables, must

necessarily enter into a precise definitional account of such

behavioral contingencies. Within the framework of these empirical

referents, however, the likelihood, strength, and persistence of

behavior can be more readily understood than by any other means.

What has all this to do with common mechanisms in substance abuse?

To the extent that the substances of concern can serve a

reinforcing function (i.e., consequate a self-administration

performance and increase the probability of its reoccurrence), a

common operant behavior mechanism can be presumed operative in

substance-seeking and substance-taking. Moreover, to the extent

that such performances occur in a given environmental context and

in accordance with the ubiquitous rule governance of virtually all

behavioral interactions, the common functional mechanisms of

14
stimulus control and reinforcement scheduling (along with the

history of the behavioral interactions in these regards) will exert

a powerful influence upon the likelyhood, strength, and persistence

of substance abuse, regardless of its specific topography or formal

characteristics.

I would beg your indulgence to entertain at least a few striking

(and I believe relevant) illustrations of the limits to which

control by these common behavioral mechanisms can be extended. In

citing these admittedly atypical cases, I have chosen to focus upon

the demonstrably potent influence of schedule and stimulus control

upon the strength and persistence of behavior because these

properties frequently appear as the most baffling and recalcitrant

aspects of the substance abuse scene. Moreover, the explanations

frequently offered to account for such phenomena in the form of

appeals which range from biochemical defects to personality

variables and other creative constructs like "associative bonds"

and "opponent processes" tend to violate the law of parsimonyLloyd Morgan's canon. The field of substance abuse is ill-served

by explanatory fictions which, at the very least, fail to take

account first and foremost, of those operationally defined

behavioral relationships which emerge on the basis of observation

and experiment in laboratory settings.

Of particular relevance in this regard would seem to be the

experimentally (and clinically) documented effects of scheduling

conditions which determine under what circumstances and in

accordance with what behavioral requirements a valued commodity or

substance, be it food, drug, money, social interaction or whatever,

can be obtained. All such consequating events are subject to this

kind of rule governance, some of which is very complex, as those of

you know who have suffered through the Ferster and Skinner

"catalogue" (1957). But they all appear to be variations and/or

combinations of a few basic types, and a great deal has been

learned about their properties and effects, both in the

experimental laboratory and in the natural ecology. The two major

classes into which such effects can be categorized appear to be

those which are schedule-maintained, on the one hand, and those

which are schedule-induced on the other. Both of these areas have

been generously covered by experts in the succeeding pages of this

volume. The curious side effects of reward-enhancing intermittent

schedules and complex historical circumstances (e.g., maintenance

of shock-producing performances and great strengthening of

adjunctive or ancillary behaviors) certainly provide ample grist

for the "commonalities" discussion mill (Falk 1971, Kelleher and

Morse 1968). But it is to the power of the kind of environmental

constraints imposed by such scheduling to entrain performances of

remarkable persistence that I would like to call particular

attention in the context of the search for common mechanisms in

substance abuse.

Figure 1 illustrates a typical segment of a cumulative record from

an experiment in which a chimpanzee sustained performance on a

ratio-schedule which required 120,000 responses on a heavy

15
push-button manipulandum for access to food (Findley and Brady

1965). After each 4,000 responses toward the total requirement, a

brief flash of light was presented - the same light that was

illuminated continuously during food access once the total ratio

was completed. Of particular interest iS the pause which follows

each flash of light after a block of 4,000 responses illustrating

the control acquired by this conditioned reinforcing stimulus

event. Subsequent extension to a 250,000 response ratio and

manipulations involving removal and reintroduction of the light

flash after each 10,000 responses documented the critical

interactions between rule-goverance and stimulus control in the

establishment and maintenance of such remarkably persistent

performance repertoires. It seems important to recognize that

while such unusual and extreme examples of schedule and stimulus

conditions may appear to push the limits of adaptive functions,

they are not tricks or circus acts. They do in fact represent the

orderly and lawful operation of general relationships which are

common to all behavioral interactions, including substance seeking

and substance taking, and appear to be of particular relevance to

the excessive or abusive aspects of such performances.

FIGURE 1

16
One final point, I believe, bears on the relationship of the

"common behavioral mechanisms" argument to substance abuse. While

the thrust of this obviously provincial commentary may suggest an

empty-organism denial of relevance with respect to anything going

on Inside the skin, the ubiquity with which a host of substances,

and particularly a variety of drugs, can maintain common behavior

patterns leading to their self-administration in both animals and

man clearly attests to the fact that some basic biochemistry must

be involved. By the same token, there would seem to be little need

to appeal to special pathophysiological conditions to account for

the excesses which define continued abuse. That at least some of

the more basic behavioral mechanisms represented as common in this

abbreviated essay can be demonstrated operative with respect to

events and processes uniquely confined within the skin iS

illustrated in Figure 2.

This figure shows the relative frequency distributions of diastolic

blood pressure from an experiment in which a baboon learned to

increase and maintain blood pressure elevations in order to obtain

food and avoid shock (Turkkan and Harris, 1980). The shaping

procedure illustrated in Figure 2 involved delivery of food pellets

for accumulation of 600 sec of time above the diastolic pressure

criterion level and delivery of a single electric shock to the tail

for accumulation of 240 sec of time below that criterion level.

When the pressure level was above criterion, a white light appeared

on the animal's work panel, and when pressure was below criterion,

a red light, accompanied by a 1000 Hz tone, was presented.

Experimental sessions began at noon each day, and ended at

midnight. Criterion levels beginning at 65 mm Hg (i.e.,

pre-experimental baseline average diastolic pressure level) were

progressively elevated at a rate approximating 2-3 nm Hg per week.

The systematic shaping of diastolic pressure elevations over a

10-12 week conditioning period iS illustrated in Figure 2 which

compares the diastolic pressure levels recorded during sessions

(open bars) with the levels recorded during the 12-hour intervals

between sessions (filled bars) under baseline conditions (top

segment) and during successive stages of conditioning. At the

highest criterion (lower right segment), diastolic pressures were

elevated above 100 mm Hg in order to maintain a food-abundant

environment throughout the 12-hour experimental session during

which less than one shock per hour was delivered. And remarkably,

there was absolutely no overlap between the distributions of

pressure levels recorded at this highest criterion and those

recorded during the baseline period. The operation of a common

behavioral mechanism is clearly reflected in the development and

maintenance of this completely new physiological response pattern.

This appeal to the participation of operant mechanisms in the

regulation of physiological processes traditionally considered

under more reactive control does not, of course, imply any claim to

exclusivity. It seems self-evident that multiple mechanisms, both

behavioral and physiological, must be concurrently operative in the

mediation of such complex psychophysiological interactions.

Certainly, in so far as the environmental stimulus events (both

17
DIASTOLIC BLOOD PRESSURE (mmHg)
internal and external) involved In these processes have common

functional properties (e.g., eliciting, reinforcing, etc.), both

operant and respondent conditioning mechanisms, at the very least,

can be presumed operative and coextensive. Considering the

magnitude of our ignorance in the substance abuse domain, however,

we can hardly afford to neglect any field of inquiry which promises

enlightenment with respect to mechanisms, common or otherwise,

particularly those so obviously related to the behavioral

interactions between organism and environment.

REFERENCES

Falk, J.L. The nature and determinants of adjunctive behavior.

Physiol & Behav, 6: 577-588, 1971.

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

York: Appleton-Century-Crofts, 1957.

Findley, J.O. and Brady, J.V. Facilitation of large ratio

performance by use of conditioned reinforcement. J Exp Anal Behav,

8: 125-129, 1965.

Griffiths, R.R. and Bigelow, G.E. Commonalities in human and

infrahuman drug self-administration. In: Fishman, J., ed., The

Bases of Addiction. Berlin: Oahlem Konferenzen, 1978, 157-173 pp.

Griffiths, R.R., Bigelow, G.E. and Henningfield, J.E. Similarities

in animal and human drug taking behavior. In: Mello, N.K., ed.,

Advances in Substance Abuse. Greenwich, CN: Jai Press, 1980, l-90

PP.

Kelleher, R.T. and Morse, W.H. Schedules using noxious stimuli.

III. Responding maintained with response-produced electric shocks.

J Exp Anal Behav, 11: 819-838, 1968.

Krasnegor, N.A. Analysis and modification of substance abuse.

Behav Mod, 4: 35-56, 1980.

Laties, V.G. I .V. Zavadskli and the beginnings of behavioral

pharmacology: An historical note and translation. J Exp Anal

Behav, 32: 463-472, 1979.

Levlson, P.K. Common Processes in Habitual Substance Use: A

Research Agenda. Washington, D.C.: National Academy of Sciences,

1977.

Maloff, D.R. and Levison, P.K. Issues in Controlled Substance Use.

Washington, D.C.: National Academy of Sciences, 1980.

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, 1977.

19
Pomerleau, O.F. and Brady, J.P. Behavioral Medicine: Theory and

Practice. Baltimore: Williams and Wilkins, 1979.

Siegel, S. Morphine analgesia tolerance: Its situation specificity

supports a Pavlovian conditioning model.

1976.

Science, 193: 323-325,

Turkkan, J.S. and Harris, A.H. Differentiation of blood pressure

elevations in the baboon using a shaping procedure. Behav Anal

Letters, 1981, 1: 97-106.

Wikler, A. Conditioning factors in opiate addiction and relapse.

In: Wilner. D.M. and Kassebaum, G.G., eds., Narcotics. New York:

McGraw-Hill, 1965.

ACKNOWLEDGMENTS

Supported in part by NIDA Grants DA-00018, DA-01147 and DA-02490;

NIDA Contract 271-80-3718.

AUTHOR

Joseph V. Brady, Ph.D.

Division of Behavioral Biology

The Johns Hopkins University

School of Medicine

720 Rutland Avenue

Baltimore, Maryland 21205

20
Towards a Rapprochement

Between Clinical Pharmacology

and Behavioral Pharmacology

Louis Lasagna, M.D.

Every scientist is a prisoner of his own background, training, and

interests, and I am no exception. My experience is largely limited

to human experimentation, involving healthy volunteers, patients, or

addicts, and I therefore read the literature on behavioral pharmacology as a sort of scientific voyeur. But it may be helpful for

those who are expert in operant conditioning research to hear the

benighted remarks of an amateur who at least has a dilettante’s

acquaintance with the field. I can assure you that most clinical

pharmacologists are almost virginal with regard to classical behaviorism and its experimental consequences. (I know that wearing a

tie in a nudist colony doesn’t make one a fashion plate in the world

at large.)

Let me begin by stating that my attitude is really a very positive

one, so that the reservations that I shall begin with should not

be taken as an index of my overall position.

Let me start, then, with some difficulties that plagued behavioral

pharmacology in its early days. One trouble was a tendency to overpromise. Many people were led to believe that the discovery of new

drugs, for example, would be revolutionized by the use of operant

techniques. This proved to be a foolish hope, and the result was

an unfortunate overswing of the pendulum. For some, the pendulum

fell clear off its hook, and the potential contributions of behavioral pharmacology were cruelly denigrated.

There was also at one time an excessive preoccupation with schedules

qua schedules. At times one sensed almost a perverse pride in trumpeting the merits of FI, VI, FX, DFU, etc. schedules for their own

sake. If someone asked for a translation of these data into terms

that bad more meaning for non-Skinnerians, one met with either scorn

or abuse.

I must stress that this is not a problem unique to behaviorists.

I have the same feeling about a lot of biochemical or pharmacokinetic

research, for example, where no biological, correlates are provided to

allow one to Incorporate the data into ones gestalt.

21
This is not to say that bits of data cannot eventually prove of

considerable use -- that would be silly. But it is unrealistic

to ignore the aversive effects on non-behaviorists of data and

conclusions which cannot be readily integrated into a biologic

framework. If I am told that morphine has differential effects on

visual and food reinforcers, I appreciate some insight into whether

this might be due to something like pupillary effects, and whether

this has been studied. To be told that it is important just to

know that the reinforcers perform differently is off-putting.

I believe that this problem affects science a great deal these days,

in part because it reflects our specialization and the increasing

difficulty of studying in an expert fashion two very different kinds

of data. To make correlations, one has to have behavioral and other

sorts of data (pharmacokinetic, for example) that are both measured in

expert fashion. They don’t necessarily have to be gathered by the same

people, but the data have to be of high quality.

It is also a pity that in the past one sensed often a preoccupation

with what could be easily (or automatically) measured, rather than

with other sorts of behavior that might also be of interest. Again,

this is not a sin of the Skinnerians alone. We are all guilty at

times of ignoring those things that we didn’t set out to measure,

or that are difficult to measure. But to make a good out of this

constitutes a kind of hubris.

Residuals of these problems remain. There is still a reluctance to

deal with subjective reports, despite abundant evidence that subjective

responses can be quantified in a reproducible way that satisfies all

the requirements of good science. Reports of pain and analgesia have

been useful in this way for years, and in my own experience have provided occasional important insights. Some years ago, for example,

I noticed that an occasional patient who received a narcotic antagonist complained of “pain all over." This was seen again when we studied

naloxone, another antagonist, some years later. Now, I can appreciate

that this was probably a blocking of endogenous opiate-like materials,

but even at the time it was obvious that something important was going

on. Similarly, I think it important to know when addicts “like” drug

effects. I admit that this doesn’t tell us a lot about what they

mean by the word “like” or why they “like” a drug, but they don’t

often abuse drugs whose effects they don’t enjoy in some sense.

The traditional interests of the clinical pharmacologist concerned

with substance abuse are not, I believe, generally different from

those of the behavioral pharmacologist with some exceptions. Both

types of researchers are interested in the factors that initiate substance use and abuse, those that maintain it, the somatic consequences,

and the conditions that may act to stop or decrease substance abuse.

The fact that the nature of the factors may vary considerably from the

street to the laboratory does not mitigate what I have just said.

Peer pressure, the mystique surrounding drugs, the desire to flout

authority or gain social status by “hustling” may not be readily

studied in the lab, but “price” certainly can. So can the effects

of withdrawal after induction of physical dependence. so can to1-

erance.

22
The big differences, to me at least, lie in the economic and legal

aspects of substance abuse, and those drug effects or co-factors whose

appreciation requires the ability of our research subjects to talk to

us. Some verbalized experiences (like hallucinations) can only be

guessed at in non-human subjects. (The same is true for painting or

poetry or philosophical insights that may follow as a consequence of

drug experience. It is not the fault of a rat or a pigeon--or even of

the researcher studying them -- that the subhuman repertoire is importantly different from that of humans.)

Differences between experiment and “naturally” occurring events are

also a problem. When one tries, e.g., to correlate “drug abusability”

in animals and humans, one is hampered by the confounding factors at

play in the street. “Popularity” will show better correlations between

humans and animals in the lab, I’m sure, than if one tries to equate

“addiction potential” in the lab with street abuse. The latter is

affected to a large degree by availability and price of drug. What

is being “pushed” is an important determinant of quantity of usage.

Supply affects demand at least as much as demand affects supply.

Some years ago, when morphine and heroin were both trafficked illegally

to a considerable degree in the U.S., heroin would be the illegal drug

of choice in one big city, whereas morphine would be in another. Such

patterns illustrate the danger in equating abuse figures quantitatively

with addiction liability, yet we continue to play this game -- as if

availability, mystique, and media coverage were trivial determinants

of drug abuse.

The field of substance abuse has, in my view, provided perhaps the

most impressive opportunity for BP to help those scientific colleagues

who perform other kinds of research. The remarkable correlations

between effects in ex-addicts and animal self-administration data

(Griffiths and Balster 1979)) e.g., cannot be ignored. The fact

that dextromethorphan and a few other drugs don’t fit neatly into the

correlation is hardly cause for despair.

Nor is the fact that hallucinogens are not successfully predicted by

self-administration techniques (Griffiths et al. 1979), for a lot of

reasons (von Felsinger et al. 1956). The ability to predict abuse

liability for stimulant drugs (Griffiths et al. 1979) is also reasonably impressive, although my own guess is that diethylpropion looks

more “abusable” in BP studies than in fact it has proven to be in man.

This might be due, however, to pharmacokinetic or other differences

between species. We know that in human beings diethylpropion undergoes a rapid but limited first pass effect, metabolically speaking.

Oral doses are more potent than subcutaneous in man, and the possibility exists that the activity of diethylpropion depends on the

formation of active N-deethylated metabolites. If so, this might

explain a tendency for diethylpropion to be less attractive by the

intravenous route than other stimulants that don’t require conversion to active metabolites, and also allows the possibility of

greater abuse potential appearing in animals that are more “active”

metabolically and are therefore able to produce greater amounts of

the active metabolites. This may not be the correct explanation,

but I pose It as a scenario that might explain differences of this

sort when they occur.

23
The “negative” evidence is also helpful, i.e., the knowledge that

some drugs that have little or no abuse liability in humans also

have little appeal to animals. And it is very impressive that animals

will actually “self-destroy” if allowed to self-administer certain

drugs without restraint. This, too, is similar to the human situation.

Behavioral pharmacology offers certain advantages over clinical

pharmacology, in part because it allows true experimentation rather

than simply description of “natural” events. I realize that true

experiments can be done (and have been) in humans, but there are

serious legal and ethical restrictions on what one can do in people

(such as full exploration of dosage effects).

But equally import is the heuristic value of animal experiments

that mimic human situations. Self-administration experiments with

animals somehow underscore human behavior in a remarkable -- they

contribute a type of “legitimacy” in the minds of many, to say

nothing of generalizability. Also, it is often possible to define

quantitative and even qualitative differences more reliably in the

animal lab than in the human lab or clinic.

Another advantage of behavioral pharmacology is that its proponents

often have reminded us to be careful not to be trapped by inference

or theory that goes far beyond the fact. I believe that pharmacologists have, for example, been trapped by the orientation of the

field of drug abuse for many years around the opiate model. This

model has dominated the field for decades, and for good reason.

Human abuse of heroin, other opium derivatives, or synthetic

morphine-like substances has been a social problem for centuries;

and one can defend this widespread research interest in opiates?

especially since morphine was the first alkaloid ever isolated in

pure form (in 1803). But we have paid a price for this, in that

models of physical dependence, tolerance, and withdrawal effects

tended to be set up in the image of morphine. I believe that this

largely explains the long delay in appreciating the existence and

nature of physical dependence to alcohol and barbiturates? which is

so different in kind, severity, and risk from that seen with opiates.

I believe, further, that this preoccupation plagues us with respect

to the amphetamine class of drugs, for which one continues to read

and hear that no physical dependence exists. What should we demand

of a drug before we decide on its ability to produce physical dependence? I submit that all that is needed is a predictable pattern of

behavior that occurs over a certain time frame after discontinuance

of drug and which can be relieved or abolished by reinstituting the

drug.

I suggest that amphetamine’s withdrawal effects fit the bill. After

significant and prolonged use of amphetamine, stopping the drug is

followed by severe somnolence and then hyperphagia. Emotional depression is not uncommon. Reinstituting amphetamine reverses this

picture. Note that (as with other drug classes) the withdrawal syndrome is in many respects the mirror image of the “primary” effects

of the drug. All of this adds up to physical dependence, in my view.

The fact that it is unlike opiate withdrawal is no more relevant than

24
the fact that barbiturate and alcohol withdrawal effects are different from those induced by heroin.

There are many important questions begging to be answered.

1.

2.

3.

4.

5.

Why do some people, with ready access to illicit drugs, never

experiment with them? Why do some try, but never get “hooked”?

Is the same true for animals? I know that behaviorists have

often been most interested in phenomena that seem very “orderly,”

and go across not only individuals but species. I should like

to make a plea for interest in “disorderly” behavior, not behavior

that is chaotic, but that is predictably different from one

individual of the species to another. Amphetamine given to human

beings doesn’t make everybody alert, stimulated, and euphoric.

Some people are made sleepy and dysphoric, and predictably so.

What underlies the relationship between food deprivation and certain forms of habitual behavior and substance abuse?

What underlies “compensatory” behavior in cigarette smokers who

switch to low tar, low nicotine cigarettes? What substance or

substances are they “tracking”? What subjective effects? (Since

nicotine doesn’t seem to be an impressive reinforcer in animals,

these studies may need to be done in humans.)

What is the basis for abuse of oral analgesic combinations? Is

it really due to the phenacetin component, which clearly has

behavioral effects in humans (Eade and Lasagna 1967)?

How different are the various anorexigonic agents in their effects

on the behavioral repertoire of anunals and humans (Garattmi et al.

1974)? Are differential effects, e.g.,on appetite and satiety

(defined as initiation and cessation of eating), present? Are

they important in achieving weight loss? Do any of the drugs

facilitate fundamental changes in eating behavior (perhaps

achieved by concomitant behavior modification therapy) that will

outlast the taking of the drug?

I find myself fascinated by experimental obesity models and excessive

food consumption in humans. We now have a variety of ways of producing

obesity in animals, ranging from the genetic to repeated tail pinching.

These models are of interest to a pharmacologist at least in that

drugs may affect the obesity differentially.

The work of Rogers and Blundell (1979) is also provocative. In their

studies of healthy volunteers, a detailed analysis of the microstructure of eating behavior was abstracted from videotaped recordings of the test meal. When one studies latency to initiation of

eating, the rate of food ingestion, the change in rate of feeding

across the course of the meal, etc., it appears that drugs like

amphetamine and fenfluramine differ importantly in their effects.

Such studies may be enormously important not only in understanding

how these drugs work, but in planning more effective interventions

for the future in the management of human obesity.

25
I believe that we have long since passed from the period of scientific

hostility or isolation to an era where behavioral pharmacology and

other types of pharmacology research are ready, willing, and able

to work together to combine the best of what each approch has to

offer. Clearly, looking at drugs to the exclusion of other variables is as silly as ignoring drugs as a major component in substance abuse. No one can pretend any longer that human substantiation of animal experiments is unimportant, or vice versa.

We will, I believe, make the most rapid progress by integrating and

comparing the empiric data obtained by different techniques and

different populations. Both commonalities and exceptions have the

capability of providing new insights as well as better general

theories. The exciting work reported at this meeting shows the

wisdom of the NIDA program for support of behavioral pharmacology.

Research funds allocated by NIDA have obviously been put to good

use, and I can only pray that this kind of work receives full

support in the future as in the past.

REFERENCES

Fade, N.R.,and Lasagna, L. A comparison of acetophenetidin and

acetaminophen. II. Subjective effects in healthy volunteers.

J Pharmacol Exp Ther, 155:301, 1967.

Garattini, S. , Bonaccorsi, A., Jori, A., and Samanin, R. Appetite Suppressant Drugs: Past, Present and Future. In: Lasagna, L., ed.

Obesity: Causes Consequences and Treatment. New York: Medcom,

1974. pp. 70-80.

Griffiths, R.R., and Balster, R.L. Opoids: Similarity between

evaluations of subjective effects and animal self-administration

results. Clin Pharmacol Ther, 25: 611-617, 1979.

Griffiths, R.R. Brady, J.V., and Bradford, L.D. Predicting the

abuse liability of drugs with animal drug self-administration procedures : Psychomotor stimulants and hallucinogens. Adv Behav

Pharmacol 2:163-208, 1979.

Rogers, P.J., and Blundell, J.E. Effect of anorexic drugs on food

intake and the micro-structure of eating in human subjects. Psychopharmacology, 66:159-167, 1979.

von Felsinger, J.M., Lasagna, L., and Beecher, H.K. The response

of normal man to lysergic acid derivatives (di- and mono-ethyl amides).

Correlation of personality and drug reactions. J Clin Exp Psychopath

17:414, 1956.

AUTHOR

Louis Lasagna, M.D.

Department of Pharmacology and Toxicology

University of Rochester School of Medicine

601 Elmwood Avenue

Rochester, New York 14642

26
Discussion

An Analysis of Commonalities in

Substance Abuse and Habitual

Behavior

Peter K. Levison, Ph.D.

INTRODUCTION

What is the problem? Societies have long been concerned about

ingestion of nonnutritive substances that, used in excess, have

unacceptable effects and may lead to states of dependence.

Concerns have centered on the health, welfare, and significant

social relationships of heavy users, and on the physical,

psychological, and social consequences that even episodic use may

produce. Moral judgments about substances and their users weigh

heavily in the policies, practices, and legal categories with which

societies attempt to contain excessive use. There have been strong

efforts to treat or incarcerate the afflicted, to control

production and markets, and to discover through research how these

substances gain such a terrible hold on heavy users. Policies are

further complicated by the many occasional and moderate users who

regard temperate consumption of some substances under appropriate

circumstances as desirable. More recently, there has been concern

that some, perhaps many, activities other than intake of substances

may share important attributes with the classic pharmacological

dependencies.

Given the variety of factors operating, no single theory or set of

principles can be expected to organize all or even most features of

the disparate set of phenomena we refer to as substance abuse and

related habitual behaviors. However, some characteristics may be

common to most of these patterns, especially when the focus is on

very heavy use. The purpose of this paper is to consider the

possible common features, weigh their importance, and suggest how

research on common factors may increase our understanding and

control of addictive-like phenomena.

On Commonalities

The popularity of the idea of “commonalities” in discussions of the

self-administration of psychoactive substances for recreational

27
purposes is relatively new, especially the extension of this idea

to cover, e.g., binge eating and heavily involving activities such

as gambling, TV watching, or exercise, in which no substance is

ingested. This readiness to think of such phenomena as having

common properties, which hardly existed ten years ago, has

scientific, clinical, and political implications. The term

"substance abuse" has gained wide currency, including as the title

of a broad section of the influential DSM-III (1980). New

symposia, books and articles, including some written for a general

audience (e.g., Peele and Brodsky 1975) feature cross-substance

discussions of basic principles and treatment applications. There

also appears to be a greater willingness for the major treatment

constituencies--notably "drug addiction" and "alcoholism"--to

acknowledge their similarities rather than insist upon their

differences.

"Commonality" is defined by Webster's Third New International

Dictionary (1976) as "possession with another of a certain

attribute." This definition places a strong requirement on the

attributes being compared to be alike at some fundamental level.

It is easy to point out some descriptive similarities in excessive

substance use and other habitual behaviors; "commonalities,"

however, implies that at some deeper level a common set of

mechanisms organizes and energizes the variety of patterns we call

compulsive habitual behaviors. Similarities in the excessive use

of opiates, alcohol, tobacco, opportunities to gamble, etc., have

been pointed out many times. But the task becomes different if one

posits that the similarities reflect powerful underlying

mechanisms, still to be discovered, which give rise to socially

intrusive phenomena.

The Task

The general task is to discern frameworks to organize knowledge

about common properties of different addictions. Identification of

commonalities can provide better understanding of the addictions

and greater potential for preventing or bringing them under control.

The first step is to characterize the common phenomena. Second,

the characterizations are to be refined on the basis of

understanding their important features, and new instances of

commonalities may be included while some initially included may be

discarded. The tentative subject matter, then, consists of

phenomena which are commonly labeled addictions: dependencies on

such drugs as opiates, alcohol, tobacco, barbiturates, and

stimulants; and compulsive pursuit of activities such as gambling,

TV viewing, or long-distance-running. The task is to find the

attributes these phenomena have in common, and to rule out from a

commonalities analysis attributes that are specific to a small

subset.

A useful starting point is to compare addictive phenomena with

other strongly motivated behavior patterns that have a clear

28
biological basis and are not considered to be addictions, such as

the search for food, sex, warmth, pain avoidance, etc. Although

some features of a starving person seeking food in a famine-struck

environment (total involvement, craving) may resemble addictive

behavior, the biological necessity of food-seeking for survival

excludes it from the category of addiction. Addictions are induced

by repeated but in general biologically superfluous contact with

certain substances or environmental conditions; people not exposed

do not become addicted or suffer from being "deprived" of them.

The starving person's actions can resemble an addictive pattern,

but starvation-related behaviors are themselves excluded by

definition from the addictions.

COMMONALITIES

The following discussion covers a number of major commonalities

which have received attention, describes them briefly, and points

out their limitations.

Loss of Self-Control

Loss of "self-control" is the preeminent criterion for addiction:

when stimuli in the environment indicate availability to the

addict, steps to taking a substance or engaging in an activity

appear to be inexorable. The victim loses "self-control," and

perhaps vhile concurrently expressing severe self-criticism,

despite the best intentions at other moments, engages in the

addictive behavior. Loss of control is not absolute, however.

"Availability" does not totally determine use. Under threat of

detection or punishment, the addict may refrain. It might be

better to describe addiction as an extreme loss of personal

flexibility (Jaffe 1980).

"Self-control" usually describes motivational conflicts in which

strong tendencies are pitted against strong personal efforts to

contain them. The basis for containment has usually been learned

as part of a socialization process; i.e., the person's attempts not

to use or behave in some habitual way result from a history of -

moral training. Self-control issues are attributed only when such

a conflict is recognized. For cigarette smokers to describe

themselves as addicted has become common only since smoking was

recognized as health threatening and large numbers of smokers

attempted to quit. Decisionmaking conflicts between positive

alternatives do not involve self-control, e.g., should I go to a

movie or to a concert; should I order steak or chicken from the

menu?

"Loss of self-control" is a common and often vivid subjective

experience, and is also frequently reported by others, often as an

apology to explain their own unwanted actions. Hence, there is a

high degree of intersubjective agreement that loss of self-control

29
is a valid mechanism to explain a part of the addictive process.

However, the concept of self-control is difficult to specify

objectively in a behavioral analysis, and its place in any

biological inquiry at present is highly questionable. Moreover.

because self-control conflicts are private events they may for many

reasons be distorted in public self-reports. The addict may report

loss of control because punishment for undesirable behavior is

tempered when a person is judged "not responsible" by others, and

addiction is commonly regarded as a state that includes loss of

control. The term "compulsive" in "compulsive habitual behavior"

or "compulsive substance use" also implies loss of self-control.

If one is "compelled" to act, then responsibility lies

elsewhere--for example, with "society," for providing the

temptations, or with heredity, for determining an innate

vulnerability. Hence, the addict can be partially forgiven for

irresponsible acts.

Personal conflicts between strong urges and attempts at

self-control can be construed in normative terms which bring a

moral quality to issues in addictions. This quality is central in

any psychosocial or political consideration of addictive

behaviors. Whatever its difficulties for a scientific analysis,

self-control is likely to persist as a main concept in public

discussions of the addictions.

Involvement

Jaffe's (1980) definition of addiction is a "behavioral pattern of

drug use characterized by overwhelming involvement with the use of

the drug (compulsive use), securing of its supply, and a high

tendency to relapse after withdrawal." "Involvement" may also

include shared social rituals, emphasis in discussions and

planning, and self-acceptance of a label such as "addict."

Seeking the substance or activity. The degree of involvement with

securing a supply depends upon a drug or activity's price, the

proximity of a market, and its legal status. Heroin is illegal,

expensive, and sometimes scarce at any price. A heroin user may be

required by the conditions of the drug's availability to be heavily

"involved" much of the time in obtaining it. In contrast, the

heavy smoker may pay virtually no attention to cigarette supply,

except on the unusual occasions when they are difficult to obtain.

Involvement may be most pronounced in states of extreme

deprivation; the individual can hardly think of anything or do

anything which does not relate to the addictive substance or

activity--the starving person analogy applies. The subjects in the

Minnesota starvation experiments during World War II had imagery,

conversations, and pastimes which were completely dominated by food

(e.g., Keys et al. 1950). In considering involvement, it is

important to distinguish the addict in a satisfied state from a

deprived one. Otherwise, as in cigarette use, the dependency will

30
be unobtrusive when the substance (or activity) can be easily

obtained. The behaviors involved in obtaining addictive substances

may not be compatible with (incapable of concurrent occurrence) and

therefore displace normatively more desirable behaviors. The

uninvolved observer may consider the addict's disregard for

personal health or social obligations to be totally irrational, and

the effect of some disease-like process. Indeed, it is a hallmark

of the classic addictions that these patterns are personally and

socially destructive, largely because they displace socially

desirable ones.

The effects of altered states. Involvement which competes with

normal activities may occur not only during substance or activity

seeking, but during the main phase of the drug effect, e.g.,

intoxication. The distinction is clearest in the initial stages of

a cycle of excessive heroin or alcohol use. (The case is less

clear for other drugs such as tobacco, and for nondrug habitual

behaviors.) Substances and activities regarded as addictive

generally may produce strong alterations in many of the following

traditional categories: mood, social behavior, psychomotor skills,

problem-solving and attentional and perceptual processes. There

are elaborate experiential reports of drug effects, some of which

try to account for repeated use by the quality of the psychological

effect. However, complex psychological effects presumably unique

to the human species are not necessary for drug dependencies. All

the species of animals that have been studied in behavioral

pharmacology laboratories repeatedly self-administer most of the

same substances taken by humans (Griffiths et al. 1980).

There are psychological effects of drugs and habitual behaviors

which appear to be essential for persistent involvement with use.

These effects have been described both in behavioral and in

experiential frameworks; i.e., as reinforcement or as hedonic

effects: heroin is a powerful reinforcer, or it produces

euphoria. Roth views posit a strong positive effect as an

important commonality in the development of addictive patterns;

however, reinforcement can be more directly specified than

experiential states and so has become preferred for experimental

research with living organisms. "Powerful" suggests that given the

opportunity to choose among an array of familiar reinforcers, the

organism (human or not) will tend to select the addicting drug or

activity. "Euphoria" has been difficult to describe, in part

because it is a private event. It has been suggested that

"euphoria" as a drug response was invented to fill the need for an

exceptionally powerful, hedonic effect to explain how something as

bad as drug addiction could persist so stoutly in the face of

treatment, punishment, and personal resolve.

Positive reinforcement is not, of course, an exclusive feature of

behaviors generally described as addictions. Reinforcers not

generally considered to be involved in addictions may also be

strong competitors for control of behavior, and may maintain long

chains of behavior which are frequently repeated; e.g., sex, food,

money, or praise. Excessive involvement with one of these

31
reinforcers may earn an individual a label which implies that he or

she is obsessed in a way tantamount to what is meant by

"addiction," such as "nymphomaniac," "compulsive" or "binge" eater,

"scrooge," or "exhibitionist," respectively. Considered from this

perspective, one finds insufficient reasons why "excessive"

behavior patterns reinforced by opiates, alcohol, tobacco, or

high-stakes gambling may be regarded as addictions, while those

maintained by sex, food, money, or praise are not. An adequate

definition of addictive behavior patterns cannot be based alone on

a taxonomy of reinforcers.

Habit and frequency. The term "habitual behavior" in the context

of addictions means a repetition of a pattern, or in Jaffe's terms,

involvement in use. Habit has a number of connotations: the sense

that repeated behavior wears a groove in daily life and thus

persists; chronicity--implying repeated relapses after abstemious

periods; or an activity in which the person engages much of the

time. Habit also implies a learning process; in some learning

theory frameworks, a habit is a relatively stable state of the

learned behavior. Habits may vary in strength, depending in part

on reinforced repetitions and motivating conditions; also, the

greater the variety of settings in which a behavior pattern occurs

and is reinforced, the more tenacious the habit. Thus, it is not

surprising that many Americans who used heroin in Vietnam gave it

up readily on returning home to the United States where they had

never obtained or used it (Robins 1978).

Frequent occurrence is a necessary feature of behavior which is

regarded as an addiction, but not a sufficient one. There are no

absolute frequencies which define addictive use; rather, to be a

candidate for the label "addict," an individual must use a

substance at a higher rate (frequency over some time base) than

most others in the appropriate comparison population. Frequencies

of use for individuals who comprise the treatment population for a

substance also are used to characterize "typical" addictive

patterns. However, rate of an event does not by itself define an

addiction. Some activities required for work or family care roles,

for example, occur very often, such as writing for a writer,

operating a punch press for an assembly line worker, or picking up

a small child for a parent. How many single instances form a

pattern? How can "normal," "light," or "moderate" use be

characterized and distinguished from patterns which shade into

addiction? Simple counting is insufficient.

Substance use per se is excluded as an addiction, although the term

"abuse" is often used very loosely to include either patterns of

excessive use of legally available substances or any use of illegal

ones. A one-time user of heroin may be defined as substance

abuser, but a single trial has little in common socially,

economically, psychologically, and biologically with regular

patterns of opiate use, except in popular beliefs about substance

use, or where a narrow legality is the exclusive interest.

32
Tolerance and Withdrawal

It can be clearly demonstrated that repeated administration of some

drugs results in progressive decreases in some of the effects. For

example, the socially important properties of the

opiates--analgesic and pleasurable effects--show this kind of

change, called tolerance. Tolerance was once believed to be a

requisite to addiction. Classic studies of addicts showed that

increasing dose was necessary to produce the same effects--leading

to more exposure to the drug and perhaps to greater frequency of

administration. Tolerance was closely linked to another

phenomenon, withdrawal or abstinence effects. Disuse of the drug

resulted in marked physiological reactions and psychologically

unpleasant experiences. It was assumed that eventually the addict

could not get enough drug to continue the early "euphoric"

experiences because of tolerance, but would desperately seek the

drug to prevent withdrawal effects. It was postulated that through

repeated administration the drug brought about a novel biological

requirement analogous to nutrition. Absence of the drug or its

metabolites resulted in a strong biological drive which could only

be satisfied by more drug and a restoration of the balance.

Although the biological mechanisms are not understood, some drugs,

including alcohol, result in directly observable physiological

withdrawal effects which can be extremely unpleasant or even life

threatening. However, the contribution of withdrawal effects to

maintaining addictive behavior patterns is far from clear. From

clinical and observational evidence, there appears to be a strong

short-term effect. Addicts report that they become desperate to

obtain the drug to avoid or escape the dreadful abstinence

reactions. But in a longer time frame, relapse frequently occurs

long after withdrawal symptoms have ceased.

The discussion of tolerance and withdrawal has so far been

restricted to the "classic" addictive substances. The problems in

satisfactory resolution of the role of these processes in

compulsive habitual behaviors are intensified when the analysis

turns to other drugs, and especially to nondrug habitual

behaviors. Even before the popularity of suggesting that a host of

strongly motivated, unwanted behaviors are addictions,

pharmacologists and other specialists argued over reports of

tolerance without withdrawal, withdrawal without tolerance, and

dependence without either, all within the context of drugs alone.

What problems are raised when these concepts are extended to

nondrug habitual behaviors? Interruption of some high frequency

activity suspected of having addictive properties is reported to be

accompanied by a variety of unpleasant effects. Compulsive

gamblers in "withdrawal" are said to resemble opiate addicts or

alcoholics. The restlessness, irritability, and reported craving

of cigarette smokers in abstinence is familiar. The dysphoria of

hobbled joggers is reported. The anguish of compulsive eaters

under dietary control is well known. However, it has often been

observed that initially withdrawing any reinforcer is accompanied

33
by emotional reactions. Are all unpleasant reactions to abstinence

withdrawal phenomena? Or should that concept be restricted to

highly specific patterns including specifiable physiological events?

In sum, those who would extend the concept of addiction to a far

larger set of everyday occurrences must at least be aware of the

conceptual problems engendered by using emotional disturbance, when

strongly motivated behavior is blocked, as the sole criterion of

"addictive-like." Where do we go from there? One way points to

research to specify more carefully the events which occur when a

reinforcer is withdrawn, and to map out a set of categories which

would be useful in organizing other purported properties of

addictions. Another approach is to retreat, at least temporarily,

to the classic substances--opiates, alcohol, barbiturates,

etc.--that more clearly satisfy criteria setting their use apart as

a special class of behaviors.

Addictions as Adaptations

Coping strategies. It is commonly held, although difficult to

demonstrate, that addictions are symptoms of "underlying" personal

problems. The addiction is said to be a psychological mechanism

for temporarily reducing the personal anguish caused by a personal

conflict. Although in its initial stages the habitual behavior may

provide relief, ultimately the addiction creates secondary problems

and the addict's emotional balance sheet totals up to suffering,

not relief. In one of the major clinical views of addiction,

addicts require psychological treatment, and the problem is staked

out in terms compatible with psychotherapeutic strategies. In this

view, the general commonality in addictions is a maladaptive

attempt to solve personal problems and avoid/escape psychological

pain; while clinical strategies based upon other conceptions of the

problem, e.g., current methadone maintenance systems, place greater

emphasis on biologically based vulnerabilities.

In a simplified statement of the coping strategy viewpoint, an

addictive behavior may relieve some intolerable emotional state by

distracting the person from the generative conflict, allowing the

attendant anxiety to be "bound" rather than consciously

experienced. Substance effects--intoxication is a major one--may

dampen one's response to danger signals, i.e., "tranquilize." Even

occasional users benefit in this fashion. When such relief is

sought repeatedly, an addiction may be attributed. In this

clinical framework, addicts are defined as individuals who

habitually adapt to conflicts they cannot face by a pattern of

substance use; in this pattern, the power of the substance or

activity to grip the person is multiplied. In addition to its

positive reinforcing properties--similar to those which engage

laboratory animals--the habit is reinforced by providing functional

avoidance or escape from aversive stimulation.

It is difficult to untangle the web of motives in an addict's often

disordered life to be confident whether the addictive behavior is

34
mostly cause or effect. The case for the symptomatic nature of

addictive behavior patterns has not been made, although the

experience of temporary relief by using substances is common

enough. Finally, there is the puzzle of the control cases: why

some troubled individuals have ample contact with potential

addictions but resist acquiring an addictive habit.

The addictive personality. One line of addiction research seeks to

discover relatively stable psychological characteristics that

provide unique vulnerability to some addictions. In the early

decades of substance abuse research, personality configurations

were considered substance-specific; alcoholics and drug addicts

were supposedly different. Increased awareness of drug

substitution and the perception of a polydrug abuse subgroup in the

population has been responsible for a view more oriented toward

commonalities. The evidence for the addictive personality

conception is not compelling. Identified groups of addicts in

treatment can be shown to deviate markedly from the general

population on personality scale scores. However, these studies

mostly lack sufficient controls, and differential prediction of who

will become addicted from personality-scale scores in the general

population has not been demonstrated. This caveat notwithstanding,

there are no doubt personality configurations or perhaps specific

traits which change the likelihood of the person's acquiring some

addictive habit. This is a far cry from "the addictive

personality," however.

For almost all substances and habitual activities, many more

individuals have experienced the effects and not developed

addictive patterns than have become habitual users. Scarcely more

than a generation ago, it was widely believed that a single

administration of heroin was virtually certain to lead to an

addiction; similar beliefs about marijuana, which is not now

regarded as addicting, are evident in the documentary film classic,

Reefer Madness. In fact, many people who experiment with drugs

discontinue their use after an initial experience.

The development of addictive patterns. This process appears to

follow known principles of behavior acquisition. Both operant and

Pavlovian conditioning are entailed. Are there common features in

the establishment of addictive patterns which are distinct from

well-maintained, nonaddictive habits? One strategy is to look for

new phenomena which emerge from the study of excessive habitual

behaviors. Two of these are adjunctive behaviors, repetitive

patterns associated with specific conditions under which

reinforcement is scheduled, but not attributable to the

reinforcement contingencies per se (Falk 1971); and behavior

maintained by the delivery of stimuli which in all other known

contexts are aversive (e.g., Morse and Kelleher 1970).

35
Normative Behavior and Deviance

Characterizing deviant behaviors as addictions. "Normal"

activities such as TV viewing, gambling, or taking exercise, may be

regarded as addictive phenomena when the frequency and involvement

is very high for some, relative to most other participants. People

"explain" the intense involvement of others in activities that they

themselves find uninteresting as addictions. An "otherwise

reasonable" person who has a passion for running which is not

shared by acquaintances may be considered "addicted" by them. This

attribution perhaps reflects a growing tendency in modern American

society to judge deviant behaviors in medical or psychological

frameworks rather than moral ones.

Activities suspected of addictive qualities are usually regarded as

recreational, not necessary for a "successful" life, or for

"personal survival." "Recreational" in this sense means activities

which are time-outs from "work" and other serious business of

living. Despite the frequently discussed pleasure-seeking bent of

modern Americans, excessive or intrusive activities are considered

a distortion of acceptable pleasure-seeking, and pathological

explanations are sought.

Illicit drugs are a special case which illustrates the operation of

normative standards in forming judgments about addictive

phenomena. For example, hallucinogens such as LSD are not usually

classified as addictive in technical treatises on drugs. However,

the general public has strong beliefs in the biological and

psychosocial harmfulness of "drugs"; i.e., illicit substances used

for recreational purposes. Anyone who would voluntarily risk his

or her physical and mental health must be misled about the

consequences or in the grip of some powerful force in the

substance, i.e., addicted. Therefore, hallucinogen use is

popularly regarded as addictive behavior.

Substance use practices in some population subgroups, e.g., heroin

with inner city black youth, and marijuana with the 1960's

"counterculture," have been regarded by many Americans as uniformly

destructive and dangerous. The attribution of addiction is easily

made when the practice is deviant, when the deviance is

institutionally affirmed by control policies such as law

enforcement, and when the deviant group is remote from those making

value judgments. Belief in the harmful properties of illicit drugs

is buttressed by concerns that other deviant behaviors, e.g., crime

and dangerous political views, are associated with use.

Reputations. Popular conceptions about drugs determine informal

and formal response to substance use. Reputation is a major

commonality which aligns the fates of otherwise quite different

activities (Becker, forthcoming). A commonality is established,

for example, when a drug is declared illicit and its use takes on

the features of a forbidden activity. To keep such use private,

common social practices are developed which minimize detection. A

36
reputation influences the effects a user experiences; it may, for

example, enhance the user's belief that he or she is "hooked";

reputation also partially governs the social response of others to

a user. In the extreme case, e.g., heroin, the drug's reputation

among nonusers is very firm although they have no direct contact

with users, let alone personal experience with its effects.

Intrusiveness. Phenomena which are candidates for the label

"addiction" have the property that they are in some way considered

socially intrusive by those who are abstinent or engage in the

activity "moderately." Intrusiveness is multidimensional and

difficult to characterize; in some fashion the activities disrupt

the preferred routine of others, offending them concretely or

symbolically. In some cases, the threat of danger, e.g.. heroin

leads to crime, drunks may be physically abusive, gamblers may lose

the family fortune, etc., is a basic feature of the intrusion, but

the sight of "falling-down drunks" in public may also offend the

values of observers.

Because of the complexity of social relations and symbolic

responses to intrusive activities, producing a clear analysis of

intrusiveness in addictive phenomena is difficult; but it is an

important task. Intrusiveness is a determinant of a substance's

reputation, norms about its use, and relevant control practices.

Intrusiveness may be determined either by effects on users or on

those nonusers in the environment when use occurs. An account of

intrusiveness must include historical analysis; e.g., a commonality

in a drug's reputation as dangerous is its introduction into

society by a disapproved minority, such as use of marijuana by

Mexicans in the 1930's (Musto 1973); but introduction of a drug as

a legitimate medicine may buttress its reputation as safe even when

widespread misuse occurs; e.g., minor tranquilizers. Similarly,

familiarity as a food or a major economic staple, e.g., coffee and

tobacco, may prevent application of sanctions although less

dangerous activities are forbidden.

Social Group Factors

Social pathways and gates to addiction. What are the common social

chracteristics of an environment which selectively shapes some

individuals so that the likelihood of their addiction is enhanced?

There are two kinds of influences: (1) social factors which can be

regarded as selective gates, blocking most from becoming addicted

but letting some through; these factors chiefly apply to illicit

drugs like heroin; and (2) social enhancers--the most discussed is

peer influence--which can initiate use or push a moderate habit to

excessive levels. As with many extreme, undesirable fates, we want

to know why this person, not some other from the same environment,

"went bad." Often biological or psychological uniqueness is

attributed, and proper attention is not given to social

commonalities.

37
Symbolism in use. Behavior can have a symbolic, ritual meaning for

a group, whether it be the members of an organized religion, a

group of political activists, or the patrons of a neighborhood

bar. What common, special properties do substances have that make

them useful for group cohesion and identification? Not using may

be also a distinct group value and contribute to group strength,

e.g., temperance groups.

Addictive subcultures. The use of some illicit substances, or the

excessive use of licit ones, may be differentially characteristic

of some nationalities, ethnic groups, or socioeconomic classes.

Irish and Finnish drinking practices, and heroin use in lower class

black neighborhoods are well-known examples. Eating patterns of

some groups, certainly of some families, likely engender such food

disorders as binge eating. Although some stereotyping is no doubt

involved in common social conceptions of these relationships, there

is a substantiating literature for many cultural differences (e.g.,

Blane 1976). Membership in an ethnic group or social class,

however, cannot carry a commonalities analysis very far. It needs

to focus on the opportunities and social structuring in

environments which enhance the likelihood of problematic use.

Prohibition of use at home and among the young is a well-discussed

example. Group membership also provides the setting for

transmission of cultural recipes for substance use.

Genetic Commonalities

Every measurable behavioral trait can be shown to vary in degree

among individuals; usually the data are normally distributed in a

randomly selected, genetically heterogeneous population. It is not

unreasonable to assume that genotypic differences are in part

responsible for the distributions. A single gene cannot account

for differences in such complex sociobehavioral patterns as

addictions, but combinations of genes, along with environmental

opportunities, may contribute to differences in use patterns. The

nature of the contribution may not be immediately obvious; e.g.,

reduced sensitivity to specific toxic side effects of a drug.

Neurobehavioral Commonalities

Common neural subsystems mediating addictive behaviors. Addictions

are patterns exhibited by behaving individuals. No piece of

behavior occurs in the absence of some corresponding action of the

nervous system. The assertion that there are biological

commonalities "underlying" the addictions is In that trivial sense

true. The important issue is whether relatively discrete (and

related) brain systems organize and control the impetus, direction,

and operation of patterns we characterize as addictions. The

hypothetical addictive system might be anatomically discrete, but

is more likely a functional identity, possibly with a common

38
neurotransmitter. The large question is: does such a system(s)

exist? If so, how is it arranged so that the classic addictive

substances are immediately "recognized" by it, and how do more

complex, nonsubstance addictions like gambling become subsumed by

it?

Opiate receptor-endorphin system. The discoveries of the opiate

receptor and the family of neuropeptides known as endorphins lend

powerful impetus to the idea of a discrete addictive system.

Reasonable speculations about the functions of such a system can be

provided: To maximize survival, an organism must be reactive to

dangerous stimulation, and monitor damage to itself, but not be so

swamped by these signals that it is immobilized. The findings on

the endogenous opiate system were a precursor to the discovery of

analog biochemical systems subserving other psychoactive drugs,

e.g., the benzodiazapines. With the demonstrable explanatory power

of the receptor concept, it is not surprising to find that there

are specific sites where known active compounds have their effects

chemically. How nondrug addictive behaviors would fit this model

is difficult to imagine, however.

The concept of pain is often extended to include various forms of

psychological distress. It is not unreasonable that the relief of

a broad class of physical and psychological pains might be

neurochemically mediated by opiate receptor-endorphin systems. If

this hypothetical function is combined with the

chemical-coping-with-life interpretation of the function of

addiction, then the grand commonality could be located at that

intersection. Unfortunately for this reasonable theory, research

on biochemical activity of the putative system in animals given

opiates does not yet provide support for the theory applied to

opiates, let alone a broader class of addictive behaviors.

SUMMARY

The foregoing discussion attempts to accomplish two objectives:

(1) to present criteria which are commonly employed to characterize

"addictions"; (2) to discuss the usefulness of such criteria as a

first step toward a more sophisticated analysis. It should be

obvious that no single criterion is sufficient to define an

addiction. Also, not all are necessary. These criteria, growing

out of common usage, are imprecise, but they offer a basis for

assessing common properties in more highly refined ways.

REFERENCES

Becker, H.S. Art World. Berkeley: University of California

Press, forthcoming. Ch. 11.

39
Blane, H.T. Education and the prevention of alcoholism. In:

Kissin, B., and Begleiter, H., eds., Biology of Alcoholism. Vol.

4. Social Aspects of Alcoholism. New York: Plenum, 1976.

Diagnostic and Statistical Manual of Mental Disorders, third ed.

Washington, D.C.: American Psychiatric Assoc., 1980, pp. 163-179.

Falk, J.L. The nature and determinants of adjunctive behavior.

Physiol Behav, 6:577-588, 1971.

Griffiths, R.R., Bigelow, G.E., and Henningfield, J.E.

Similarities in animal and human drug taking behavior. In: Mello.

N.K., ed., Advances in Substance Abuse - Behavioral and Biological.

Research, Vol. 1. JAI: Greenwich, CT: JA CT: JAI Press Inc., 1980

Jaffe, J. Drug addiction and drug abuse. In: Gilman, A.G.,

Goodman, L.S., and Gilman, A., eds., The Pharmacological Basis of

Therapeutics, Ch. 23. New York: Macmillan, 1980.

Keys, A., Brozek, J., Henschel, A., Mickelsen, O., and Taylor,

H.L. The Biology of Human Starvation. Minneapolis: University of

Minnesota Press, 1950.

Morse, W.H. and Kelleher, R.T. Schedules as fundamental

determinants of behavior. In: Schoenfeld, W.N., ed., The Theory

of Reinforcement Schedules. Englewood Cliffs, N.J.:

Prentice-Hall, 1970.

Musto, D.F. The American Disease: origins of narcotic control.

New Haven: Yale University Press, 1973.

Peele, S. and Brodsky, A. Love and Addiction. New York:

Taplinger, 1975.

Robins, L.N. Interaction of setting and predisposition in

explaining novel behavior: drug initiations before, in, and after

Vietnam. In D. Kandel, ed., Longitudinal Research in Drug Use:

Empirical Findings and Methodological Issues. Washington:

Hemisphere-Wiley, 1978.

Webster's Third New International Dictionary, Unabridged: The

Great Library of the English Language. Springfield, MA: G.C.

Merriam Co., 1976.

ACKNOWLEDGMENTS

This chapter was adapted from materials prepared for the Committee

on Substance Abuse and Habitual Behavior of the National Research

Council, supported in part by Contract No. 282-80-0043-SW, T.O. 6,

from the National Institute on Drug Abuse. The author gratefully

acknowledges the helpful comments and suggestions of Deborah .

Maloff, Peter B. Dews, John L. Falk, Jerome Jaffe, and especially

Dean R. Gerstein.

40
AUTHOR

Peter K. Levison, Ph.D.

Study Director

Committee on Substance Abuse and Habitual Behavior

Assembly of Behavioral and Social Sciences

National Academy of Sciences/National Research Council

2101 Constitution Avenue, N.W.

Washington, D.C. 20418

41

Historical and Personality

Factors

Personality Factors in Human

Drug Self-Administration

Roy W. Pickens, Ph.D., and Leonard L. Heston, M.D.

For several years we have been conducting experimental studies of

human sedative dependence. The studies are conducted in a

controlled hospital environment, employing adult volunteers with

established histories of sedative abuse as subjects. The aim of

the research is to identify factors controlling human oral drugtaking behavior and to determine drug and dose preference for

prototypic sedative drugs. To date, a total of 40 subjects have

been involved in the research, self-administering a wide range of

sedative compounds including pentobarbital, secobarbital, phenobarbital, diazepam, clorazepate, and methaqualone.

In the studies, subjects are given ad lib 24 hr/day drug access,

with only a 30-minute minimum interval being required between

successive drug doses. Drugs are available in standard unmarked

capsules from an automatic vending machine, which dispenses capsules in small envelopes, controls the minimum interval between

successive drug self-administrations, and records the time and

dosage amount of each capsule dispensed. In this manner, drugtaking behavior is brought under experimental control, allowing

factors that control both rate and pattern of drug-taking

behavior to be studied objectively (Pickens and Heston 1978).

As research subjects, humans show considerable individual

variability in drug-taking behavior. For example, some subjects

self-administer as little as 100-200 mg of pentobarbital per day,

while others self-administer as much as several thousand mg of

pentobarbital per day. In an attempt to identify sources of this

variability, we assessed metabolism rate and CNS sensitivity

(tolerance) of subjects to pentobarbital and then related such

measures to their daily rate of pentobarbital intake. We found

mean daily pentobarbital intake was higher for individuals with

faster metabolic rates and lower CNS sensitivity to pentobarbital. This indicated that metabolic rate and CNS sensitivity to

pentobarbital may be factors controlling pentobarbital selfadministration in humans (Pickens et al. 1977).

45
In the present report we describe relations between personality

measures and drug-taking behavior. Subjects were administered

the Minnesota Multiphasic Personality Inventory (MMPI) while

engaged in ad lib pentobarbital self-administration. Scores on

the various scales that comprise the personality inventory were

correlated with both amount and pattern of daily pentobarbital

intake.

THE MMPI

The MMPI is the most widely used personality inventory in the

world today. It was developed in the late 1930s and early 1940s

by Starke Hathaway and Charnley McKinley at the University of

Minnesota. The test consists of 550 items, each written in a

first-person self-report format. Examples of items include “I

believe people are plotting to get me," and “I sometimes think

about things that are best kept to myself." Subjects are asked

to answer each item either "True" or "False," depending on

whether the statement accurately describes their behavior,

thinking, or mood. Items appearing on the test were validated

empirically, by comparing differences in endorsement frequency in

psychiatric and normative populations (Butcher and Owen 1978).

In constructing the MMPI, individual items were selected to form

scales. For example, if 90% of paranoids answered affirmatively

to a given item while only 10% of the normal population did so,

then the item became part of the paranoid cluster. Any subject

answering the item affirmatively has a point added to the raw

score on the paranoia scale. For each scale, raw scores are converted to T-scores, with a T-score of 50 being the average score

for the reference group. In general, the higher the scale score,

the more psychopathology is evidenct. T-scores above 70 are

typically taken to be clinically significant (Dahlstrom, Welsh,

and Dahlstrom 1972).

Both validity scales and clinical scales are derived from scoring

the MMPI. Validity scales are measures of test-taking attitude,

while clinical scales are measures of subject deviation from the

normal reference group. Brief descriptions of validity and

clinical scales on the MMPI are given in Table 1.

SUBJECT CHARACTERISTICS

Characteristics of subjects employed in the research are shown in

Table 2. There were 8 male and 14 female subjects. All were

adults, referred to the ward for treatment of sedative dependence. 411 subjects volunteered for the research prior to drug

withdrawal and start of treatment. Their mean age was 43.2 years

and their mean body weight was 68.8 kg. The majority used only

sedative drugs (predominantly barbiturates and benzodiazepines 3 ,

several used combinations of sedatives and stimulants or sedatives and analgesics, while only one subject could be classified

as a polydrug abuser. All subjects indicated sedatives as their

preferred drugs.

46
TABLE 1

Personality Characteristics Associated with Elevations

on the Basic MMPI Scales

Scale Characteristics of High Scores

L (Lie)

F (Validity)

K (Correction)

1 (Hypochondriasis)

2 (Depression)

3 (Hysteria)

4 (Psychopathic

Deviate)

5 (Masculinity

Femininity)

6 (Paranoia)

7 (Psychasthenia)

8 (Schizophrenia)

9 (Hypomania)

0 (Social

Introversion)

Tendency to present oneself in an

overly favorable light

Carelessness, confusion, or claiming

an inordinate amount of symptoms

Subtle measure of defensiveness

Cynical, defeatist, preoccupied with

self, complaining, hostile, presenting numerous physical complaints

Moody, shy, despondent, pessimistic,

distressed

Repressed, dependent, naive, outgoing, multiple physical complaints

Rebellious, impulsive, hedonistic,

antisocial

Males: sensitive, aesthetic, passive

Females: aggressive, rebellious,

unrealistic

Suspicious, aloof, shrewd, guarded,

worrisome, overly sensitive

Tense, anxious, ruminative, preoccupied,

obsessional, phobic, rigid

Withdrawn, shy, unusual, strange,

having peculiar thoughts or ideas

Sociable, outgoing, impulsive, overly

energetic, optimistic

Modest, shy, withdrawn, self-effacing,

inhibited

Adapted from Butcher, J.

© 1971.

Objective Personality Assessment.

Silver Burdett Co.

47
TABLE 2

Subject Characteristics

Total N = 22

Sex

Males N=8

Females N = 14

Age (years)

Mean - SEM 43.2 + 2.7

Range 24 - 67

Body Weight (kg)

Mean ± SEM 68.8 + 3.9

Range 41 - 100

Drug History

Sedatives only N = 14

Sedatives/Stimulants N=3

Sedatives/Analgesics N=4

Sedatives/Multiple N=l

Self-administration data for the subjects are shown in Table 3.

While several drugs were self-administered by some subjects as

part of the research design, only data on single-dose pentobarbital self-administration are included in the present report. The

selection of unit dose of pentobarbital for self-administration

was based on sensitivity of subjects to the sedative effects of

the drug. This was assessed by determining the magnitude of

subject's response to a single challenge dose of 200 mg pentobarbital administered (typically) on the second hospital day.

Subjects showing moderate sedation from the challenge dose were

allowed to self-administer 30/mg capsule of pentobarbital; subjects showing minimal effects were allowed to self-administer 50

mg/capsule of pentobarbital; and subjects showing no effect from

the challenge dose were allowed to self-administer 100 mg/capsule

of pentobarbital. More details on this testing are presented

elsewhere (Pickens et al. 1977). Thus, an attempt was made to

adjust capsule dose to achieve approximately equivalent unit-dose

effects in the various subjects.

The subjects were tested for a mean of 5.5 days (only one subject

was tested for 1 day, with the majority for 4-6 days). Their

mean drug intake was 491.2 mg, an amount sufficient to produce

abstinence symptoms if drug administration were abruptly discon48
tinued. Their pentobarbital metabolism rate was determined by

calculating the rate of decline of blood serum levels of pentobarbital following administration of the 200 mg challenge dose

described earlier. Drug half-lives were determined individually

for each subject by exponential curve fit. The mean metabolic

rate for the subjects was 15.1 hrs (metabolic rate for pentobarbital in normals is 22-40 hrs). One subject showed an unusually

long half-life (67.1 hrs); all other half-lives were under 22.4

hrs. Mean blood serum level of drug maintained by subjects was

2.8 ug/ml.

PROFILES OF SEDATIVE ABUSERS

Figure 1 shows the mean MMPI profile of the 22 subjects in our

sample (solid line). The profiles were obtained during the

subjects' first week on the research ward, with pentobarbital

available on an ad lib basis for oral self-administration. Also

shown is the mean MMPI profile of 269 sedative-dependent patients

from another, larger treatment center (dashed line). These profiles were also obtained during the patients' first week at the

treatment center, but while they were drug-free (i.e., with no

drug self-administration allowed). Both groups were composed of

patients from the same geographical region and referred to treatment by similar types of referral agencies. The mean age of subjects in our sample was 43.2 years, while that from the other

treatment center was 40.2 years.

In the figure, combined scores for males and females in both

samples were plotted for all scales except Scale 5 (MasculinityFemininity), where the scores of males and females are scored

differently. Both samples showed almost identical scores on the

validity scales, indicating similar attitudes regarding testtaking. A similar clinical profile pattern was also seen for

both groups, with highest elevations on Scale 2 (Depression),

Scale 8 (Schizophrenia), Scale 4 (Psychopathic Deviate), and

Scale 7 (Psychasthenia). Elevation on these scales is not

unusual for drug-dependent individuals. Gilbert and Lombardi

(1967) found this profile to be the mean MMPI profile in their

study of male heroin addicts. Elevation on the same scales has

also been frequently reported with alcoholics (Owen and Butcher

1979).

The most significant difference between the two profiles is the

considerably higher scores obtained by subjects during pentobarbital self-administration than by comparable subjects during drug

abstinence. Since higher scores indicate greater deviation from

the population norm, more psychopathology and personal distress

are being exhibited by subjects during pentobarbital selfadministration than by similar subjects during drug abstinence.

Clinically, both groups would be described as-depressed, tense,

irritable. and immature (Marks and Seeman 1963). However. the

characteristics were more exaggerated in subjects during drug

self-administration than in subjects during drug abstinence.

49
FIGURE 1

MMPI Scale

Mean MMPI profile of sedative dependent subjects during pentobarbital self-administration (solid line)

an during drug abstinence (dashed line). See Table 1 for names of scales. Score on Scale 5

(Masculinity-Femininity) not plotted, since scale is scored differently for males and females.
TABLE 3

Drug Self-Administration Characteristics

Drug

Dose

30 mg/capsule

50 mg/capsule

100 mg/capsule

Days Tested

Mean ± SEM

Range

Daily Intake (mg)

Mean ± SEM

Range

Metabolic Rate (t1⁄2)

Mean ± SEM

Range

Blood Serum Level (us/ml)

Mean ± SEM

Range

Pentobarbital, p.o.

N= 4

N = 13

N= 5

5.5 ± .6

1 - 12

491.2 ± 62.1

105 - 1300

15.1 ± 3.6

4.2 - 67.1

2.8 ± .3

.9 - 4.9

The finding that pentobarbital self-administration increases

depression, irritability, etc., in sedative-dependent subjects

should not be surprising. Several investigators have experimentally administered ethanol to alcoholics and measured the resulting personality changes. In most cases, ethanol increased both

depression and anxiety scores in the subjects (McNamee, Mello,

and Mendelson 1968). The present findings suggest that when

sedative-dependent subjects are allowed to regulate the amount

and temporal pattern of pentobarbital administrations, drugrelated increases in depression and irritability are also seen.

For a more detailed discussion of this issue, see Mello (1978).

MMPI CORRELATES OF SEDATIVE SELF-ADMINISTRATION

Table 4 shows MMPI correlates of drug-taking behavior. The relationship was determined by correlating scores on each MMPI scale

with mean mg/day pentobarbital intake. While the 2, 8, 4, and 7

scales had been previously found to be significantly elevated in

profiles of sedative subjects, none of these scale scores was

51
significantly correlated with amount of daily pentobarbital

intake. However, a significant correlation (4 = +.45, p < .Ol)

was found between daily pentobarbital intake and score on Scale 9

(Hypomania) of the MMPI. In general, the higher the score on

this scale, the greater was the amount of daily pentobarbital

intake.

TABLE 4

Correlation Between MMPI Scale Scores and

Mean Daily Pentobarbital Intake

MMPI Scale Pearson r

L (Lie)

F (Validity)

K (Correction)

-.03

+.02

+.20

1 (Hypochondriasis)

2 (Depression)

3 (Hysteria)

4 (Psychopathic Deviate)

6 (Paranoia)

7 (Psychasthenia)

8 (Schizophrenia)

9 (Hypomania)

0 (Social Introversion)

+.12

+.03

+.04

-.09

+.14

+.29

+.19

+.45*

-.06

On the MMPI, the Hypomania scales is a measure of the individual's energy level. As the score on this scale increases,

individuals tend to become increasingly involved in activities.

While individuals with low scores show low energy levels, those

with moderately elevated scores are active, exuberant, and

energetic. With T scores above 70, hyperactivity, irritability,

and grandiosity characterize the individual's behavior (Marks and

Seeman 1963).

Unfortunately, correlation coefficients indicate strength, not

causal directions of relationships. The finding of a significant

correlation between Hypomania score and drug intake can be taken

to indicate either that subjects who are hyperactive, irritable,

and grandiose tend to take higher daily amounts of drug, or that

as daily drug intake increases, subjects tend to become more

hyperactive, irritable, and grandious. Both of the above could

also be true, or both could be determined by a third factor as

yet unknown. Since pentobarbital is classified as a sedative

drug, one might expect hyperactivity to decrease rather than

increase with increases in daily pentobarbital intake. That this

does not occur is suggested by our previous research, where no

52
effect of daily pentobarbital intake was found on behavioral measures of subject performance on the research ward (Pickens et al.

1977). If drug intake were responsible for the personality scores

obtained, the effect of pentobarbital must be primarily on irritability and grandiosity, rather than hyperactivity.

These findings also indicate that the elevated profiles found in

subjects during pentobarbital self-administration were not due

simply to the effect of the drug on behavior, since as Table 4

shows, elevations on the various scales were not directly related

to pentobarbital intake.

When these results were analyzed separately by sex of subject,

the relationship between drug intake and Hypomania score was

found to be localized primarily in female subjects (see Table 5).

The correlation between drug intake and Hypomania score was +.74

for females (p < .OOl), while only +.25 for males (n.s.). This

difference in relationship for males and females cannot be explained

by sex differences in body weight producing differential drug

effects. When variability in body weight was controlled for by

partial correlation, a statistically significant correlation between

drug intake and Hypomania score still remained (r = +.46, p < .05).

Except for the Hypomania scale, no other clinical scale was significantly correlated with drug intake for either sex.

There was a significant effect of sex on the correlation between

drug intake and K-scale score for males (r q +.64). This can be

taken to indicate either that males tend to become more defensive

and guarded as their drug intake increases, or that the more

defensive and guarded the male, the higher will be his level of

drug intake.

Concerning the relationship between drug intake and Hypomania

score for females, a scatterplot of each individual's drug intake

and Hypomania score was constructed to determine the validity of

the obtained correlation coefficient. The scatterplot is presented in Figure 2. Daily drug intake is plotted along the vertical axis and Hypomania score is plotted along the horizontal

axis. A line of best fit, calculated by the least-squares

method, is also shown. As can be seen, most data points fall

along this line. From these data, the correlation coefficient

appears to accurately reflect the relationship between the two

variables. Low scores on the Hypomania scale are associated with

low daily amounts of drug intake, and high scores are associated

with high daily amounts of drug intake.

That the relationship between Hypomania score and daily drug

intake holds primarily for females was unexpected. While one

might expect a sex difference in sedative self-administration

based on the fact that women are more likely to be sedative

abusers than men, this difference is apparently related to the

fact that women are more likely to be prescribed sedative drugs

than men, with the incidence of abuse relative to use being about

the same for the two sexes (Cooperstock 1976).

53
FIGURE 2

MMPI Score on Scale 9 (Hypomanta)

(Females n=14)

Scatterplot of daily drug intake and score on hypomania scale for female subjects during ad lib - - pentobarbital self-administration.
TABLE 5

Correlation Between MMPI Scale Scores and Mean

Daily Pentobarbital Intake for Male and Female Subjects

MMPI Scale

Males Females

(N=8) (N=14)

L (Lie) +.29 -.30

F (Validity) -.08 +.20

K (Correction) +.64* -.03

1 (Hypochondriasis) +.55

2 (Depression) +.22

3 (Hysteria) +.48

4 (Psychopathic Deviate) -.18

6 (Paranoia) +.07

7 (Psychasthenia) +.47

8 (Schizophrenia) +.06

9 (Hypomania) +.25

0 (Social Introversion) +.19

-.14

-.23

-.16

.oo

+.21

+.19

+.40

+, 74**

-.32

* p < .05

** p < .OOl

DEPRESSION AND SEDATIVE SELF-ADMINISTRATION

Depression is a disorder frequently associated with both alcoholism and drug dependence (Cadoret and Winokur 1974; Schuster,

Renault, and Blaine 1979). However, in the present research no

significant relationship between daily drug intake and score on

Scale 2 (Depression) was found, either for men or women (see

Tables 4 and 5). One reason for this could be that all subjects

tended to score high on the Depression scale and therefore

between-subject variability was insufficient to yield significant

correlation coefficients. However, when the patterning of drug

responding was examined, a significant relationship was found

between Depression score and pattern of drug-taking behavior.

This relationship is shown in Figure 3.

For this analysis, the experimental day was divided into two

halves. While drugs were available to subjects 24 hr/day, 6 AM

to midnight was considered to be the experimental day, excluding

midnight to 6 AM as the sleep period. The first half of the

experimental day was from 6 AM to 3 PM, and the second half was

from 3 PM to midnight. If drug-taking behavior were evenly

spaced throughout the day, then equal numbers of drug responses

would be expected during the first half and second half of the

55
FIGURE 3

MMPI Score on Scale 2 (Depression)

(n=l6)

Scatterplot of percent of total capsules taken during first half of experimental day and score on

Depression scale for subjects during ad Lib pentobarbital self--administration.
FIGURE 4

MMPI Scale Scores

Scatterplots of daily drug intake and score on Hypochondriasis

(1), Hysteria (3), Paranoia (6), Schizophrenia (8), and Hypomania

(9) scales for clinically depressed subjects during ad lib

pentobarbital self-administration.

57
day. Only subjects with event records showing daily pattern of

drug intake for three or more days of pentobarbital selfadministration were employed in the study. Correlation coefficients were computed between mean percent of drug capsules

taken during the first half of the day and score on each MMPI

scale. Only scores on the Depression scale were found to be

significantly related to pattern of drug intake (r = t.47, p =

.03). As is evident from the line of best fit through the individual data points, a greater proportion of drug capsules was

taken during the first half of the day by subjects with high

scores on the Depression scale than by subjects with lower scores

on the scale.

On the MMPI, Depression scale scores reflect the degree of pessimism and depression felt by the individual at the time the MMPI is

administered. Individuals with low scores tend to be optimistic,

alert, and gregarious, while those with moderate elevations tend

to be dissatisfied and prone to worry. Marked elevations on the

Depression scale are associated with depression, pessimism, and

social withdrawal (Marks and Seeman 1963).

The relationship found between Depression score and pattern of

drug-taking behavior may reflect altered sleep patterns in

depressed individuals. Depressed subjects may awaken earlier or

go to sleep at night earlier than other individuals, thus

altering the distribution of their daily drug responses.

However, since patients on the ward are routinely awakened at 7

AM and ward activities typically continue until approximately 10

PM, the ward schedule insured that all patients were awake

throughout most of the experimental day. Alternatively, the pattern of drug taking may be related to depression in yet another

way. Depressed patients typically report most distress in the

early morning, with progessively less distress as the day continues. Taking more drug in the morning may be an attempt at

self-medication to lessen the increased distress they feel at

that time of day. However, the results may equally indicate that

depression is worsened in individuals who tend to take most of

their drugs in the morning, an interpretation which is more consistent with other findings that show sedative drugs tend to exacerbate depression in drug-dependent individuals (McLellan, Woody,

and O'Brien 1980).

In another attempt to examine the relationship between depression

and sedative self-administration, subjects were divided into two

groups depending upon whether or not their discharge summary

included a psychiatric diagnosis of depression in addition to

sedative dependence. The diagnosis of depression was made after

the subjects had been treated for sedative dependence (i.e., were

drug abstinent). The diagnosis was made by experienced psychiatrists who were blind to the eventual use of the information.

Differences between clinically depressed and non-depressed subjects are shown in Table 6. For both groups of subjects, corre58
lations between mean daily pentobarbital intake and score on

each MMPI scale are shown. No significant correlation was found

between drug intake and any MMPI scale for clinically nondepressed subjects. However, very strong relationships between

drug intake and MMPI scores were found on several scales for

clinically depressed subjects. These scales were 1 (Hypochondriasis), 3 (Hysteria), 6 (Paranoia), 8 (Schizophrenia), and 9

(Hypomania). Except for Scale 9 (Hypomania), none of these

scales approached statistical significance for non-depressed subjects.

TABLE 6

Correlation Between MMPI Scale Scores and Mean Daily

Pentobarbital Intake for Depressed and Non-Depressed Subjects

MMPI Scale

Depressed All Other

(N=7) (N=15)

L (Lie)

F (Validity)

K (Correction)

-.07 .oo

+.15 -.Ol

+.36 +.21

1 (Hypochondriasis)

2 (Depression)

3 (Hysteria)

4 (Psychopathic Deviate)

6 (Paranoia)

7 (Psychasthenia)

8 (Schizophrenia)

9 (Hypomania)

0 (Social Introversion)

+.89**

+.01

+.79*

+.60

+.72*

+.63

+.87**

+.69*

-.46

+.06

+.03

-.12

-.35

.oo

+.28

+.06

+.41

-.02

* p < .05

** p < .Ol

Because only seven subjects comprised the depressed group, scatterplots were constructed for each scale that significantly

correlated with drug intake. These scatterplots are shown in

Figure 4. The data points are homoscedastically distributed

along the lines of best fit, indicating the correlation coefficients were accurately reflecting the relationship between the

measures. The findings indicate that for clinically depressed

subjects, increases in drug intake are associated with increases

in distress as measured by several scales of the MMPI.

Alternatively, however, the findings could also indicate that

higher levels of distress are associated with higher rates of

drug intake. Regardless of the direction of the association, the

59
same relationship does not hold for clinically non-depressed

sedative-dependent subjects.

These results do not appear to be a statistical artifact. While

varying degrees of inter-correlations are found among the various

scales of the MMPI, none of these scales (including the depression scale) was previously found to be significantly correlated

with drug intake. Perhaps clinically depressed individuals

simply represent a different biological substrate upon which

drugs act.

In clinically depressed subjects, if personal distress increases

with increases in pentobarbital intake, this finding may be

related to the individual's relative preference for different

doses of the drug. Earlier we reported a curvilinear relationship between capsule dose and dose preference (Pickens et al.

1977). Preference tended to increase for doses up to about

100-150 mg/capsule, and then to decline. Several of our original

subjects were included in the present report. Five of these

seven are included in the group of clinically depressed subjects.

Perhaps for these subjects, higher capsule doses of pentobarbital

produced increased levels of distress, which was responsible for

the decrease in mean preference scores found across all subjects

at the higher capsule doses.

SUMMARY

By comparing MMPI profiles of sedative-dependent subjects during

pentobarbital self-administration with comparable subjects during

drug abstinence, the present study has found that self-administration tends to increase rather than decrease indicators of

personal distress (MMPI scale scores). This finding agrees fully

with other studies of drug effects on mood of drug-dependent subjects. (This finding should disturb only those who equate reinforcement with euphoria and other pleasurable states. Those

familiar with the concept of reinforcement understand that reinforcement deals only with behavior and implies nothing about

corresponding subjective states). Only scores on the Hypomania

scale of the MMPI were found to correlate significantly with

amount of daily drug intake, and this relationship occurred primarily in females. Scores on the Depression scale were correlated significantly with the daily pattern of drug-taking

behavior. However, in neither case is it known whether the relationship reflects influences of personality factors on drugtaking behavior, or influences of drug-taking behavior on the

obtained personality measures. Other research will be needed to

answer this question. Clinically depressed individuals may

constitute a special sub-group of subjects in which scores on

many MMPI scales are related to daily amount of drug intake.

Studies of human drug self-administration provide an excellent

opportunity for more detailed research into these and other

clinical research questions.

60
ACKNOWLEDGMENTS

This work was supported by Grant 00939 from the National

Institute on Drug Abuse. We thank Margaret L. Healey, Juanita J.

Klukken, and Philip Catchings for their assistance in collection

and analysis of the data.

REFERENCES

Butcher, J.N. Objective Personality Assessment. New York:

General Learning Press, 1971. (Now Silver Burdett Co.)

Butcher, J.N., and Owen, P.L. Objective personality inventories.

In: Wolman, B.B., ed. Clinical Diagnosis of Mental Disorders:

A Handbook. New York: Plenum Press, 1978. pp. 475-545.

Cadoret, R., and Winokur, G. Depression in alcoholism. Ann N Y

Acad Sci, 233:34-39, 1974.

Cooperstock, R. Women and psychotropic drugs. In: MacLennan,

A ed. Women: Their Use of Alcohol and Other Legal Drugs.

Toronto: Addiction Research foundation of Ontario, 1976. pp.

83-111.

Dahlstrom, W.G., Welsh, G., and Dahlstrom, L. An MMPI Handbook:

Volume I. Clinical Interpretation. Minneapolis: University of

Minnesota Press, 1972.

Gilbert, J., and Lombardi, D. Personality characteristics of

young male narcotic addicts. J Consult Psychol, 31:536-538,

1967.

Marks, P., and Seeman, W. The Actuarial Description of Abnormal

Personality. Baltimore: The Williams and Wilkins Co., 1963.

McLellan, A.T., Woody, G.E., and O'Brien, C.P. Development of

psvchiatric disorders in drug abusers: relation between primary

drug and type of disorder. In: Harris, L.S., ed. Problems ofDrug Dependence, 1979. National Institute on Drug Abuse Research

Monograph 27 DHEW Pub. No. (ADM) 80-901. Washington, D.C.:

Supt. of Docs., U.S. Govt. Print. Off., 1980. pp. 86-92.

McNamee, B., Mello, N.K., and Mendelson, J.H. Experimental analysis of drinking patterns of alcoholics: concurrent psychiatric

observations. Amer J Psychiat, 124:1063-1069, 1968.. -

Mello, N.K. Control of drug self-administration: the role of

aversive conseauences. In: Peterson. R.C.. and Stillman. R.C..

eds. Phencyclidine Abuse: An Appraisal. National Institute on

Drua Abuse Research Monograph 21. DHEW Pub. No. (ADM) 78-728.

Washington, D.C.: Supt.-of Docs.. U.S. Govt. Print. .Off., 1978.

pp. 289-308.

Owen, P.L., and Butcher, J.N. Personality factors in problem

drinking: a review of the evidence and some suggested direc61
tions. In: Pickens, R.W., and Heston, L.L., eds. Psychiatric

Factors in Drug Abuse. New York: Grune and Stratton,

Pickens, R., Cunningham, M.R., Heston, L.L., Eckert, E., and

Gustafson, L. Dose preference during pentobarbital self-administration by humans. J Pharm Exp Ther, 203:310-318, 1977.

Pickens, R., and Heston, L.L. Experimental studies of sedative

self-administration by humans. In: Krasnegor, N., ed. SelfAdministration of Abused Substances: Methods for Study.

National Institute on Drug Abuse Research Monograph 20 DHEW

Pub. No. (ADM) 78-727. Washington, D.C.: Supt. of Dots., U.S.

Govt. Print. Off., 1978. pp. 86-92.

Schuster, C.R., Renault, P.F., and Elaine, J. An analysis of the

relationship of psychopathology to non-medical drug use. In:

Pickens, R.W., and Heston, L.L., eds. Psychiatric Factors in Drug

Abuse. New York: Grune and Stratton, 1979. pp. l-19.

AUTHORS

Roy W. Pickens, Ph.D.

Leonard L. Heston, M.D.

Psychiatry Research Unit

Mayo Box 392

University of Minnesota

Minneapolis, Minnesota 55455

62
Personality Factors in Methadone

Self-Administration by Heroin

Addicts

George E. Woody, M.D., A. Thomas McLellan, Ph.D.,

Charles P. O’Brien, M.D., Ph.D., and Lester Luborsky, Ph.D.

INTRODUCTION

Causes for the pattern of compulsive, repetitive self-administration

of psychoactive drugs by humans that is known clinically as drug

addiction are poorly understood. What differentiates the person who

receives narcotics for post-operative pain and never develops drugseeking behavior, from the individual who has the same experience but

goes on to become a narcotic addict? As we look for answers to this

question, several areas come to mind: the individual's sociocultural experiences, both past and current; biological variables

that may influence one's vulnerability; and psychiatric illnesses.

This paper presents data which explores relationships between

personality and addiction that are found in the last of these areas,

namely those existing between psychiatric illness and substance

abuse. The data to be presented comes from a study aimed to measure

what benefits may be obtained by adding professionally trained psychotherapists to routine counseling services in a methadone treatment

program. Preliminary analyses of general treatment effects have

shown superior results for patients receiving psychotherapy.

However, because there iS great variability among patients in the

treatment groups, these general effects can be examined for the

purpose of studying important treatment-patient interactions. The

specific interaction we have examined for this paper iS the effect of

psychiatric symptoms, and of psychotherapy, on drug use and other

measures of treatment outcome. The hypotheses tested are that (1)

psychiatric symptoms act as Internal stimuli that can set the stage

for drug-taking behavior and that (2) psychotherapy done by trained

professionals can reduce drug self-administration by diminishing the

intensity of psychiatric symptoms.

METHOD

Subjects and Design - The Subjects are opiate addicts who are starting

a new treatment episode with methadone maintenance. Patients eligible

for this study must be between 18 and 55 years of age, cannot be

63
psychotic, and must not have subnormal intelligence or a persistent

and clinically significant organic brain syndrome. They must also

have some interest in psychotherapy and give informed consent to

participate. After initial screening for eligibility, patients

complete an intake evaluation and are randomly assigned to one of

three treatment conditions: drug counseling (DC). counseling plus

supportive-expressive therapy (SE) and counseling plus cognitivebehavioral therapy (CB). Each therapy is described in a treatment

manual. An outline of the design is seen in Figure 1. All sessions

are taped and 15-minute segments of each recording are rated by

independent observers to determine their fit with the specifications

in the manuals. Evaluations are done at 1, 7, and 12 months postintake. An outline of these evaluations is presented in Table I.

Figure 1

INTAKE

TREATMENTS

Drug Counseling - Drug counseling is a treatment that focuses on

identifying specific needs and delivering concrete services. Its

major emphasis is on providing external services rather than dealing

with intrapsychic processes. Counselors monitor patient progress by

reviewing urinalysis reports, personal, vocational, and legal

situations. They provide liaison services with physicians, courts,

and social agencies. A typical counseling session might begin when a

counselor meets with his patient, reviews the clinic chart and

observes that the urine tests show opiates. He questions the patient

regarding what has been happening and how he is feeling. The patient

says his methadone dose is not high enough, that he is having withdrawal symptoms beginning about 16 hours after he takes his methadone

and that he has been using heroin. The counselor then arranges for

the patient to meet with the program physician to be evaluated for an

increase in the methadone dose. At the same time, the patient

mentions that he has a court appearance in 2 weeks and requests a

note for the judge saying that he is participating in a treatment

program. The counselor has the patient sign a release of information

statement, prepares a note and gives it to the patient to take to his

lawyer. Counselors sometimes also intervene directly in emergencies

such as loss of a place to live, family crises, or management of

intense affects, such as anxiety or anger. In these situations, they

meet with the patient, form an opinion regarding the cause of the

problem and often arrange for a meeting with a program physician for

a brief session which may include ventilation of affect, tranquilization or encouraging the patient to take positive action.

64
Table I

PSYCHOTHERAPY STUDY

SCHEDULE OF TESTING

CONSENT FORM

MAUDSLEY PERSONALITY INVENTORY

BECK DEPRESSION INVENTORY

SOCIAL ADJUSTMENT SCALE (WEISSMAN)

SCL 90

SHIPLEY

RELATIONSHIP INVENTORY- COUNSELOR

RELATIONSHIP INVENTORY - THERAPIST

HELPING RELATIONSHIP - COUNSELOR

HELPING RELATIONSHIP - THERAPIST

PATIENT TERMINATION

SCHEDULE FOR AFFECTIVE DISORDERS &

SCHIZOPHRENIA -LIFE TIME VERSION (SADS-L)

RESEARCH DIAGNOSTIC CRITERIA

DSM III

PREVIOUS TREATMENT FORM

SCHEDULE FOR AFFECTIVE DISORDERSCHANGE VERSION (SADS-C)

ADDICTION SEVERITY INDEX (ASI)

BACKGROUND DATA INTERVIEW (BLAINE)

SOCIAL INFORMATION FORM (LUBORSKY)

FOLLOW-UP FORM

THERAPIST FACILITATIVE BEHAVIOR

GOALS OF THERAPY - THERAPIST

TERMINATION FORM - THERAPIST

COUNSELOR FACILITATIVE BEHAVIOR

TERMINATION FORM - COUNSELOR

Supportive-Expressive Therapy - Supportive-expressive therapy is an

analytically oriented, focal psychotherapy modeled after that

described by Sifneos (1972) and Malan (1963). It aims to help the

patient identify and work through problematic relationship themes.

The therapist identifies these themes via the relationship with the

patient (transference), or according to what the patient says about

other important relationships such as those with wife or other family

members. Special attention is paid to the meaning that the patient

attaches to the drug dependence. For example, a therapist might have

a patient who denies having any problems. He keeps appointments out

of "curiosity" or because he thinks he "ought to," but he maintains

that things are going well in spite of being unemployed and having an

unstable living situation. When he has a problem with his girlfriend,

he refuses to discuss it, misses several sessions, and uses drugs,

then asks his counselor to have his methadone increased. In this

case, the therapist identifies the patient's denial as it appears in

the transference, in the relationship with his girlfriend and in his

drug use. The therapist works with the patient, aiming to diminish

65
the denial. If the therapist is successful, treatment should help

the patient address his problems more directly, and thus increase the

likelihood of finding better solutions to life problems than using

drugs.

Cognitive-behavioral Therapy. Cognitive-behavioral therapy is a

treatment that aims to identify and change false beliefs, unhealthy

moods and problematic behavior. It is a-treatment that has been -

developed by Dr. Aaron T.Beck and has been shown to be effective for

treating certain types of depression (1976). Dr. Beck and his

colleagues have found that depressed patients often have false and

negative beliefs such as seeing themselves as helpless or worthless

and that these beliefs can have a profound influence on mood.

Reversing these false beliefs can significantly improve mood. For

example, a person is withdrawn, depressed and feels that he is

worthless and cannot succeed at anything. A CB therapist, having

identified these false beliefs, attacks them actively and directly,

aiming to show the patient how and why they are untrue. If the

therapist succeeds in reversing them, the patient's mood brightens

and the associated social withdrawal decreases. During CB therapy,

the patient may be required to do "homework" such as recording daily

activities and thoughts or deliberately altering certain behaviors.

Some false beliefs commonly seen in narcotic addicts are, "I'm a

Junkie, I'll never get better," or "I can't possibly feel good

without drugs." The CB Therapist identifies these beliefs and works

actively with the addict to change them.

Initiating Treatment

After being randomly assigned to one of these three treatment

conditions, the patient is given a brief explanation of the kind of

treatment he will receive. The importance of keeping regular appointments is emphasized at this time. All patients are then required to

have at least three meetings with their counselor and their therapist

(if they are assigned a therapist) within the first 4 weeks. These

mandatory sessions are required to make sure that all patients have

an opportunity to gain some familiarity with the treatment conditions.

After these three sessions are completed, patients are encouraged but

not required to keep appointments. Patients who do not complete the

initial sessions are not counted as part of the study, though data is

collected on their progress. Those patients who are assigned a

therapist have an opportunity to continue with that person for 6

months.

DATA ANALYSIS

To examine our hypotheses, we examined data on the first 62 patients

to complete therapy and divided them into four groups based on ratings

of psychiatric symptoms that were obtained at intake, and upon their

treatment assignment. The measures used to make these subdivisions

were the Beck Depression Inventory, the Maudsley Neuroticism Scale,

and the psychological scale of the Addiction Severity Index. The

Addiction Severity Index is a structured 20-30 minute, clinical

research interview designed to assess problem severity in six areas

66
commonly affected by addiction These problem areas include:

medical, legal, substance abuse, employment, family and psychological

status. In each of the problem areas, Objective data on the number,

extent and duration of problem symptoms in the patient's lifetime is

collected, along with the recent (prior 30 days) subjective report of

the severity and importance of the treatment problem from his

perspective. The interviewer assimilates the two types of information

to produce a rating (O-9) of the SubJect's need for treatment. These

10-point ratings have been shown to provide reliable and valid

general estimates of problem severity for both alcoholics and drug

addicts (McLellan et al. 1980).

We felt that these pre-treatment measures provided a valid estimate

of general psychological status and on this basis we selected two

extreme groups: those showing high levels of symptoms and clear, if

presumptive, evidence of psychological problems (N=21), and those

showing low levels of psychiatric symptoms (N=21) A total of 42

patients were included in these four groups, leaving 20 patients who

were in the midrange and who were not included. We selected only the

extremes since we felt that this method would give us the best chance

to test our hypotheses.

We then subdivided these groups on the basis of their treatment

assignment into high severity counseling (N=lO), high severity

therapy (N=ll), low severity counseling (N=ll), and low severity

therapy (N=lO). No distinction was made between the two psychotherapy

groups because preliminary analyses showed no significant differences

in outcome between them. A summary of the psychological test results

for these four groups is presented in Table II. As seen, the groups

are distinctly different in terms of the amount of psychopathology.

The number of DSM III diagnoses (other than drug dependence) for

these groups is seen in Table III. About 76 percent (7 of 10; 9 of

11) patients in the high severity groups had a DSM III Axis I diagnosis while only about 28 percent (2 of 10; 4 of 11) of the low

severity patients were given DSM III diagnoses other than drug

dependence. Axis II diagnoses were equal between the groups and were

almost always antisocial personality disorder.

TABLE II

PSYCHOLOGICAL STATUS OF THE FOUR

GROUPS AT THE START OF THE SURVEY

HIGH-SEV LOW-SEV. HIGH-SEV. LOW-SEV.

COUNS. COUNS. THER. THER.

N 10 11 11 10

Beck 18 10 21

Maudsley-N 41 24 37 20

Shipley IQ 100 102 96 104

Shipley CQ 80 87 80 94

ASI Psych. Sev. 5.1 2.7 5.6 2.3

67
TABLE III

DSM III DIAGNOSES

HIGH SEV-COUNS. LOW SEV.-COUNS. HIGH SEV.-THER. LOW SEV.-THER.

# Patients w/Axis I 7/10 2/10 7/11 4/11

Diagnosis

Bipolar Affective Bipolar Affective Bipolar Affective Bipolar Affective

EXAMPLES General Anxiety Single Depressive Chronic Depreseive Manic Disorder

Chronic Affective General Anxiety General Anxiety

# Patients w/Axie II

Diagnosis 7/10 9/11 7/11

Ave. Axie IV 4

(Strees Severity)

5/10

3 4 1

Ave. Axis V 4

(Highest Function)

4 4 2
Pre-to Post-treatment Improvement

We examined pre-to post-therapy improvement for patients in each

group using the ASI. The ASI severity scores and other related items

are presented in Table IV. As seen, the high severity counseling

group shows improvement only in areas clearly related to drug use.

One might expect this since the patients were on methadone. The low

severity counseling group demonstrated significant improvement in

several areas, indicating the counselors are having a distinctly

greater impact on this group than on the high severity patients.

Conversely, the high severity therapy group demonstrated significant

improvement in several areas, equal to that seen in the low severity

counseling group. The low severity therapy group is also making

considerable improvement, perhaps of greater magnitude than the low

severity counseling group.

TABLE IV

PRE TO POST THERAPY (7-MONTHS) IMPROVEMENT

N

Medical Sev.

Days Med. Probs.

Employment Sev.

Days worked

Money earned

Abuse Sev.

Days drunk

Days opiate

Days non opiate

Money for drugs

Legal Sev.

Days crime

Illegal income

Psychological Sev.

Days psych. prob.

* = PC.01

+ = PC.05

HIGH-SEV.

COUNS.

10

3.1 2.4

4 2

4.5 4.6

9 1

272 306

5.7 + 3.8

4 2

6 3

10 8

430 * 190

3.1 3.0

6 3

216 181

5.1 4.8

17 13

During Treatment Results

LOW-SEV. HIGH-SEV. LOW-SEV.

COUNS. THER. THER.

11 11 10

1.7. 3.2 2.5 3.5 1.8 0.7

2 4 3 3 1 1

5.1 + 3.2

10 13

242 + 380

3.8 * 1.4

2 1

10* 2

4 2

164 * 47

4.5 + 3.1

10+ 4

506 + 300

2.7 1.8 5.6 + 3.0 2.5 + 1.0

8 3 15+ 8 4 +1

3.8 3.0 3.9 + 2.7

7 10 9 13

309 + 482 318 * 523

4.9 + 3.0

3 2

2

:+3

344 * 65

4.0 * 1.4

2

+ 03

38 1

188* 8

2.8 + 0.7 2.0 + 0.8

5 +0.8 1 0.4

186 * 43 166 * 10

The mean methadone doses for each group are seen in figure 2. There

was a significantly (p <.01) higher mean methadone dose for the high

severity counseling than for any of the other three groups. The low

severity therapy group received a significantly (p <.05) lower dose

than any of the other three groups, and the high severity therapy and

69
low severity counseling groups received comparable intermediate

dosages. The mean dosage of the high severity counseling group IS

significantly greater than the other groups in both a statistical and

clinical sense. In addition to methadone we often prescribe

ancillary psychotropic medications for temporary symptomatic

complaints of depression, anxiety or insomnia. These medications

include doxepin, oxazepam, flurazepam or chloral hydrate. The

percentage of subjects who were prescribed ancillary psychotropic

medication is seen in figure 3, and the data show a pattern identical

to the methadone doses. We feel these data indicate fewer symptoms

and a corresponding reduction in need for medication among both

groups of therapy patients and also among the low severity counseling

patients. Urine drug screening results are seen in figure 4. The

high severity counseling group has significantly (p <.05) more

"dirty" urines than either of the other three groups, who have about

the same frequency of positive urines. Nonprescribed benzodiazepines

were counted as a positive urine in this category which may mask

slight differences between groups because one dose of a benzodiazepine

can be detected in the urine for 3-5 days.

COMMENT

These data tend to confirm our hypotheses. Patients with high levels

of psychiatric symptoms use more drugs (both prescribed and illicit)

than patients with low levels of symptoms. This finding is especially

clear in Figures 2,3, and 4, where high severity therapy patients have

higher methadone doses, use more ancillary medications and have more

drugs in their urine than low severity therapy patients. These same

relationships are seen in the high and low severity counseling groups.

Similarly, the psychotherapy patients appear to be doing better than

patients receiving only counseling. This is particularly evident

when we examine the high severity groups. In these very difficult

patients, the counselors seem to be having little impact, whereas the

therapists are having an impact in several areas, including the ASI

rating of psychological severity.

In terms of behavioral pharmacology, psychiatric symptoms appear to

act as internal stimuli that set the stage for drug-taking behavior.

Thus, psychiatric symptoms appear to increase one's vulnerability to

self-administration of non-prescribed drugs.

We did not look at the relationships between specific symptoms and

specific drugs, such as the one which may exist between depression

and amphetamine use, or between anxiety and benzodiazepine use.

These and further analyses of the relationships between psychiatric

symptoms and drug self-administration appear to us to be areas that

should be explored with the hope of finding practical solutions to

the problem of drug addiction.

70
FIGURE 2

MEAN METHADONE DOSAGE BY GROUP

71
FIGURE 3

PATIENTS RECEIVING ANCILLARY MEDICATION BY GROUP

72
FIGURE 4

POSITIVE URINES BY GROUP

73
REFERENCES

Beck, A.T. Cognitive Therapy and Emotional Disorder. New York:

Int. Univ. Press, 1976.

Malan, D. A Study of Brief Psychotherapy. Phila.: J.P. Lippincott.

1963.

McLellan. A.T., Luborsky, L., Woody, G.E., O'Brien, C.P. An improved

diagnostic evaluation instrument for substance abuse patients: The

addiction severity index. J. Nerv. and Ment. DIS., 168 (1): 26-33,

1980

Sifneos, P. Short Term Psychotherapy and Emotional Crisis.

Cambridge: Harvard University Press, 1972.

Acknowledgements

This work was supported by NIDA Contract 271-81-3833.

Authors

George E. Woody, M.D., Drug Dependence Treatment Service, VA Medical

Center, Woodland and-University Avenues,

Philadelphia, PA 19104

A. Thomas McLellan, Ph.D., Drug Dependence Treatment Service,

VA Medical Center, Woodland and University

Avenues, Philadelphia, PA 19104

Charles P. O'Brien, M.D., Ph.D., Drug Dependence Treatment Service,

VA Medical Center,

Woodland and University Avenues,

Philadelphia, PA 19104

Lester Luborsky, Ph.D., Drug Dependence Treatment Service, VA Medical

Center, Woodland and University Avenues,

Philadelphia, PA 19104

74
History of Drug Exposure

as a Determinant of

Drug Self-Administration

Alice M. Young, Ph.D., Seymore Herling, Ph.D.,

and James H. Woods, Ph.D.

The purpose of this paper is to review how a drug’s effectiveness

in initiating and maintaining self-administration can be

influenced by a subject’s past experience with drugs. Drug self-

-administration by humans and laboratory animals is considered an

instance of operant behavior (e.g., Schuster and Thompson, 1969;

Goldberg, 1976), controlled by the subject’s genetic constitution,

past history, and the current circumstances of drug availability

(of Skinner, 1938). The influence of history of drug exposure on

current drug-maintained behavior may be controlled, in turn, by

the particular drugs and doses employed and the conditions under

which the drug is administered. This discussion will focus on the

ways in which a history of drug exposure can control later drug

self-administration in laboratory animals.

EFFECTS OF HISTORY OF DRUG EXPOSURE ON INITIATION OF DRUG

SELF-ADMINISTRATION

In order to study drug self-administration by laboratory animals,

an experimenter must set up a situation in which subjects are

exposed to some contingency between the occurrence of a specific

response and delivery of a particular drug. For many drugs, no

explicit behavioral or pharmacologioal history is necessary for

the drug to maintain behavior. In one initial study, for example,

Deneau et al. (1969) surgically prepared drug-naive rhesus monkeys

with Indwelling venous catheters and presented the monkeys with a

response lever. Presses on the lever delivered an intravenous

injection of a drug. If a monkey did not press the lever at all

during the experimental periods, a raisin or bit of candy was

taped to the lever so that the monkey would depress the lever when

grabbing for the food. Under these conditions, for the majority

of monkeys tested, lever pressing was Initiated and maintained by

Injection of appropriate doses of morphine, codeine, cocaine,

d-amphetamine, pentobarbital, or ethanol. On the other hand,

lever pressing was not maintained by injections of nalorphine,

chlorpromazine, mescaline, or saline. These initial results have

been amply replicated and extended to other drugs by numerous

75
investigators (see reviews by Pickens et al., 1978; Schuster and

Balster, 1973; Woods, 1978). Thus, for many drugs, a history of

drug exposure is not necessary for the drugs to function as

reinforcers. Exposure to the contingency between a specific

behavior and drug delivery is sufficient for the drugs to function

as reinforcers and maintain subsequent behavior.

While prior drug administration is not necessary for the

Initiation and maintenance of self-administration of many drugs,

it can hasten the development of asymptotic performance at a

particular drug dose and schedule parameter. For example, if a

monkey whose behavior has been maintained by intravenous injection

of codeine loses its catheter and does not self-administer the

drug for some period of time, replacement of the catheter is

quickly followed by a return to the previous response rates.

Additionally, exposure to schedule contingenoies for the delivery

of other drugs or other events such as food can increase rates of

behavior that may be initially low when maintained by a drug such

as ethanol. Winger and Woods (1973) reported that for certain

rhesus monkeys, intravenous delivery of ethanol under a FR 1

schedule maintained fen responses when available 24 hr per day.

When injections of cocaine or methohexital replaced the ethanol,

responding was initiated and maintained during 3 hr access

periods. When ethanol was then reintroduced, responding continued

at the higher levels. Moreover, the intake of ethanol for these

subjects under the 3 hr access conditions did not differ from that

for subjects that initiated ethanol self-administration without

exposure to cocaine or methohexital.

Under certain conditions, the availability of a drug is not

sufficient for it to function as a reinforcer. In a well-studied

example, behavior often is not readily maintained by the oral

delivery of drugs. However, a history of drug exposure that

ensures that an organism will readily ingest an effective dose of

a drug can increase the likelihood that certain drugs will serve

as oral reinforcers. A good example of this effect of history of

drug exposure is provided by the procedures developed by Meisch

and colleagues (see review by Meisch, 1977) to establish ethanol

as an oral reinforcer in rhesus monkeys. When ethanol is

presented to monkeys, they do not readily drink large quantities,

and, above small concentrations (5%), they may drink water to the

exclusion of ethanol (Mello, 1973). Under certain schedules of

food delivery (e.g., Falk, 1971), however, monkeys will

adjunctively drink large quantities of ethanol (Meisch et al.,

1975). After a history of adjunctive or schedule-induced drinking

of gradually increasing concentrations of ethanol, high concentrations of ethanol can maintain responding in the absence of the

original inducing schedule (Henningfield and Meisch, 1978).

Subsequent work (e.g., Carroll and Meisoh, 1978, 1980) has shown

that a variety of inducing schedules are also effective in

establishing drugs such as etonitazene and phencyolidine as oral

reinforcers in rhesus monkeys. These compounds do not maintain

behavior initially, but after gradually Increasing concentrations

have been consumed under an inducing procedure, each will maintain

76
behavior in the absence of the original Inducing condition. To

date, the particular history used to establish a drug as a

reinforcer has not been shown to control the later behavior

maintained by the drug. The behavior maintained by oral ethanol

after exposure to an inducing schedule, for example, varies as a

function of the current schedule conditions in the same nay as

does behavior maintained by the intravenously delivered drugs that

do not require prior exposure to inducing schedules to function as

reinforcers (Heisch, 1977).

IMPORTANCE OF PHYSIOLOGICAL DEPENDENCE

For those drugs that have been extensively studied, it appears

that prior physiological dependence is not necessary for a drug to

function as a reinforcer (e.g., Woods and Schuster, 1971). The

conditions under which such dependence is maintained, however, can

influence the later probability of drug self-administration. In

the case of physiological dependence on morphine, the likelihood

that a post-dependent subject will self-administer morphine is

controlled, in part, by the conditions under which the dependence

was maintained. Rats that have maintained their physiological

dependence on morphine by oral or intravenous self-administration

will self-administer more morphine following a withdrawal period

than will subjects that received the same maintenance doses of

morphine noncontingently (Nichols et al., 1956; Weeks and Collins,

1968).

Current physiological dependence can alter the likelihood that

certain drugs will serve as positive reinforcers. In particular,

narcotic dependence can alter the reinforcing properties of a

variety of narcotic mixed agonist-antagonists. While morphine-

-like agonists such as morphine, heroin, and the systemically

active met-enkephalin analogue FK 33-824 maintain behavior in both

nondependent and morphine-dependent rhesus monkeys (e.g.,

Hoffmeister, 1979; Mello and Mendelson, 1978; Roemer et al., 1977;

Thompson and Schuster, 19641, mixed agonist-antagonists such as

profadol, propiram, and pentazooine maintain behavior only in

nondependent monkeys (see review by Hoffmelster, 1979). A second

group of mixed agonist-antagonists, including nalorphine and

cyclazocine, and the narcotic antagonist naloxone generally do not

maintain responding by either nondependent or morphine-dependent

monkeys (Downs and Woods, 1976; Hoffmeister, 1979). Morphine

dependence can also alter the negative reinforcing properties of

the mixed agonist-antagonists and antagonists. The mixed

agonist-antagonist profadol maintains responses leading to the

termination or postponement of its injection in morphine-

-dependent monkeys, but not in nondependent monkeys. The mixed

agonist-antagonists nalorphine and cyclazocine and the antagonist

naloxone, on the other hand, maintain responding leading to

termination or postponement of their injection in both dependent

and nondependent monkeys (Downs and Woods, 1976; Hoffmelster,

1979). The doses of these drugs required to maintain such

behavior, however, are up to 1000 fold lower in dependent than in

nondependent monkeys.

77
The reinforcing properties of narcotic antagonists can be altered

dramatically under certain conditions (e.g., Downs and Woods,

1976; Goldberg et al., 1971b). As described above, the narcotic

antagonist naloxone will readily function as a negative

reinforcer, maintaining behavior leading to the postponement or

termination of its injection in both dependent and nondependent

monkeys (Downs and Woods, 1976). In morphine-dependent monkeys

with an appropriate behavioral history, however, the same naloxone

doses that maintain behavior leading to postponement or termination of their injection will also maintain behavior leading to

the presentation of an injection. Downs and Woods (1976)

conditioned morphine-dependent monkeys to terminate and/or

postpone injections of 2 microgram/kg naloxone. Characteristic

fixed-ratio performance was maintained by termination and

postponement of naloxone injections. Then, the schedule oontingencies were changed so that completion of each ratio produced a

brief light flash; completion of every fifth or tenth ratio

produced the light flash and an injection of naloxone. Behavior

was maintained by the injection of naloxone in these morphinedependent monkeys for as many as fifteen sessions. This apparently

disparate effect of a presumably noxious pharmacological stimulus

underlines the importance of the behavioral contingencies under

which a subject is exposed to a drug in determining the later

likelihood that the drug will maintain behavior leading to its

administration.

EFFECTS OF SELF-ADMINISTRATION HISTORY

A history of drug self-administration can influence the dose of a

drug that will subsequently maintain behavior. In general,

behavior is maintained by lower doses of drug in subjects with an

extensive self-administration history than in subjects with a more

limited history. For example, Goldberg (1973) showed that a low

cocaine injection dose (12 microgram/kg) initially failed to

maintain fixed-ratio responding in monkeys with a limited history

of cocaine-maintained behavior, but maintained high response rates

in the same subjects after a period during which responding was

maintained by higher cocaine doses. The actual response rates

maintained by certain doses of a drug can also be altered by a

history of drug-maintained behavior. For example, Downs and Woods

(1974) reported that the response rates maintained by injections

of low doses of cocaine (3 and 10 miorogram/kg) in rhesus monkeys

increased dramatically when these doses were retested after

exposure to other cocaine doses. Similarly, Carney et al. (1976)

showed that the response rates maintained by several doses of

ethanol increased when monkeys had a history of behavior

maintained by higher ethanol doses.

The rate and pattern of behavior maintained by one drug can also

influence both the initial pattern of intake of a substituted drug

and the dose of that drug that will maintain behavior. For

example, Schlichting et al. (1971) reported that when amphetamine

was substituted for cocaine, codeine, or pentobarbital under a

78
fixed-ratio schedule in rhesus monkeys, the pattern of behavior

initially maintained by amphetamine varied with the drug used to

engender responding. Initially, the spacing of amphetamine

injections was similar to that maintained by the maintenance drug.

Cocaine maintained responses at regular intervals throughout

experimental sessions, and all substituted amphetamine doses

(0.005 to 0.05 mg/kg) maintained response rates above those

maintained by saline, with responses spaced at regular intervals.

The maintenance drugs codeine and pentobarbital, on the other

hand, maintained frequent Injections at the beginning of the

session, followed by long pauses interspersed with bursts of

injections over the remainder of the session. When substituted

for these drugs, low amphetamine doses (0.005 and 0.01 mg/kg)

maintained patterns of responding similar to those maintained by

codeine or pentobarbital. When the high dose of amphetamine (0.05

mg/kg) was substituted for these drugs, however, several

injections were taken rapidly, followed by no responding until the

end of the experimental session. Thus, as a result of the pattern

of injections engendered by the maintenance drug, higher doses of

amphetamine maintained more behavior when substituted for cocaine

than when substituted for codeine or pentobarbital.

The drug used to maintain behavior in the monkey can also alter

the behavior maintained by substitutions of narcotic agonists and

mixed agonist-antagonists. Hoffmeister and Schlichting (1972)

reported that codeine, morphine, & propoxyphene, pentazocine, and

propiram will maintain behavior at lower doses when substituted

for codeine than when substituted for cocaine. In addition,

although the doses of each narcotic that maintained the maximal

number of Injections did not vary with the drug used to engender

responding, the maximally effective doses of all the narcotics

except morphine maintained more injections when substituted for

codeine than when substituted for cocaine. As was the case for

amphetamine, such differences in behavior may have resulted from

the different patterns of drug Injections engendered by the

maintenance drugs. Thus, under similar behavioral schedules, the

asymptotic pattern of drug intake can vary markedly among drugs

from different pharmacological classes. When behavior is

initially established with a particular drug, however, the pattern

of intake maintained by that drug can control the initial pattern

of intake of quite different drugs.

Under certain conditions, a monkey’s self-administration history

can alter not only the dose of a substituted drug that will

maintain responding and the initial pattern of such responding,

but also the likelihood that any dose of the new drug will

maintain behavior. For example, self-administration of the

antitussive dextrorphan is controlled, in part, by the subject’s

self-administration history. Dextrorphan does not maintain

behavior following one type of self-administration history, but

readily maintains behavior following certain other histories.

When dextrorphan is substituted for codeine under a FR 30 TO 10

min schedule of intravenous injection in rhesus monkeys, no dose

maintains response rates higher than those maintained by saline

79
(young et al., 1981). However, when dextrorphan is substituted

for codeine under a FR 1 schedule, it maintains response and

injection rates similar to those maintained by codeine. Figure 1

compares the behavior maintained by dextrorphan when substituted

for codeine under these two conditions. The upper panel shows the

response rates and injections per hour maintained under the FR 1

(or CRF) schedule by codeine (C), saline (S), and various doses of

dextrorphan. Dextrorphan injection doses of 0.32 and 0.56 mg/kg

maintained response rates similar to those maintained by 0.1 mg/kg

codeine. However, as shown by the closed circles in the lower

panel, the same doses of dextrorphan did not maintain responding

when substituted for 0.32 mg/kg codeine under a different

schedule, FR 30 TO 10 min.

These differences in the ability of dextrorphan to maintain

behavior when substituted for codeine may be due to several

factors. Dextrorphan may be relatively ineffective in maintaining

behavior at high ratio requirements (cf Goldberg et al., 1 197la) .

Alternatively, the monkeys’ behavioral histories may have

contributed to the differences in dextrorphan self-administration.

The monkeys performing under the FR 1 schedule continued to

respond for an average of 20 injections per session when saline

replaced codeine, while the monkeys performing under the FR 30 TO

10 min schedule rarely completed the ratio requirement to deliver

more than 4 or 5 injections. The maintenance of behavior under

the FR 1 contingenoies may have resulted in the monkeys’ selfadministering sufficient dextrorphan for it to acquire a

reinforcing function.

The importance of self-administration history in controlling the

ability of dextrorphan to maintain behavior under FR schedules was

given added weight by the results of an additional experiment

(Young et al., 1981). In this study, other monkeys self-administered the dissociative anesthetic ketamine under the FR 30 TO 10

min schedule of intravenous injection. During selected sessions,

various doses of dextrorphan were substituted for the ketamine

maintenance dose. As shown by the open circles in the lower panel

of Figure 1, dextrorphan readily maintained behavior when

substituted for ketamine under the FR 30 TO 10 min schedule.

Thus, under the FR 30 TO 10 min schedule, dextrorphan maintained

response rates higher than those maintained by saline when

substituted for ketamine but not when substituted for codeine.

Two other compounds, the dissociative anesthetic phenoyolidine and

the analgesic dexoxadrol, also maintained behavior under the FR 30

TO 10 min schedule when substituted for ketamine but did not

maintain behavior when substituted for codeine (Young et al.,

1981).

These differences in the ability of dextrorphan, dexoxadrol, and

phencyclldine to maintain behavior when substituted for ketamine

or for codeine may be controlled in part by the similarities in

the behavioral properties of these compounds and ketamine. These

drugs that maintained behavior only when substituted for ketamine

share discriminative stimulus effects with ketamine, but not with

80
Figure 1

MG/KG/INFUSION

DEXTRORPHAN

Behavior maintained by intravenous injection of various doses of

dextrorphan tartrate under different conditions. Upper panel:

Injections per hr and responses per s maintained by dextrorphan

under a CRF schedule when substituted for 0.1 mg/kg injections of

codeine (C) for 10 consecutive 1 hr sessions. Each point

represents the mean ± SEM for three monkeys. Lower panel:

Responses per s maintained by dextrorphan under a FR 30 TO 10 tin

schedule when substituted for 0.32 mg/kg codeine (C : closed

cirles) or 1.0 mg/kg ketamine (K: open circles) during single

experimental sessions. Each point represents the mean ± SEM for

two observations in each of three monkeys. In both panels, saline

substitutions are indicated at S.

81
codeine, in the rhesus monkey (Young et al., 1981; unpublished

observations). Common discriminative effects among ketamine,

phencyclidine, dextrorphan, and dexoxadrol have also been reported

in rats, pigeons, and squirrel monkeys (Brady and Balster, 1980;

Herling et al., 1981; Holtzman, 1980). Similarities among the

discriminative stimulus properties of ketamine and those of

phencyclidine, dexoxadrol, and dextrorphan may increase the

relnforcing effectiveness of the latter three compounds when

substituted for ketamine as compared to their effectiveness when

substituted for codeine.

The control of the reinforcing effectiveness of a substitution

drug by the maintenance drug Itself Is modulated by several

factors. The maintenance drug is not a primary determinant of the

ability of certain drugs to maintain behavior. For example,

codeine, cocaine, and ketamine each maintain behavior when

substituted for the other, while certain other drugs, such as

cyclazocine and SKF-10,047 (N-allyl-normetazocine), do not

maintain behavior when substituted for either codeine or ketamine

(e.g., Hoffmeister, 1979; Young and Woods, 1980; Young et al.,

1981). The duration of exposure to a substitution drug and the

prevailing schedule contingencies may also modulate the effects of

the original maintenance drug. For example, with repeated

exposure to phencyclidine or dextrorphan these compounds will

maintain behavior in monkeys whose behavior is initlally

maintained by codeine or cocaine (Figure 1; Balster et al., 1973;

Pickens et al., 1973). Furthermore, drug-naive monkeys will

initiate and continue responding leading to phencyolidine

lnjection under FR 1 schedules during repeated daily sessions

(Balster et al., 1978; Balster and Woolverton, 1980). Thus,

control of the self-administration of a new drug by a subject's

self-administration history varies with the particular drug under

study, the drug with which the subject is experienced, and the

behavioral conditions under which the new drug and the maintenance

drug are available.

EFFECTS OF PRIOR PAIRING BETWEEN ENVIRONMENTAL STIMULI AND

DRUG ADMINISTRATION ON SELF-ADMINISTRATION BEHAVIOR

The general environmental context in which prior drug administration has occurred can be an Important determinant of drug

self-administration. For example, environmental stimuli paired

with morphine self-administration can control the degree of

self-administration by subjects previously dependent on morphine.

If subjects self-administer sufficient morphine to develop

physiological dependence in one environment and are subsequently

withdrawn and then reexposed to morphine, the probability that

they will later self-administer morphine varies as a function of

the similarity of the environments in which the initial selfadministration and reacquisition occur (Thompson and Ostlund,

1965). Rats exposed to the same environment in which

self-administration originally occurred drink much more morphine

after withdrawal than do rats reexposed to morphine in a different

environment after withdrawal. Thus, the environmental stimuli

82
associated with previous narcotic self-administration can control

the likelihood that morphine self-administration will be

reestablished in post-dependent subjects.

Under appropriate circumstances, environmental stimuli paired with

the scheduled delivery of a drug can powerfully control the rate

and pattern of ongoing drug-reinforced behavior (see review by

Goldberg, 1976). Following exposure to certain behavioral

schedules, stimuli paired with the administration of drugs such as

cocaine and morphine can control behavior in the same way as do

injections of the drug themselves. Moreover, the environmental

stimuli associated with prior nonoontingent administration of one

drug can control the later self-administration of a second drug.

For example, under appropriate conditions, stimuli associated with

narcotic antagonists can produce conditioned changes in the rate

of morphine self-administration by morphine-dependent subjects. In

morphine-dependent monkeys, administration of the antagonist

nalorphine increases the rate of responding maintained by morphine

(e.g., Thompson and Schuster, 1964). With a history of repeated

exposure to nalorphine, these increases occur with a much shorter

latency and can be elicited by environmental stimuli paired with

nalorphine (Goldberg et al, 1969). Such conditioned stimuli can

produce large but transitory increases In morphine self-administration in morphine-dependent subjects. These conditioned stimuli

are also capable of eliciting certain of the signs of morphine

withdrawal, including emesis, salivation, changes in heart rate,

and disruption of the rate of food-maintained operants (Goldberg

and Schuster, 1967; 1970). These latter oonditioned stimulus

effects, in contrast to the effects on morphine self-administration, are remarkably resistant to extinction and persist after

monkeys have been withdrawn from morphine for two to four months.

A history of exposure to nalorphine can also control its potency

in altering rates of morphine self-administration. Goldberg et

al. (1971c) assessed the effects of nalorphine on the rate of

responding maintained by morphine injections in morphine-dependent

monkeys. In monkeys with a limited history of nalorphine

injections, high nalorphine doses (1 to 3 mg/kg) suppressed the

rate of morphine-maintained responding. In contrast, in monkeys

that had received ascending doses of nalorphine and so had several

sessions' experience with lower nalorphine doses, 1 and 3 mg/kg

nalorphine slightly increased the rate of morphine self-adminlstration. Likewise, in monkeys repeatedly exposed to 0.1 mg/kg

nalorphine injections, the first injection of 1 mg/kg nalorphine

increased the rate of morphine self-administration in two of four

monkeys. This increase was transitory, however; the second

injection of 1 mg/kg nalorphine did not Increase morphine

self-administration, and all succeeding 1 mg/kg nalorphine

Injections markedly suppressed morphine-maintained responding. It

is likely that, with repeated exposure to low doses of nalorphine,

interoceptive stimuli associated with the injection procedure

became conditioned stimuli for increases in morphine self-administration. The Initial effect of the higher nalorphine dose was

then a conditioned increase in responses maintained by morphine.

83
With repeated exposure to high nalorphine doses, this response

rapidly extinguished.

Recently, Herling (1981; unpublished observations) has presented

evidence that a history of exposure to the narcotic antagonist

naltrexone may also produce conditioned changes in the rate of

narcotic-maintained behavior in nondependent monkeys. In these

experiments, responding was maintained by codeine or food in

alternate components of a multiple reinforcement schedule. Low

doses of naltrexone antagonized the actions of codeine, increasing

the injection dose of codeine required to maintain behavior and

the cumulative dose necessary to decrease rates of food-maintained

behavior. Higher doses of naltrexone suppressed responding

maintained by all doses of codeine. In certain monkeys, some

doses of naltrexone initially increased the rates of behavior

maintained by codeine but suppressed behavior following repeated

exposure. This suppression of codeine-maintained behavior by

naltrexone was often greater than the effect produced by substituting saline in the session; i.e., extinction (Carney, 1976;

Herling, 1981; Woods and Schuster, 1971). Herling and others

(Harrigan and Downs, 1978; Woods et al., 1975) have suggested that

such decreases in narcotic-maintained behavior may reflect a

punishing effect of agonist-antagonist combinations, an effect

that may be exacerbated by a history of repeated exposure to such

combinations.

SUMMARY

Drug self-administration is controlled, in part, by the subject’s

history of drug exposure. Although a history of drug administration is not necessary for many drugs to function as reinforcers,

prior exposure can increase the likelihood that certain drugs,

such as ethanol, will maintain behavior. While it has been

demonstrated that physiological dependence is not necessary for a

drug to function as a reinforcer, the conditions under which such

dependence is maintained can control the later self-administration

of the drug. Once drug-maintained behaviors are established, the

particular drug that maintains behavior can influence the Initial

pattern of intake of a new drug and thus the dose of that drug

that will maintain behavior. Additionally, under certain

conditions, similarity between the discriminative stimulus effects

of the drug that previously maintained behavior and those of a new

drug can increase the likelihood that the new drug will function

as a reinforcer. Finally, stimuli that have been paired with drug

administration can powerfully control later drug-maintained

behavior, the direction of such control being determined by the

conditions under which such pairing occurred. In summary, both

the type of drug with which a subject has experience as well as

the contingencies governing that experience contribute to

subsequent drug self-administration.

84
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behavioral dependence on drugs. A Rev Pharmacol, 9:488-502,

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ACKNOWLEDGMENTS

The research data reported here and the preparation of this paper

were supported by National Institute on Drug Abuse Grants DA 00254

and DA 00154. We thank Dr. J.L. Katz for critical comments on the

manuscript and G. Renard and K.L. Watson for excellent technical

assistance.

88
AUTHORS

Alice M. Young, Ph.D.*

Seymore Herling, Ph.D..

James. H. Woods, Ph.D.

*Present Address:

Department of Psychology

767 Mackenzie Hall

Wayne State University

Detroit, MI 48202

Department of Pharmacology

M6322 Medical Science Building I

University of Michigan Medical School

Ann Arbor, Michigan 48109

**Present Address:

National Institute on Drug Abuse

Division of Research

Addiction Research Center

Lexington, KY 40583

89
Contributions of Reinforcement

Schedule Histories to Our

Understanding of Drug Effects in

Human Subjects

Harold Weiner, Ph.D.

ABSTRACT

Like other reinforcing stimuli, drug effects may vary with the

reinforcement history of an individual. Data are presented which

demonstrate that histories contribute to individual differences

in response to reinforcement contingencies and modification of

maladaptive behavioral persistence. Possible relevance of these

findings to an understanding of drug effects in humans is

discussed.

INTRODUCTION

Drug-seeking is a form of operant behavior under the control of

schedules of reinforcement (Schuster and Thompson, 1969;

Kelleher, Goldberg, and Krasnegor, 1976). Usually, the

schedules are complex, involving chains of behavior under the

control of discriminative stimuli and conditioned reinforcers

unique to a particular drug-related environment. The precise

nature of behavior related to drugs is determined by a number of

antecedent factors as they interact with current environmental

circumstances.

Antecedent factors may contribute to the development of a drug as

a reinforcer, may determine the rate and form of drug-controlled

performances, and may account for idiosyncratic and sometimes

paradoxical drug effects (Griffiths, Bigelow, and Henningfield,

in press). Among the more prepotent antecedent variables found

to affect drug-related behaviors are prior exposure to the drug

in question or related types of drugs (McMlllan, Harris,

Frankenheirn, and Kennedy, 1970; McMillan, Dewey, and Harris,

1971); conditioned effects produced by past pairings of stimuli

or activities with drug administrations (Pickens and Crowder,

1967; Goldberg, Woods, and Schuster, 1969); the state of drug

deprivation (Woods, Downs, and Villarreal, 1973) and its

interaction with the amount of previous reinforcement (Surgh and

Manocha, 1966); and the nature of the acquisition of the

performances under investigation (Terrace, 1963).

One of the more important current environmental variables

affecting drug-seeking behavior is the formally defined

90
reinforcement contingencies. Another factor is the likelihood

that drug-maintained performance will be punished (Thompson,

Pickens, and griffiths, 1973).

The behavior maintained by a given drug reinforcer is determined

by a dynamic interplay between current schedules of drug

reinforcement and performances brought to the current situation

as a result of reinforcement schedule histories. Features of

performance which we often portray as arising from personality or

other dispositional states can be characterized as the product of

the interaction between reinforcement schedule histories and

contingencies in the current environment. Thus, some people are

"perseverant" and others are "impetuous," referring to the degree

of schedule-controlled persistence. Individual differences in

such features, though seemingly bewildering, may actually be

subject to analvsis if we begin to look at historical variables

in a more systematic way.

Although the effects of prior experience have always been

regarded as important in a number of fields of psychology, in the

early period of the growth of operant conditioning there was a

strong emphasis on the power of current schedule contingencies to

control behavior. There was a tendency to ignore prior

experience. Indeed, it was common practice to use the same

subjects, particularly pigeons, repeatedly from one experiment to

the next, because it was assumed that the effects of the earlier

histories were erased by the powerful current conditions.

However, we find that a satisfactory account of operant behavior

in all but the simplest and most powerfully controlled schedule

conditions requires taking Into account both histories and

current conditions.

This is particularly true when one works with human subjects in

operant research. A major problem encountered in the laboratory

with humans under Schedules of reinforcement is inter-subject

variability. Experimental situations may look strange to humans

at first, but are not unfamiliar to them as categories of

experience. Generalization from other situations (e.g., problem

solving in work or school) is more likely with humans than with

infrahuman (animal) subjects. This is especially true Of the

task component of the situation. Inter-subject variability

commonly exhibited by humans in free operant experiments is

largely due to the variety of their behavioral histories.

Inter-subject variability implies lack of control by the current

schedule of reinforcement. When the behavior of an individual is

so inappropriate to its current schedule conditions that the

person loses reinforcement or Buffers unnecessary punishment, we

sometimes label the behavior as pathological or maladaptive.

This is true both in "real life" and in the laboratory (Weiner,

1965). The label remains even when we can attribute the behavior

to persisting effects of earlier conditions which are no longer

appropriate for current reinforcement requirements.

91
In most non-laboratory settings, we are not able directly to

observe, manipulate, and systematically analyze the effects of

histories on human operant behaviors such as drug-seeking. Like

clinicians concerned with psychopathology, we often have to infer

the nature of these histories from the individual's current

verbal, motor, and/or physiological responses.

The experimentalist in an operant laboratory is in a somewhat

better position. While acknowledging the simplicity of the

laboratory situation, the relatively short temporal duration of a

laboratory experiment, and the open question concerning the

relation between experimentally induced behavior and behavior in

more natural contexts, the investigator can, nevertheless,

deliberately program and manipulate a variety of historical

experiences and svstematically examine the effects of such

experiences upon the subsequent development and maintenance of

operant behavior (Sidman, 1960, p. 300).

For a number of years, I have been conducting research with

humans on the effects of reinforcement histories in conjunction

with a number of other procedures (e.g., response cost,

biofeedback) in individual and social operant contexts, with both

normal and psychiatric subject populations (e.g., Weiner, 1969,

1970a, 1970b, 1977, 1981). In this paper, I will present

samples from this research and its implications for understanding

drug effects in humans. These examples involved normal adult

humans and employed conditioned reinforcers. The findings which

have emerged have been replicated with a wide variety of

reinforcers and have also been replicated in drug studies with

animals (Urbain, Poling, Millam, and Thompson, 1978). Their

relevance to human drug-seeking is further suggested by

considerable research which has demonstrated that drug

reinforcers regulate operant performances of animals in ways

similar to other reinforcers (Johanson, 1978) and that

drug-maintained behavior in animals bears striking resemblance to

drug-seeking in humans (Criffiths, Bigelow, and Henningfield, in

press).

92
RESEARCH FINDINGS

Figure 1. Subject and experimental apparatus.

Consider the following experimental situation depicted in Figure

1 . A normal adult human sits in front of a console and is

Instructed to either press or not press a key in order to

maximize his/her point score on a counter. Various schedules of

reinforcement (100-point additions to the counter score) are

programmed, each for 10 one-hour sessions. The subject is told

nothing about the purpose of the experiment, the nature of the

point reinforcement schedules, or at what rate to press the key.

Rates and patterns of responding under the different point

reinforcement schedules are recorded continuously over time using

standard cumulative recorders.

Early operant research with humans in this experimental context

produced surprising results in my own laboratory and in others.

Our data showed that all schedules were not equal in terms of

producing orderly and predictable performances from humans

without resorting to special procedures not required with animal

subjects. Good control with humans was obtained using schedules

which one might refer to colloquially as “authoritarian.” These

schedules reduced behavioral degrees of freedom by making

reinforcement frequency directly contingent upon particular rates

and patterns of responding. Two examples of authoritarian

schedules are fixed-ratio (FR) and differential-reinforcement-oflow-rates (DRL) schedules. FR schedules provide reinforcement

whenever a fixed number of responses is emitted, while DRL

schedules provide reinforcement only when two successive

responses are spaced by a minimum period of time.

93
Figure 2. Final FR 40 and DRL 20-sec performances. Vertical

marks on the records indicate the occurrence of

100-point reinforcements.

Figure 2 shows cumulative records of final performances obtained

from human subjects under a 40 response fixed-ratio (FR 40)

schedule and under a 20-second differential-reinforcement-oflow-rates (DRL 20-set) schedule. High constant rates of

responding are typically emitted under FR 40. Low rates of

temporally spaced responding commonly occur under a DRL 20-set

schedule. Human performances under FR 40 and DRL 20-sec schedules

resemble those obtained from animals under these schedules.

Rates and patterns of human responding under FR 40 and DRL 20-sec

schedules tend to show minimal individual differences. This is

because reinforcement rate under these schedules is contingent

upon a narrow band of response rates and patterns. Any deviation

from this narrow band would produce adverse reinforcement

consequences, i.e., loss of opportunities for reinforcement.

Other schedules, more "democratic" in nature, permit individuals

to "do their own thing" and still get reinforced. Inter-subject

variability (poor schedule control) tends to increase and human

94
performances deviate from those of animals under democratic

schedules, where a variety of response rates and patterns can

result in the same rate of reinforcement. A fixed-interval (FI)

schedule is a democratic schedule which provides reinforcement

for a single response if sufficient time has passed from a

previous reinforcement. Unlike DRL, an FI schedule does not

require a minimum interresponse time for reinforcement.

Responses emitted before enough time has elapsed from a previous

FI reinforcement do not affect the frequency of reinforcement

(i.e., they are unnecessary). Under an FI schedule, humans tend

to exhibit a variety of rates and patterns of responding. High

rates of unnecessary responding are not uncommon under an FI

schedule with humans whereas low rates of positively accelerating

responding (i.e., scalloping) are comnonly obtained from animals

under FI schedules.

Figure 3. Final FI 10-sec to FI 10-sec cost to FI 10-sec

performances. Other details as in Figure 2.

The cumulative records on the left side of Figure 3 show typical

stable FI 10-sec performances obtained from humans. Under an FI

10-sec schedule, reinforcement depends upon a single response

after at least 10 sec have elapsed from a previous reinforcement.

All other responses are unnecessary.

Two general types of FI 10-sec responding can be distinguished:

high and relatively constant response rates without

post-reinforcement pauses (hereafter referred to as high-rate

responding) and lower response rates with post-reinforcement

pauses (hereafter referred to as low-rate responding). From an

95
efficiency point of view, low-rate FI 10-sec responding is, of

course, more desirable because it consists of fewer unnecessary

responses between reinforcements. It is also more desirable for

inter-species comparisons because a wide variety of animals tend

to produce low-rate responding under an FI 10-sec schedule.

Much of my research and that of others in the human operant

laboratory has been directed toward identifying and manipulating

conditions that could suppress high-rate FI resoonding to reduce

inter-subject variability and produce human performances in

concert with those obtained from animals. Studies have shown

that high-rate FI responding can be suppressed by increasing the

effort required to emit a response, by providing schedule

information, by adding discriminative stimuli of a temporal

nature, and by disrupting responding either by introducing an

incompatible response or by adding punishment contingencies (cf.,

Weiner, 1969; Matthews, Shimoff, Catania, and Sagvolden, 1977).

My own research focused upon schedule conditions which might

contribute to high-rate FI responding. Initially, I attempted to

reduce high-rate FI 10-sec responding by introducing a type of

punishment procedure called response cost. This procedure

consisted of the subtraction of one point from the score on the

reinforcement counter for each response between reinforcements.

As can be seen from the data in the middle of Figure 3, cost

suppressed the unnecessary FI 10-sec responding of most of the

subjects. The degree of responding following the removal of cost

(relapse) varied as a function of the amount of low-rate

responding under FI 10-sec prior to the introduction of cost.

Cost punishment had no effect on one of the subjects. He

maintained similar high-rate responding under FI 10-sec and FI

10-sec cost. Under the latter, his high-rate responding produced

unnecessary (avoidable) punishment because reinforcement was

possible without cost.

Thus, although cost produced more low-rate FI 10-sec

performances, it did not entirely remove inter-subject

variability. Since the two patterns of FI 10-sec responding

produced by humans bore some resemblance to responding under FR

and DRL schedules, I wondered whether histories under these

schedules could account for the different FI 10-sec and FI 10-sec

cost performances shown in Figure 3. If this was the case, I

could control individual differences In FI 10-sec performances

and produce systematic effects by arranging various FR and DRL

reinforcement histories.

96
Figure 4. Final performances obtained under FR 40 to FI 10-sec

to FI 10-sec cost; DRL 20-sec to FI 10-sec to FI

10-sec cost; DRL 20-sec to FR 40 to FI 10-sec to FI

10-sec cost; and FR 40 to DRL 20-sec to FI 10-sec to

FI 10-sec cost. Other details as in Figure 2.

The effects of FR 40 and DRL 20-sec histories upon FI 10-sec

performances are summarized in Figure 4. Final FI 10-sec and FI

10-sec cost responding of four groups of subjects with different

reinforcement schedule histories is presented. One group had an

FR 40 history, another group had a DRL 20-sec history, a third

group had a DRL 20-sec to FR 40 history sequence, and a fourth

group had an FR 40 to DRL 20-sec history sequence. It can be

seen that subjects with an FR 40 history emitted high-rate

responding under FI 10-sec with and without cost. Subjects with

a DRL 20-sec history produced low-rate responding under FI 10-sec

and FI 10-sec cost. Subjects with both histories, i.e., either a

DRL 20-sec to FR 40 or FR 40 to DRL 20-sec history sequence,

emitted either high-rate or low-rate responding (mostly low-rate

responding) under FI 10-sec without cost. When cost was

Introduced under FI 10-sec, all of these history subjects

produced low-rate responding. In other words, cost consistently

suppressed responding whenever subjects had a DRL 20-sec history,

i.e., there was an interactive effect between cost and

reinforcement schedule histories.

97
It should be noted that FR 40 and DRL 20-sec responding persisted

under FI 10-sec, whereas FR 40 responding did not persist under

DRL 20-sec or vice-versa. Under FI 10-sec, high-rate or low-rate

responding can persist without adversely affecting reinforcement

frequency. High-rate FR 40 responding cannot persist under DRL

20-sec nor can low-rate DRL 20-sec responding persist under FR 40

without reducing the frequency of reinforcement.

It should also be noted that ongoing behavior immediately prior

to FI was not always predictive of FI performances. Thus,

different FI 10-sec and FI 10-sec cost performances were obtained

from the FR 40 history and DRL 20-sec to FR 40 history subjects

even though their FR 40 responding just prior to FI 10-sec was

similar. These FI performances were affected by the presence or

absence of a DRL 20-sec history which occurred prior to FR 40 and

which was not reflected in the rates and patterns of final FR 40

responding.

The persistence of FR responding (without a DRL history) under FI

and FI cost has been subjected to considerable experimental

analyses (Weiner, 1969, 1970a, 1970b). Two important

findings should be mentioned. First, in moving from FR to FI,

subjects may occasionally emit low-rate responding. Despite

differential reinforcement for such low-rate responding, subjects

who only have an FR history do not produce low-rate FI

performances. Said another way, unless histories have

established needed repertoires (e.g., DRL), merely making contact

with differential current contingencies of reinforcement may not

be sufficient to produce adaptive changes in behavior.

A second finding of importance is that high-rate FI performances

are obtained even when FR responding is extinguished prior to FI.

History effects cannot be removed by simply extinquishing

behavior. Said another way, organisms whose behavior has been

extinguished are not necessarily organisms who have been returned

to their pre-history state.

The data in Figure 4 provide information on the etiology and

prevention of maladaptive excessive responding, i.e., they show

how one can produce it or prevent its occurrence by arranging

reinforcement schedule histories. Can we treat such behavior

successfully after it has occurred? The answer is yes. The

method of treatment is the same as the method of prevention shown

in Figure 4, i.e., it requires providing subjects with a

repertoire of DRL responding.

98
Figure 5. Final performances obtained under the following

sequence of schedules: FR 40 to FI 10-sec cost to

DRL 10-sec cost to FI 10-sec cost to FR 40 to FI

10-sec. Other details as in Figure 2.

Figure 5 presents the data of two FR 40 history subjects who

persisted in their high-rate responding under FI 10-sec cost.

This persistence represents not just response induction but

contingency induction as well. These FR 40 history subjects were

responding under FI 10-sec cost "as if" an FR contingency was in

effect. If an FR schedule was in effect, high constant rates

would have been produced despite cost, unless the cost was equal

to or greater than the reinforcement, whereupon responding would

have ceased (Weiner, 1964). Rates of responding under FI 10-sec

cost were such that the cost of responding was less than the

reinforcement.

The FR 40 history subjects were therefore acting appropriately

under FI 10-sec cost in terms of their history but not in terms

of the reality of current contingencies. Given that they were

under FR rather than FI control, increasing cost punishment would

not have been a successful treatment because it would have

produced response cessation rather than low-rate FI 10-sec cost

responding. What these high-rate FI 10-sec cost responders

needed was not more punishment, but a new behavioral repertoire

(i.e., DRL responding) in order to produce low-rate FI 10-sec

cost responding.

As you can see from Figure 5, whereas high-rate responding

persisted under FI 10-sec cost, low-rate responding was produced

99
under DRL 10-sec cost. As mentioned previously, under FI 10-sec

cost, these FR 40 history subjects could maintain high-rate

responding and still obtain a net gain of reinforcement. A net

gain was possible because they were emitting less than 100

responses between reinforcements. Reinforcement was 100 points

while cost was only one point per response. Under DRL 10-sec

cost, however, high-rate responding following FR 40 produced

reinforcement loss rather than net gains of reinforcement because

the DRL reinforcements were contingent upon low-rate responding.

As a result, high-rate responding changed to low-rate responding

under DRL 10-sec cost.

After acquiring a history of DRL 10-sec cost responding, low-rate

responding was produced under FI 10-sec cost. This was true even

after reconditioning under FR 40. It may be said, therefore,

that high-rate FI cost responding can be treated successfully by

making all net gains of reinforcement contingent upon its

cessation, thereby enabling the acquisition of a DRL repertoire.

Exposure to the original condition responsible for the high-rate

FI cost responding will not produce relapse when individuals are

armed with this repertoire.

FINAL COMMENTS

The data presented in this paper have shown that individuals may

differ in their operant behavior under a schedule of conditioned

reinforcement (e.g., FI 10-sec) and that such inter-subject

differences may result from their reinforcement histories. In

addition, it was shown that history-related differences in

response rates and patterns may persist despite extended exposure

to new contingencies and despite the fact that such persistence

is maladaptive, i.e., produces avoidable punishment or net loss

of reinforcement.

To the extent that point reinforcers and drug reinforcers have

similar properties, these findings have significant implications

for analyses of drug effects with humans. Different, persistent,

and sometimes maladaptive drug-seeking behaviors by two or more

individuals, though the current environmental conditions appear

identical, may be related to distinctively different

reinforcement histories.

Support for the notion that drugs may have different effects as a

function of different reinforcement histories has been obtained

from laboratory research with animals. Barrett (1977) found that

the effects of d-amphetamine on punished and unpunished

responding differed, depending on whether the animals had a prior

history of Sidman avoidance. Animals with avoidance histories

showed rate increases with d-amphetamine, while animals without

the avoidance histories showed rate decrements during punishment.

Urbain, Poling, Millam, and Thompson (1978) replicated some of

the human data presented in this paper with rats. Further, they

investigated the effects of d-amphetamine upon terminal FI

lever-pressing. Rats with a history of DRL showed dose-dependent

rate increases when administered d-amphetamine, whereas rats

100
having FR reinforcement histories exhibited rate decreases

following d-amphetamine administration. Such sensitivity to

reinforcement history-drug manipulations suggests that analyses

of reinforcement history factors in drug-maintained performances

may be fruitful.

In the present study, cost punishment was shown to be effective

in reducing point-maintained FI responding for subjects with

certain reinforcement histories. The use of punishment

procedures to regulate drug-maintained responding has not been

explored extensively, but our data suggest that, under certain

conditions, punishment may be effective in this regard. Research

with animals using ethanol and cocaine as reinforcers and with

human alcoholics using ethanol as the reinforcer has demonstrated

that drug-related performances can be controlled by a variety of

punishment procedures . Well-established principles and effects

of punishment, generally similar to those reported for cost

punishment in this paper, were obtained in these studies

(Griffiths, Bigelow, and Henningfield, in press).

I have presented a set of laboratory methods for systematic

evaluation of history effects with human subjects and have tried

to demonstrate that histories can be manipulated to provide a

wide variety of rates and patterns of responding with a high

degree of reliability. Such experimental control might be

important for the behavior pharmacologist in attempts to pinpoint

the behavioral mechanisms of drug effects.

I have also attempted to show that histories can be manipulated

to enable the experimental production of persistent human

behavior which is costly to the individual. In this respect,

this work could provide models of addictive behavior. It could

be carried out in conjunction with other types of experimental

analyses in which addicted humans are brought into the laboratory

and studied when access to their addictive substance is

controlled.

Finally, my data suggest that histories can be introduced in the

laboratory and studied in terms of their effects upon maladaptive

human operant behavior, either in terms of precluding its

occurrence or of modifying it after it has occurred. This

suggests the possibility that the operant laboratory may be able

to provide Interesting analogs to the prevention and treatment of

undesirable drug-related operant behaviors.

Assuming that the findings I have presented pertain to drug

reinforcement as well as point reinforcement, a number of

tentative hypotheses may be offered:

First, it may be suggested that drug effects with humans depend

upon reinforcement schedule histories as they interact with

current contingencies of reinforcement;

101
Second, histories may make two or more individuals behave

differently in relation to drugs even when current contingencies

of reinforcement are the same for each individual;

Third, consistent drug effects may be produced by controlling the

reinforcement schedule histories of individuals;

Fourth, histories may induce the persistence of undesirable human

behavior which is unaffected by conditions of drug reinforcement;

Fifth, this persistence may be prevented and/or modified

(treated) without relapse by arranging reinforcement schedule

histories which enable an individual to acquire behavioral

repertoires critically needed for change when drug reinforcers

are introduced.

It seems clear that powerful laboratory procedures now exist to

test these hypotheses. Hopefully, such testing will occur.

There is a critical need for more research on the contribution of

historical influences to drug effects in humans (Griffiths,

Bigelow, and Henningfield, in press).

ACKNOWLEDGMENT

The author would like to give acknowledgement to Drs. Travis

Thompson and Peter Levison for their considerable aid and

many suggestions with regard to relating his research to the

field of human drug dependence.

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behavioral dependence of drugs. Annual Review of Pharmacology,

9, 483-502, 1969.

Sidman, M. Tactics of Scientific Research. New York: Basic

Books, 1960.

Surgh, S.D., and Manocha, S.N. The interaction of drug effects

with drive level and habit strength. Psychopharmacologia, 9,

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Effects of chlorpromazine and imipramine. Science, 140, 318-310,

1963.

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variables influencing drug self-administration by animals:

Implications for controlling human drug use. In L. Goldberg and

F. Hoffmeister (Eds.) Psychic Dependence: Bayer Symposium IV.

Berlin: Springer-Verlag, 1973.

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Weiner, H. History-related effects upon human escape responding:

Are induction or extinction processes involved? Psychonomic

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AUTHOR

Harold Weiner, Ph.D.

National Institute of Mental Health

Alcohol, Drug Abuse, and Mental Health Administration

Saint Elizabeths Hospital

Washington, D.C. 20032

104
Stimulus Control and Drug

Dependence

Classically Conditioned

Phenomena in Human

Opiate Addiction

Charles P. O’Brien, M.D., Ph.D., Joseph W. Ternes, Ph.D.,

John Grabowski, Ph.D., and Ronald Ehrman

INTRODUCTION

Classical and operant conditioning factors are both potentially significant in the maintenance of opiate use. Analysis from the perspective of the operant conditioning paradigm emphasizes the importance of discriminative stimulus control and the efficacy of opiates

as reinforcers (e.g., Griffiths, Bigelow, and Henningfield 1980).

In the context of the classical conditioning paradigm, emphasis is

placed on environmental correlates of drug effects and withdrawal

symptoms as elicitors of overt behavioral and physiological

responses. Concurrently it must be recognized that a model based on

integration of both paradigms probably reflects most accurately the

reality of human opiate dependence (Grabowski and O'Brien 1981).

In the context of either the operant or classical conditioning

paradigms, seemingly contradictory and diverse effects of stimuli

and events may be identified. However, careful analysis leads to

the conclusion that systematic results prevail and that findings

parallel those involving other behaviors and reinforcers. As has

been discussed in a recent review (Grabowski and O'Brien 1981), the

primary problems appear to arise in delineating the phase of opiate

action (e.g., onset, termination, withdrawal) with which stimulus

events are associated. A secondary problem arises in differentiating patterns of use and determining presence or absence of dependence and the withdrawal syndrome. That is, certain behavioral

features, development of conditioned correlates, and hence the

nature of explanatory concepts are related to certain aspects of

drug effects or sequelae.

Two major categories of events are associated with chronic administration of opiates. One is drug onset, with its diverse physiological effects. The second is characterized by the myriad physiological and behavioral responses in the physically dependent

organism following termination of a regimen of opiate administration.

The first major category was the object of early investigations of

conditioning phenomena in relation to drug effects. These involved

the classical conditioning paradigm and focused on conditioned

107
responses correlated with the drug effects. A neutral stimulus was

presented in temporal contiguity with an injection of morphine.

After repeated pairings the formerly neutral stimulus became clearly

established as a conditioned stimulus (CS) as indicated by physiological or behavioral changes elicited when it was presented without

the morphine injection. This response or group of responses, termed

the conditioned response (CR), typically reflected, but was not

necessarily identical to, the unconditioned effects of morphine.

The seminal work of Pavlov entailed analysis of this aspect of

conditioning in relation to drug effects. Much of the operant selfadministration research likewise involves examination of aspects of

conditioning in relation to drug onset effects.

The second major category of experiments entails analysis of two

aspects of phenomena generally associated with physical dependence.

One class of experiments involves analysis of conditioned stimuli

established in relation to the opiate withdrawal syndrome which

reliably emerges at some point following administration of the last

opiate dose in the physically dependent Subject. In these experiments the environmental stimulus previously paired with either

antagonist- or metabolism-induced withdrawal symptoms elicits

similar symptoms. That is, the conditioned response resembles the

unconditioned responses of the abstinence syndrome. In a second

class of experiments for which the observed response is similar to

withdrawal syndrome, the phenomenon under study is "conditioned

tolerance." The experimental design is similar to that in which

conditioned drug effects are examined. The resultant CR, however,

is abstinence-like and is termed a "counteradaptive" (Wikler 1973)

or "conditioned tolerance" response (Siegel 1975). Although this

second class of withdrawal phenomena remains controversial, it

continues to be of considerable scientific interest (e.g., Eikelboom

and Stewart 1979, Sherman 1979). While these phenomena have been

demonstrated in the laboratory to be robust, the extent to which

they obtain in the natural environment of opiate-using patients is

unclear; further, the extent to which they may contribute to

persistence of opiate use is yet to be Objectively determined.

A series of investigations directed at the analysis of conditioned

responses in opiate-dependent or postdependent human sujects has

been implemented at our University of Pennsylvania/Veterans Administration Medical Center laboratory. Analysis has involved responses

which have been established either naturally or experimentally.

That is, in some cases the circumstances for development of classically conditioned responses have been established in the laboratory,

and exposure to these situations has elicited appropriate responses.

In other cases the investigations have involved analysis of the

behaviors established in the Subjects' natural environment which are

elicited through various experimental manipulations and evaluated in

the laboratory setting. Evidence has emerged for both conditioned

drug effects and conditioned withdrawal effects. The focus of the

current discussion will be elicitation of withdrawal-like responses

and description of the circumstances under which these responses

evolve.

108
OPIATE-LIKE CONDITIONED RESPONSES

There have been several clinical reports of what may be identified

as "conditioned drug responses" associated with the behavior of

self-injection (Blachly 1971, Levine 1974, O'Brien 1975). This

so-called "needle-freak" phenomenon, which also represents a clear

"placebo response," is characterized by pleasurable subjective

effects during and following self-administration of saline or other

pharmacologically inert solutions. Presumably conditioned physiological changes also occur, and the analysis of these responses is

of considerable interest since it clearly indicates the potential

importance of drug-use-correlated behaviors serving as conditioned

reinforcers. Although this phenomenon has not been studied systematically, it has been observed that some subjects exhibited morphinelike subjective and physiological effects when saline was selfinjected (O'Brien 1975, O'Brien et al. 1980). Typically, these

opiate-like effects follow self-injection rather than occurring

during the preinjection period. Meyer and Mirin (1979) have also

reported opiate-like postinjection autonomic changes in 11 of 22

patients who self-injected heroin while opiate agonist effects were

blocked by naltrexone. As shown in figure 1, the injection ritual

(CS1) may act as a complex conditioned stimulus which, after

repeated pairing with opiate agonistic effects (UCSl), attains the

ability to evoke weak agonistic effects (CRl).

FIGURE 1

Dependent Subject

UCS1 UCRl UCR1A

Occupation of Opiate Agonistic Adaptation to opiate

opiate receptors effects effects "tolerance

CS1 CR1 CR1

Injection Conditioned Conditioned "tolerance"--

opiate-like withdrawal-like effects

effects

UCS2 UCR2

Evacuation Withdrawl

of opiate syndrome

receptors

CS2

CR2

Drug-procuring Withdrawal-like

environment responses

The foregoing reports and observations parallel studies with animals

in which environmental stimuli previously associated with drug

effects can serve as conditioned reinforcers or classically

conditioned elicitors of behavior. Thus, for example, Woods and

109
Schuster (1967) noted that a stimulus previously associated with

drug self-administration in monkeys can, for a period of time,

maintain responding for saline infusions. Similarly, but in the

context of the classical conditioning paradigm, La1 and coworkers

(1976) reported that a stimulus previously paired with drug effects

can attenuate a component of the opiate withdrawal syndrome. Therefore, it is clear that mechanisms associated with either operant or

classical conditioning may directly or indirectly contribute to

persistence in responses associated with drug-correlated stimuli.

In turn, it can be argued that conditioned drug effects may contribute to the general pattern of persistence observed in human drugseeking behavior.

OPIATE WITHDRAWAL-LIKE CONDITIONED RESPONSES

Since one phase of opiate action (i.e., onset) can serve as the

basis for a conditioned response and can generate behaviors

associated with opiate self-administration, conditioned responses

may also be expected to emerge in relation to the other major

physiological/behavioral event associated with opiate use--that is,

the withdrawal syndrome. Wikler's early observations led to the

proposal that conditioned responses might serve to generate

drug-seeking behavior. Thus, for example, conditioned withdrawal

has been presumed to underlie case reports involving drug-free

postdependent patients who exhibit physical and subjective evidence

of opiate withdrawal when they return to the environment in which

drugs were used (Wikler 1965. O'Brien 1975). In the laboratory the

conditioned withdrawal phenomenon has been established in patient

volunteers maintained on a methadone regimen by pairing naloxoneprecipitated withdrawal (unconditioned response, UCR) with a novel

stimulus (CS). The resultant CR resembles the UCR (opiate withdrawal) (O'Brien et al. 1975, 1977). Similar physiologic,

behavioral, and subjective responses have been observed when

methadone-maintained patients were exposed to videotaped sequences

of themselves using drugs in the laboratory (O'Brien et al. 1975)

and when stimuli such as drug-related videotapes, slides, or objects

were shown to drug-free or methadone-maintained patients (Ternes et

al. 1980). Sideroff and Jarvik (1980) also reported that both

physiologic and subjective withdrawal effects occur in patients

undergoing detoxification after viewing a videotape of drug use by

other individuals.

Analysis of the above-described phenomena is of course difficult and

complex, and unresolved questions exist despite numerous and

repeated observations of dependent and postdependent patients in the

laboratory setting. For example, it appears that typically when

patient SubJects perform the preinjection rituals, i.e., "cook up"

(drug preparation) and "tie off" (tourniquet application), their

physiologic, subjective, and behavioral responses resemble opiate

withdrawal (O'Brien et al. 1980). Only rarely have drug-like

responses been observed. Several factors may contribute to the

observed preponderance of "withdrawal-like" responses. First, it

should be noted that the physiological concomitants of opiate withdrawal are similar to those of nonspecific autonomic arousal

110
reactions evidenced when individuals with no drug use history view

drug-related stimuli, including videotapes of individuals injecting

drugs.

Second, it is at times difficult to identify separately the physiological correlates of drug-like and withdrawal-like phenomena since

some of the physiological responses (but presumably not mechanisms)

are similar. One direct effect of opiates is nausea; indeed, this

iS sometimes used as an indicant of "street drug" quality and is

termed a "good sick" by opiate users (Stolerman and Kumar 1972).

Yet, nausea iS also one of the clearly observable responses during

opiate withdrawal. This is just one example of possible problems in

analysis. It should be noted that the physiological response

changes correlated with stimulus presentations for patients tend to

be more durable and robust than in drug-naive subjects.

A third consideration iS the possibility that responses elicited by

preinjection stimuli differ from those immediately post injection.

That is, withdrawal-like responses may precede injection, while

conditioned drug-like responses may follow placebo self-administration. This issue too requires further analysis, and the data of

Eikelboom and Stewart (1979) suggest that more refined analyses may

permit differentiation of these phenomena.

It was noted that withdrawal-like responses may emerge via a second

mechanism reflected by "conditioned tolerance" (Siegel 1976, 1978),

although this explanation is at present tenuous. Figure 1 shows

conditioning paradigms which could be expected to produce

withdrawal-like CR's in dependent subjects. One procedure involves

opiate withdrawal occurring as the opiate is metabolized and opiate

receptors are evacuated (UCS2). Since UCS2 iS directly paired

with drug procurement or preinjection stimuli (CS2), the preinjection stimuli acquire the ability to evoke conditioned withdrawal

(CR2).

The other procedure leading to withdrawal-like responses involves an

adaptive or homeostatic response (UCRlA) to the occupation of the

opiate receptors. This adaptive response may be partially responsible for tolerance phenomena because it tends to oppose or diminish

the agonistic action of the opiate. The tolerance response UCRlA.

reliably follows UCSl (receptor occupation), so that an adaptive

conditioned response (CRlA) may also be conditioned to preinjection stimuli (CSl).

Since the drug procurement (CS2) and preinjection rituals (CSl)

are usually paired with both receptor evacuation (the UCS for the

withdrawal UCR) and subsequently with receptor occupation (the UCS

for the compensatory UCR), these stimuli may elicit either adaptive

reactions or the withdrawal reactions as conditioned responses.

However, in terms of physiological variables, both types of conditioned response resemble opiate withdrawal (UCR2). Thus, what

appear as withdrawal responses in a drug procurement area actually

may be the result of two different conditioning processes, conditioned tolerance and conditioned withdrawal. Because both may be

111
operative, a redundancy occurs which may increase the apparent

strength of the conditioned response observed.

EXTINCTION OF CONDITIONED OPIATE EFFECTS IN HUMANS

If, as has been suggested, drug-like and drug withdrawal-like

effects can be established via operant and classical conditioning,

it should be expected that they can similarly be extinguished. That

is, if the unconditioned stimulus eliciting classically cnnditioned

responses is no longer paired with the conditioned stimulus or if

the operant behavior is no longer reinforced, a decrease in response

strength should be expected. Goldbero and Schuster (1970) reported

that conditioned withdrawal in morphine-dependent monkeys was quite

resistant to extinction. With humans, the laboratory investigations

have produced variable results in resistance to extinction. Thus,

for example, in the analysis of experimentally conditioned withdrawal in humans using a novel conditioned stimulus and a small

number of training trials. O'Brien and coworkers (1975. 1977)

reported that conditioned-withdrawal symptoms diminished rapidly

during repeated unreinforced (test) trials. In contrast to these

studies of laboratory conditioned withdrawal responses, studies of

withdrawal CR's in response to naturalistic conditioned stimuli

("cook-up" and "shoot-up" rituals) indicate great resistance to

extinction. Presumably, these naturally conditioned CR's are

established during an extensive history of opiate use involving a

large number of "training" trials in the user's natural environment. In addition, a schedule of intermittent reinforcement in the

natural environment may evolve with respect to some features of

operant behaviors, thereby adding to the complexity of factors

contributing to behavioral persistence. These differences between

the laboratory and natural environment may contribute to the

apparent disparity of resistance to extinction (Grabowski and

O'Brien 1981).

In a double-blind experimental design, the effects of systematic

repetition of drug-associated rituals under circumstances in which

opiate reinforcement was either absent or blocked by an antagonist

have been further examined. Opiate-free postdependent subjects were

permitted, in the laboratory setting, to engage in the preinjection

and self-injection rituals (using opiate or saline) while being

maintained on the opiate antagonist naltrexone (O'Brien et al.

1980). Typically, withdrawal-like autonomic responses were observed

during the preinjection ritual. Initially opiate-like subjective

and physiological effects occurred after injection regardless of the

contents of the syringe. Subsequently, the opiate-like subjective

effects disappeared (extinguished) after a few unreinforced trials.

Interestingly, on later trials, when opiate-like effects no longer

occurred, the injection ritual was followed by an increase in the

autonomic withdrawal-like responses (O'Brien et al. 1980).

In another study (Ternes et al., in preparation) it was found that

detoxified patients who were allowed to self-inject either opiate or

saline showed compensatory (i.e., withdrawal-like) autonomic changes

prior to self-injection and opiate-like autonomic changes after the

injection. In contrast, the same subjects given an unsignalled

112
infusion of an opiate showed only the opiate-like changes and these

effects only occurred after the infusion. These findings are strikingly similar to those of Eikelboom and Stewart (1979), who reported

differing response patterns to the two stimulus conditions previously paired with preinjection withdrawal responses and postinjection drug effects. Thus in both human subjects (postdependent

patients) and a nonhuman species, the preinjection stimuli elicited

withdrawal-like responses and the postinjection stimuli elicited

opiate-like changes. Whether or not these differential responses

reflect conditioned tolerance or conditioned compensatory responses

prior to injection is, of course, unclear. Both patterns of

responses can be observed in experimental paradigms designed to

reflect a sequence of events which prevails in the natural environment for some opiate users. Efforts to eliminate both patterns of

responding using extinction procedures in the laboratory thus far

suggest that the conditioned positive reinforcing effects diminish

more rapidly than the conditioned withdrawal responses. In addition

it appears that elements of both response patterns may persist in

some human subjects (Grabowski et al. 1980). The difficulties in

experimental analysis of these phenomena are considerable, and it is

clear that further research is required.

CONCLUSIONS

Laboratory investigations with postdependent and dependent human

Subjects, as well as studies with rodents and primates, have demonstrated that behavioral and physiological correlates of drug and

withdrawal responses can be conditioned using operant and/or classical procedures. In addition it appears that the behaviors and physiological responses of the several phenomena may coexist and be

evident concurrently or sequentially in the same Subject. Presumably when the more complex patterns emerge, as is typical with human

Subjects who are former opiate users, the results reflect the complexities of an extensive and variable past history. Many factors

potentially may influence the relative strengths of both operant and

respondent behaviors. For example, opiate users who are not physically dependent because they use insufficiently high daily drug

doses may experience unconditioned withdrawal rarely or not at all.

These subjects could be expected to show mainly opiate-like CR's;

theoretically, however, some compensatory CR's should also occur,

albeit less intensely. On the other hand, for subjects who are

physically dependent, two mechanisms for withdrawal-like conditioned

responses (figure 1) exist: compensatory CR's and withdrawal CR's.

This redundancy may explain why, in investigations with some human

opiate users, withdrawal-like CR's dominate and are difficult to

extinguish.

While it is apparent that conditioning in opiate users is complex

and incompletely understood, the effects appear strong enough to

have clinical implications. Studies involving opiate-using patients

or postdependent individuals present special problems because of

their variable "training" histories. Perhaps further research with

both humans and animals will elucidate the conditions under which

the different types of condioned responses are most likely to

develop.

113
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of repeated self-injection in former I.V. heroin users. Presented

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in animal and human drug taking behavior. In: Mello, N.K., ed.

Advances in Substance Abuse, Vol. I. Greenwich, CT: JAI Press,

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showing and videotape related stimuli. Int J Addict, 15(4):529-536,

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AUTHORS

Charles P. O'Brien, M.D., Ph.D.; Joseph W. Ternes, Ph.D.; John

Grabowski, Ph.D.; and Ronald Ehrman

Department of Psychiatry, University of Pennsylvania, and

Philadelphia VA Medical Center, Philadelphia, Pennsylvania 19104

115
Internal Stimulus Control and

Subjective Effects of Drugs

Charles R. Schuster, Ph.D., Marian W. Fischman, Ph.D., and

Chris E. Johanson, Ph.D.

For many years psychotropic drugs have been characterized and classified

using methods designed to measure their subjective effects in humans

(Beecher 1959). This research approach has two principal purposes: 1)

to investigate the efficacy of a drug in attenuating unwanted subjective

states in patients (e.g., pain, anxiety, depression), 2) to investigate the

abuse potential of new drugs by comparing their subjective effects in

experienced drug abusers to those produced by known drugs of abuse.

In regard to the latter, such methods have been used to determine

whether there are any common subjective states produced by all drugs

of abuse (e.g., euphoria).

Systematic studies of subjective methods for drug classification have

been conducted at the Addiction Research Center (ARC) in Lexington,

Kentucky, now part of the National Institute on Drug Abuse. A major

mission of the ARC has been to evaluate new analgesic compounds to

determine whether they produced morphine-like effects. The subjective

effects of morphine and related compounds were an important aspect

of this evaluation. The research demonstrated that morphine and related

narcotic analgesics produced a unique spectrum of subjective effects

that can be reliably discriminated from subjective effects produced by

other psychotropic drugs in experienced narcotic addicts (Hill et al.

1963). Even within the analgesic class, mixed agonist-antagonists (e.g.,

cyclazocine) can be readily discriminated from morphine in terms of

their subjective effects (Haertzen 1974). Other studies have also shown

that the methods for measuring the subjective effects of drugs are

useful for characterizing and differentiating other classes of abused

drugs (e.g., psychomotor stimulants: Martin et al. 1971; sedativehypnotics: Martin et al. 1974, Jasinski, 1977; hallucinogens: Martin 1973).

Thus, it is possible to determine whether an unknown drug belongs to

the opiate, psychomotor stimulant, sedative-hypnotic, or hallucinogenic

drug class on the basis of its subjective effects.

Until recently, measurement of drug-induced changes in subjective

effects was possible only with humans, since only this species has the

necessary verbal skills to describe how a drug makes them feel. However,

behavioral methods have been developed over the past decade which

116
allow animals to report on discriminations between psychotropic drugs

(Schuster and Balster 1977). There IS a striking concordance between

drug classes based on similarities in the subjective effects produced in

humans and on similarities as discriminative stimuli in animals (Schaefer

and Holtzman 1977, Shannon and Holtzman 1976, 1977). This has led

many researchers in behavioral pharmacology to make the working

assumption that the components of drug action responsible for the

discrimination among various classes of psychotropic drugs by animals

are the same as those responsible for the differences in the subjective

effects of these drugs in humans. In part, the purpose of the present

paper is to show that this concordance across species is not surprising,

since the same learning processes are involved in both species. The

fact that humans learn to apply a topographically unique response (verbal)

to drug-induced discriminative stimuli should not mask the fact that the

same fundamental processes are involved. A second major purpose of

this paper is to examine the hypothesis that although each class produces

certain distinctive subjective effects, all drugs of abuse produce certain

common subjective effects (e.g., euphoria) and it is these effects which

are responsible for their abuse.

BEHAVIOR ANALYSIS OF DRUG-INDUCED CHANGES IN SELFREPORTS

An analysis of the processes involved in measuring drug-induced changes

in subjective states requires a review of precisely what subjects are

asked to do in these experiments. The most common instruments used

to measure subjective states are paper and pencil inventories. Some of

these instruments are composed of a list of adjectives commonly used

to describe mood (e.g., happy, angry) and the subject is asked to rate

how he/she feels in relation to that mood (e.g., the Profile of Mood

States: POMS). Other instruments consist of statements related to

sensations and perceptions about which subjects are asked to indicate

their agreement or disagreement (e.g., the Addiction Research Center

Inventory developed at the ARC). In some procedures, greater

quantification is obtained by having subjects indicate the strength of

then mood or agreement with each adjective or statement on an ordinal

scale. Instructions to the subjects indicate that they should respond in

a manner which best reflects how they feel at that moment. The

responses before and after drug or under drug and placebo conditions

are compared to determine whether the drug has produced a significant

change. It is usually assumed that the verbal behavior accurately

represents a matching between the subject’s feelings and the statements

or adjectives checked. Since the individual’s feelings are a private

event, there is no way for the investigator to determine the degree of

accuracy of the subject’s verbal report, i.e., how precisely it reflects

a feeling state. For most purposes, such as drug classification, this

problem can be ignored as long as the data produced are lawful (i.e.,

show comparable dose-related changes across individuals).

The self-reporting response is operant behavior controlled by its

consequences and thus susceptible to change by a variety of influences

117
besides the drug administered. It is well established for example, that

verbal behavior can be markedly altered by social contingencies. The

Greenspoon phenomenon (1955) has amply demonstrated that powerful

control can be exerted over the verbal behavior of subjects who were

unaware that their behavior was being manipulated by subtle responses

of the experimenter. In the Greenspoon study, human subjects were

instructed to "say words" during a 50-minute experimental session. When

the experimenter made a specific verbal response ("mmm-hmm")

following every plural noun uttered by the subject, there was a significant

increase in that class of verbal responses (plural nouns). The existence

of such influences make one less comfortable in assuming the accuracy

of the reporting of private events.

Therefore, one approach in dealing with self-report data is to treat the

verbal response as devoid of a referent. Thus, if after being given a

sedative drug, Subjects say “I feel sleepy,” one can record this as a

change in verbal behavior induced by the drug, without any inference

about changed in subjective state. Thus, a positive answer to that

statement conceived of in this way would have no value in predicting

other behavior of the individual, such as the likelihood of reclining on

a bed, or of exhibiting a sleep-appropriate EEG. However this “black

box” approach iS inadequate to account for the subjective drug effects

data. If drug-induced changes in verbal responses are treated as devoid

of a referent the meaning of the verbal response should be irrelevant.

Subjects could be asked to check off boxes labeled with color names or

numbers rather than mood descriptors. Since we usually have no

discriminative training for applying such color names or numbers to

internal states, we would probably get little consistency in drug effects.

On the other hand, as we will illustrate, when we allow subjects to

respond using common adjective or simple descriptive statements of

mood words, we see a fair degree of agreement in responses across

individuals who are given certain psychotropic drugs. This agreement

is based on a common conditioning history in which certain adjectives

or mood descriptions have been associated with certain internal states.

Whether or not one chooses to ignore the internal cues, we are taking

advantage of a conditioning history based on these internal cues when

self-report methods are used for investigating drug effects.

How do humans learn to apply verbal labels to private events? It is

clear how children can be differentially reinforced for correctly labeling

colors, sounds, and other publicly observable stimulus events. Internal

stimuli represent a special problem for such differential conditioning

since the mediator of reinforcement cannot observe the private event

to determine the accuracy of the labeling. Under these conditions, the

trainer uses a combination of observing the external environment for

significant cues and collateral responses as an indication of the veracity

of the verbal label. For example, we would agree with (i.e., reinforce)

a child who says she is sad when found sitting hunch-shouldered in her

bedroom with tears streaming down her face if we also sew that her

favorite toy had been ruined by the family dog. Conversely, if she

comes bounding in the door, whistling and swinging her lunch pail with

a smile on her face to show us her good report card, we would reinforce

118
her for saying she is happy. As a child matures, some of the more

observable parts of these behavior patterns (e.g., crying, whistling) may

diminish, but the label is still accurately associated with the internal

stimulus events. It is this type of conditioning history which we utilize

when subjects are asked to match their internal state with a list of

adjectives or statements. It is most remarkable that such conditioning

histories are consistent enough across individuals so that drugs induce

a fairly close agreement in self-reports of internal states. Although

some radical behaviorists may still choose to deal with such self-reports

as simply verbal behavior and ignore the internal cues setting the occasion

for the responses, it is obvious that the subjects do not ignore them.

DRUG DISCRIMINATION STUDIES IN ANIMALS

It is well established that animals can be trained to discriminate between

the internal cues associated with food and water deprivation (Hull 1933,

Leeper 1935). For example, we could arrange conditions so that following

24 hrs of food deprivation an animal would be reinforced with the

termination of electric shock for turning right in a T-maze. Turning

left would not be reinforced under these stimulus conditions but would

be reinforced when the animal was not food deprived. After several

trials, the animal’s behavior would become appropriate to the deprivation

conditions. The animal is correctly identifying an internal state in the

same way that a human subject might check the adjective “hungry”

under similar food deprivation conditions. In the case of the animal,

we have controlled the conditioning history, whereas in the human we

usually assume that such discriminative training has already occurred.

In the same manner, animals can be taught to discriminate between

various drugs (Schuster and Balster 1977). Holtzman and his colleagues

have developed a method using a discrete-trial avoidance-escape

paradigm in which animals (rats and monkeys) can prevent the onset of

or terminate an electric shock by pressing one of two choice levers

(Schaefer and Holtzman 1977, Shannon and Holtzman 1976, 1977). The

animals were trained to press one lever after drug injection (morphine

or cyclazocine) and the other lever after placebo administration.

Specifically, rats were injected 30 minutes prior to each daily 20-trial

session. During the session, a light was illuminated for 5 seconds prior

to the onset of electric shock . Depression of the correct choice lever

terminated the light (an avoidance response) or both the light and shock

(escape response). On days when a rat had received morphine, one of

the choice levers was correct; on days when saline was administered,

the other choice lever was correct. Rats were trained until they

completed at least 18 trials on the appropriate choice lever (90% correct).

After this criterion for discrimination between drug and placebo was

reached, drug test sessions were periodically conducted with a new drug

or new dose. During training trials only one of the two choice levers

was operable and could terminate a trial. Thus, after the first trial

was completed, the reinforcement, i.e., the shock and/or warning stimulus

termination, might then serve as the cue to the correct choice lever

for the remainder of the session. To deal with this problem, on test

119
days depression of either lever satisfied the avoidance-escape

contingency. Thus, the effectiveness of the response could not function

as a cue to signal the animal which choice lever was correct. Amazingly,

when drug pretreatment times were arranged so that the onset of drug

effect occurred half way through the session, animals switched from

responding on the saline-appropriate lever to the drug-appropriate lever.

Clearly, the drug cues are a more effective discriminative stimulus than

even the reinforcer (i.e., light and/or shock terminations).

Following establishment of such stimulus control, it iS of interest to

determine to what degree such control will generalize to other drug

stimuli. There are two ways in which discriminative stimuli may be

varied for generalization testing-quantitatively and qualitatively. When

a drug is used as the discriminative stimulus, quantitative generalization

tests are accomplished by varying the dose. When this is done in animals

trained to discriminate 3.0 mg/kg of morphine from saline, lowering the

morphine dose results in dose-related decrements in responding on the

morphine-appropriate choice lever with a concomitant increase in

responding on the saline-appropriate choice lever. Doses higher than

that used in training produce similar or even greater discriminative

stimulus control (i.e., responding on the morphine-appropriate lever) until

behaviorally toxic doses are reached. This relation between morphine

dose and response choice is similar to that observed when exteroceptive

discriminative stimuli (e.g., light) are varied along a quantitative

dimension (e.g., intensity). It is also the same relationship as that shown

between dose and the intensity of the subjective effects produced by a

drug in humans (Fischman et al. 1976).

When conducting generalization studies in which the discriminative

stimulus is varied qualitatively, the situation is more complex. With

an auditory discriminative stimulus, the unidimensional continuum of

frequency can be manipulated. For a visual stimulus the continuum is

wavelength. When using drug states as discriminative stimuli, however,

we do not know the relevant continua along which changes might show

a lawful relatlonship to behavior. This deficit is not unique to drugs,

however, as the same problem exists with olfactory stimuli.

Nevertheless, it iS possible to do generalization tests from training drugs

to other drugs with different structures and pharmacologic properties.

For example, after approximately 8 to 10 weeks of training in the

Holtzman experiments, most animals responded almost exclusively on

the appropriate lever when given either morphine or saline. Subsequently,

a variety of psychotropic drugs were investigated to determine which

produced "morphine-like" discriminative effects (i.e., animals responding

on the morphine-appropriate choice lever 18 out of 20 trials). For the

following reasons, the results of these generalization tests indicate that

the discriminative control exerted by morphine is a specific narcotic

effect:

(1) all narcotic drugs tested showed morphine-like discriminative control

in a dose-related manner;

(2) these narcotics showed a ranking in potencies highly correlated with

their potencies in producing morphine-like subjective effects in humans;

120
(3) the stimulus control exerted was stereospecific with only analgesically

active isomers exerting morphine-like effects;

(4) naloxone administration produced a pronounced shift in the dose

response curve relating dose of morphine to its discriminative control;

(5) tolerance to the discriminative effects of morphine developed after

repeated administration and there was cross tolerance to methadone;

and finally

(6) d-amphetamine, chlorpromazine, ketamine, mescaline, pentobarbital,

physostigmine, and scopolamine failed to exert morphine-like

discriminative stimulus control.

The results of studies in which monkeys were trained to discriminate

between cyclazocme and saline were comparable to those described for

the rat with morphine. Naloxone diminished the stimulus control exerted

by cyclazocine, i.e., on days when the animals were given both drugs,

most of their responses were made on the choice lever associated with

saline administration. Studies in humans have shown that cyclazocine

produces subjective effects distinctly different from morphine.

Accordingly, in the monkey experiments, morphine did not substitute for

cyclazocine as a discriminative stimulus. These results indicate that

cyclazocine and morphine produce distinctive stimulus effects in animals

and humans. In contrast, in monkeys trained to discriminate cyclazocine,

there was generalization to drugs such as nalorphine, levallorphan, and

ketocyclazocine, all of which produce a common set of dysphoric

subjective reactions in humans (Haertzen 1974).

This series of experiments conducted by Holtzman and his colleagues

has convincingly demonstrated that generalization tests in animals can

be used to classify drugs in the opiate class as well as those with mixed

opiate agonist-antagonist properties. Further, the classification derived

from animal experiments is in concordance with that based upon the

subjective effects of these drugs in humans (Jasinski 1972, Haertzen

1974). Similarly, animals can be trained to discriminate prototypic

agents from other classes of abused drugs (e.g., cocaine as a prototypic

stimulant) and then generalization tests can be conducted by testing

other psychotropic drugs (e.g., amphetamines, barbiturates, etc.). Again

the drug classes based upon discriminative effects in animals and upon

subjective effects in humans are in striking concordance.

THE RELATIONSHIP OF SUBJECTIVE AND REINFORCING EFFECTS

OF PSYCHOTROPIC DRUGS

Although the classes of abused drugs can be differentiated on the basis

of their spectrum of subjective effects, certain effects in common are

produced by all such drugs. When hospitalized exaddicts are tested with

the Addiction Research Center Inventory (ARCI), scores on the MorphineBenzedrine Group Scale (MBG) show dose-related increases when subjects

are administered narcotic analgesics (Jasinski 1973a,b, Jasinski et al.

1974; Martin et al. 1971) barbiturates (McClane and Martin 1976) or

amphetamine-like drugs (Martin et al. 1971, Fischman et al. 1976).

121
William Martin, Director of the ARC for several years, believes that

LSD-like hallucinogens, alcohol, and marijuana would also produce similar

results on the MBG Scale if tested in an appropriate subject population

(Martin et al. 1978). The items in the MBG Scale are related to feelings

of popularity, efficiency, social effectiveness, pleasant feelings, absence

of worry, good self-image, and feelings of insight and satisfaction. This

scale is designed to measure a drug’s ability to produce a subjective

state of “euphoria” (Martin et al. 1978). It is the opinion of many

researchers that drugs are abused by humans because they produce this

state of “euphoria” (Isbell 1958, Martin et al. 19’78, Jasinski 1977).

Another approach used to study factors contributing to drug abuse in

humans has been to develop an animal drug self-administration model

(see Griffiths et al., this volume). In these studies animals are given

an opportunity to emit a response which is followed by the drug delivery.

If responding is maintained by a drug it is said to possess positive

reinforcing properties, i.e., the drug is a positive reinforcer.

Previously we discussed the similarity in drug classifications formed on

the basis of subjective effects in humans and discriminative stimulus

effects in animals. If animals and humans have similar subjective"

responses to drugs one might predict that drugs which serve as reinforcing

stimuli in animals should produce ":euphoria” in humans. If we

operationally define "euphoria" as the state measured by the MBG Scale

of the ARCI, this relationship can easily be determined. Table 1 shows

that there is a good correlation between these two procedures. Drugs

in the opiate agonist, psychomotor stimulant, and barbiturate classes

generally serve as reinforcers in animal studies and, as well, produce

dose-related increases in MBG Scale scores (i.e., “euphoria" Further,

both opiate agonist/antagonists, such as nalorphine and cyclazocine, and

neuroleptics produce “dysphoria” and are generally not self-administered

by animals. These results are also in accord with actual street abuse

of these various drugs. That is, commonly abused drugs serve as

reinforcers in animals and produce “euphoria,” whereas drugs producing

“dysphoria” are neither abused nor do they generally serve as reinforcers

in animals. It remains to be determined whether this pattern generalizes

to alcohol, marijuana, and LSD-like hallucinogens. The data available

suggest that both drug self-administration experiments in animals and

investigations of the subjective effects of drugs in humans can be used

to predict whether a new drug has significant abuse potential. This has

led, in our opinion, to the incorrect use of the term "reinforcing” as

synonymous with “euphorigenic,” and has produced both theoretical and

practical problems.

Since it would be difficult to measure “euphoria” in animals, animal

self-administration studies cannot shed light on whether the reinforcing

effects of drugs are based upon their ability to produce “euphoria.” In

order to answer this question, human experimentation is required in

which measures of both a drug’s reinforcing properties and its subjective

effects are obtained. Only if the concordance between the two measures

is invariant can a causal hypothesis be tenable.

122
TABLE 1

Changes in “Euphoria” Rating on the ARC1 (MBG Scale)

Correlated with Animal Drug Self-Administration’

Drug

Morphine

Profadol

Propiram

Methadone

Pentazocine

Heroin

Propoxyphene

Codeine

Etorphine

Cyclazocine

Butorphanol

Buprenorphine

Naloxone

Nalorphine

Pentobarbital

Cocaine

d-Amphetamine

Methamphetamine + Martin et al., 1971

Ephedrine + Martin et al, 1971

Phenmetrazine + Martin et al., 1971

Methylphenidate + Martin et al., 1971

Diethylproplon + Jasinski et al., 1974

Phentermine + Jasinski et al., 1976

Fenfluramine - Grlfllth et al., 1975

Effect on MBG Score

Increase (+) No increase (-)

+ Jasinski, 1973b

- (chronic) Haertzen & Hooks, 1969

+ Jasinski et al., 1971

+ Jasinski et al., 1971

+ Martin et al., 1971

+ (weak) Jasinski et al., 1970

+ Jasinski & Nutt, 1972

+ Jasinski et al., 1974

+ Jasinski et al., 1974

+ Jasinski et al., 1974

+ Jasinski et al., 1966

(at some doses)

+ Jasinski et al., 1975

+ Jasinski et al., 1976

- Jasinski, 1972

- Jasinski, 1973a

+ McClane & Martin, 1976

+ Fischman et al., 1976

+ Fischman et al., 1976

Self-Admmmtratlon

Yes (+) No (-)

+ Thompson & Schuster, 1964

+ Woods, 1977

+ Hoffmeister & Schlichting, 1972

+ Woods, 1977

+ Hoffmeister & Schlichting, 1972

+ Hoffmeister & Wuttke, 1974

+ Hoffmeister & Schlichting, 1972

+ Hoffmeister & Schlichting, 1972

+ Woods, 1977

- Hoffmeister & Wuttke, 1974

+ woods, 1977

+ Woods, 1977

- Balster et al., 1977

- Hoffmeister & Schlichting, 1972

+ Goldberg et al., 1971

+ Wilson et al., 1971

+ Balster & Schuster, 1973

+ Balster & Schuster, 1973

+ Woods (unpublished)

+ Wilson et al., 1971

+ Wilson et al., 1971

+ Johanson & Schuster, 1977

+ Griffiths et al., 1976

- Woods & Tessel, 1974

1The self-administration studies were arbitrarily restricted to those using monkeys.

123
The administration of single (or a limited number of) doses of drugs in

the opiate, psychomotor stimulant, and sedative-hypnotic class produces

“euphoria” in "appropriate” subjects. To demonstrate that a drug serves

as a reinforcer, however, it is necessary to show that the drug increases

the response rate on which its administration is contingent. When this

is done, a dissociation between the reinforcing effects and mood effects

appears. Clinical data indicate that the continued use of alcohol and

opiates IS associated with progressive dysphoria, anxiety, irritability, and

aggressiveness (see review by Mello 1977). Unfortunately, most studies

have not used the MBG Scale from the ARCI as their measure of

euphoria. Nonetheless the measures of “euphoria” show a progressive

decline although the drug continues to maintain self-administration and

is by definition a reinforcer. Furthermore, Johanson and Uhlenhuth

(1980, 1981) have shown that when normal human subjects are allowed

to choose between self-administering d-amphetamme (5 mg orally) or a

placebo they initially prefer the drug. This preference is associated

with a spectrum of subjective changes on the Profile of Mood States

(McNair et al. 1971) indicative of “euphoria.” With repeated opportunities

to choose, however, the number of drug choices declines despite the

fact that when the drug I S taken (during forced “sampling”

administrations), it still produces the same changes on the POMS. Thus,

a drug can continue to serve as a reinforcer despite the development

of progressive “dysphoria,” and, moreover, a drug can continue to produce

“euphoria” but not continue to serve as a reinforcer. Thus, mood

changes do not necessarily covary with changes in the reinforcing efficacy

of drugs. This weakens the hypothesis that drugs serve as reinforcers

because of their ability to produce "euphoria."

Another line of evidence bearing on the issue of concordance between

a drug’s “euphorigenic” and reinforcing actions is based on individual

differences in response to drugs. In the preceding section we have

qualified the description of drug-induced mood changes by saying that

these occurred in “appropriate” subjects. This implies that mood changes

should differentiate those individuals for whom drugs serve as reinforcers

and those for whom they do not. There is very little acceptable evidence

on this point. Drug-induced mood changes often differ between humans

who abuse drugs and those that do not. Beecher (1959) demonstrated

that morphine generally produced “dysphoria” and aversion in normal

subjects whereas it produced “euphoria” and a desire to repeat the drug

experience in ex-heroin addicts. In contrast, amphetamines produced

“euphoria” in normals but not in the ex-heroin addicts. Unfortunately,

since the reinforcing actions of these drugs were not determined with

the same subjects, we cannot state they would have covaried with the

mood measures.

It is commonly assumed by many clinicians that patients who experience

a “euphoric” response to medically prescribed drugs are at greater risk

for iatrogenic addiction. In one recent study (Johanson and Uhlenhuth

1980), the mood changes induced by &hetamine or placebo were

compared in normal human subjects. POMS scores revealed that damphetamine produced an increase in Arousal, Positive Mood, and Elation.

After this experience subjects were given repeated opportunities to

124
choose between ingesting c-amphetamine or placebo. Though most

preferred d-amphetamine, some did not self-administer it at every

opportunity despite the fact that the drug produced comparable mood

changes in all subjects. Thus one could not predict on the basis of

similarities in drug-induced mood changes whether the drug would serve

as a reinforcer. On the other hand, it was demonstrated that there was

a subset of individuals who chose d-amphetamine on every opportunity

and these individuals did not differ in their subjective response to the

drug. They did, however, show significant differences in mood prior to

ingestion of the drug. Subjects who showed this decided preference for

d-amphetamine were more anxious and depressed as measured by the

FOMS (Uhlenhuth et al. 1981). It is important to stress that despite

these differences in pre-drug mood, their subjective responses to drug

were no different from those of the other subjects.

It is clear that we need a great deal more information on how individuals

differ in their subjective responses to drugs and the importance of these

differences as a determinant of whether the drug serves as a reinforcer.

Ideally these studies should be done in drug-naive subjects, but there

are limitations on the types of drugs, range of doses, and duration of

exposure which must be imposed for ethical and practical reasons. With

therapeutic drugs such studies are, however, of extreme importance in

order to define populations which may be at greater risk for dependence

when exposed to the drug during treatment.

The evidence reviewed suggests that drug-induced changes in the

subjective state called “euphoria” are produced by many drugs which

readily serve as reinforcers in both animals and humans. There are

circumstances, however, in which these two measures of drug effect do

not covary. Thus one effect cannot be caused by the other; rather both

are produced by the interaction of the drug with the organism (with a

unique genetic behavioral and pharmacologic history) under a particular

set of environmental conditions. Both organismic and environmental

variables may modify the reinforcing and subjective drug effects

differentially. It would not be unexpected then, using appropriate

subjects under appropriate environmental circumstances (e.g., exaddicts

in a controlled hospital setting), that one could predict the reinforcing

effects of all drugs from their subjective effects. Clearly, the ARC

has isolated effective procedures for selecting subjects and an

environmental situation for predicting a drug’s reinforcing actions from

measures of its subjective effects. This has had predictive utility for

preventing the unwitting introduction of drugs with high reinforcing

efficacy into medical practice. However, the close correlation between

these two drug effects in these carefully selected subjects under highly

controlled environmental conditions should not lead to the conclusion

that the drug’s “euphorigenic” actions produce its reinforcing actions.

These two aspects of drug action dissociate under a wide variety of

conditions. Such dissociation can only lead to the conclusion that

subjective and reinforcing effects are correlated but that neither is

causal of the other.

125
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AUTHORS

Charles R. Schuster, Ph. D.

Departments of Psychiatry and Pharmacological and Physiological

Sciences

The University of Chicago

The Pritzker School of Medicine

Chicago, Illinois 60637

Marian W. Fischman, Ph.D. Chris E. Johanson, Ph.D.

Department of Psychiatry Department of Psychiatry

The University of Chicago The University of Chicago

The Pritzker School of Medicine The Pritzker School of Medicine

Chicago, Illinois 60637 Chicago, Illinois 60637

129
Social Stimulus Factors in Drug

Effects in Human Subjects

Maxine L. Stitzer, Ph.D., Roland R. Griffiths, Ph.D.,

George E. Bigelow, Ph.D., and Ira A. Liebson, M.D.

INTRODUCTION

Effects of drugs on human behavior are frequently studied in the

laboratory under conditions in which a single isolated subject is

the focus of analysis. Much of human drug use, however, appears to

occur in social rather than isolated contexts (e.g., Babor 1978).

A complete understanding of drug effects in humans must ultimately

take into account the effects of drugs on behavior in social contexts

and the modulating influence that social stimuli may exert upon the

expression of drug effects. The present paper is concerned with the

interaction between drugs and social stimuli in humans. Three general

categories of interaction will be discussed: First, modulation of

human social behavior by drugs; second, modulation of the behavioral

and subjective effects of drugs by social stimuli; third, modulation

of drug self-administration by social stimuli. In this paper, existing data will be reviewed which support each of these categories of

interaction between drugs and social stimuli and the implications of

these interactions for the understanding of the behavioral pharmacology of drugs of abuse will be discussed.

DRUG EFFECTS ON HUMAN SOCIAL INTERACTION

It is widely believed that people behave differently within a social

context when under the Influence of drugs than when sober. Evidence

is now available from behavioral pharmacology research which supports

the observation that drugs from a variety of pharmacological classes

can modulate human social behavior.

Studies of drug effects on human social behavior have differed markedly

in their approach to the problem and in the specific experimental

methods employed. However, two general classes of studies can be distinguished which differ primarily in the subject population studied

and the methodologies employed. One type of study has its origins in

drug abuse research. Subjects employed have histories of chronic use

or abuse of the drug to be investigated, and experiments are generally

conducted while subjects reside in an inpatient research unit. During

130
the study, subjects are typically allowed to self-administer the

drugs of interest up to a maximum allowable limit of daily ingestion. Self-administration is typically permitted over a prolonged

period of time, so that drug ingestion is chronic rather than acute,

and the dose and pattern of ingestion is controlled by the subject.

Categories of behaviors including social interaction are defined

in advance and scored observationally by nursing and research staff.

Levels of social interaction observed during drug self-administration may then be compared to levels observed when drug is not

available, typically before and after the period of programmed

drug avallability. This research design allows for correlational

analyses of social behavior as a function of drug availability or

amount of drug consumed, but does not allow experimental control of

the independent variable, drug intake. Occasionally (c.g.,

Griffiths et al. 1974a) investigators have experimentally varied

drug availability or administered known quantities of drug as experimental manipulations within the context of inpatient research

with chronic drug abusers.

The second type of study which has examined drug effects on social

behavior has its origin in clinical psychopharmacology, that is, in

research concerned with behavioral or psychiatric effects of drugs.

These studies have typically examined effects of acute drug doses

and employed normal volunteers or psychiatric patients as research

subjects. Although specific procedures have varied widely from study

to study, subjects are typically studied in groups of two, three, or

four individuals seated together in the experimental situation.

Active drug may be given to a single member or to multiple members

of the group simultaneously. Dosing is generally acute, and drug

dose may be manipulated as an independent variable. Social interaction in these studies has typically been examined by using verbal

behavior as the dependent variable. Verbal behavior may occur in

the context of social conversation, in response to interview questions ,or in response to a problem-solving or group discussion task

imposed by the experimenter Observational techniques have typically been used to score both quantitative and qualitative aspects

of verbal output of study participants, while more recently,

automated equipment involving voice-operated relays has been used

to collect quantitative information on talking.

Several classes of drugs have been examined for their effects on

human social or verbal behavior using the two approaches described

above. Virtually every drug which has been studied has produced

observable alterations in social or verbal behavior. These drugs

include ethanol (Griffiths et al. 1974a; Mendelson 1964; Stitzer

et al. in press; Thornton et al. 1976)) barbiturate sedatives

(Reiss and Salzman 1973; Stitzer et al. in press), stimulants

(Griffiths et al. 1977b), opiates (Fraser et al. 1963; Babor et al.

1976), phenothiazine tranquilizers (Lennard et al. 1967; Stitzer

et al. in press), benzodiazepine tranquilizers (Salzman et al. 1974;

Kochansky et al. 1977), marijuana (Babor et al. 1974a 1974b 1978b;

Janowsky et al. 1979), and hallucinogens (Cheek and Holstein 1971).

131
In the present paper, these relationships will be illustrated by

discussing the effects of four drugs on human social behavior:

ethanol, secobarbital, chlorpromazine and d-amphetamine. These

particular drugs were chosen for discussion because their effects

have recently been studied systematically after acute administration to normal volunteer subjects. Such a systematic comparison

across several drug classes using a single methodology has not

been available previously for acute dosing studies. Where appropriate, effects of acute drug doses on social behavior of nonabuser

volunteers will be compared with effects which have been observed

in drug abusers who are chronically self-administering the drug.

Ethanol

Ethanol has been studied more than any other type of drug for its

effects on human social and verbal behavior. Two previous studies

suggested that ethanol may enhance social conversation when administered in acute doses to nonalcoholic subjects (Smith et al. 1975,

Pliner and Cappell 1974) . Smith et al. (1975) studied effects of

acute doses of ethanol (about 1 ml/kg absolute) given to both members

of a dyadic social pair, and observed small increases after ethanol

in amount of speech as well as increases in speech initiations and

overlapping speech. Pliner and Cappell (1974) studied effects of

ethanol (0.5 gm/kg) in groups of three normal volunteers. Observational ratings on an “amusement index” revealed higher scores for

groups of subjects who received ethanol than for placebo controls.

Thus, ethanol enhanced socializing and specifically the amount of

smiling, laughing, and joking observed in the social situation.

Facilitation of social conversation by ethanol in nonalcoholic subjects has recently been confirmed in a study conducted at Baltimore

City Hospitals which employed quantitative methods to investigate

effects of acute drug doses on vocalization of dyadic interaction

pairs (Stitzer et al. in press). In this study, amount of vocalization was monitored automatically and independently for each pair

member by microphones strapped around the throat and connected to

voice-operated relays. Same sexed subject pairs participated in

daily one-hour sessions scheduled five days a week, and multiple

observations were obtained of the effects of placebo and several

doses of ethanol within the same subject. Test doses were given to

only one member of each pair, referred to as the subject, while the

other pair member, referred to as the partner! received placebo

drinks (fruit juice) throughout the study. Figure 1 shows that

ethanol (l-6 oz 95 proof) ingested one-half hour prior to the

sessions enhanced the amount of vocalization recorded in the pair

member who received active drug, while talking by the partner was

relatively unaffected. The drug effect was dose-related and was

observed in all four pairs who were studied.

Available evidence supports the conclusion that acute doses of

ethanol enhance or facilitate social conversation in nonalcoholic

normal volunteers. Consistent findings have not emerged, however,

132
FIGURE 1

Effect of oral ethanol on seconds of speaking in a dyadic social

interaction pair. Data are shown in the lefthand column for four

individual subjects who received placebo (pl) and several doses

of ethanol. Shown in the righthand column are data for partners,

who received placebo only, on days when subjects received active

drug. Seconds of speaking were cumulated during sessions of

3600 sec duration. Data points indicate means, brackets indicate

± 1 S.E.M. Shown in parentheses are number of observations

included in each data point. From Stitzer et al. in press.

@ ANKHO International, Inc. Reprinted with permission.

133
when ethanol has been studied in nonalcoholic volunteers who are

allowed to self-administer the drug chronically. McGuire et al.

(1966) noted increases in socializing (at unspecified doses) in

three members of a four-man group of nonalcoholic subjects given

access to ethanol during research participation in an inpatient

unit. However, other investigators using similar methodologies

(Babor et al. 1978a; Nathan and O’Brien 1971) failed to note any

significant differences i.n amount of socializing during periods

of drinking versus nondrinking or significant correlations between

amount of drinking and amount of socializing.

Most inpatient research involving chronic self-administration of

ethanol by alcoholic subjects has revealed a drug-related facilitation of social behavior. In the pioneering studies of ethanol

self-administration conducted by Mendelson and colleagues (Mendelson 1964; McNamee et al. 1968)) it was noted that social behavior

remained intact during periods of heavy drinking by chronic alcoholic subjects and dropped out only after consumption of very

high doses of ethanol (McNamee et al. 1968). Subsequent correlational observations have indicated that social behavior in chronic

alcoholics is actually enhanced during periods of ethanol selfadministration (Docter and Bernal 1964; McGuire et al. 1966;

Thornton et al. 1976). The relationship between drinking and

socializing was demonstrated in one study by Griffiths and coworkers (1974a) by manipulating the availability of ethanol.

Amount of social interaction observed within individual subjects

was consistently higher on days when ethanol drinking occurred

(12 oz 95 proof ethanol) than on days when ethanol was not available. Another study by this group (Griffiths et al. 1975), using

a choice procedure, demonstrated that ethanol enhances the desirability of socializing as compared to receiving money. Thus, a

considerable body of data supports the conclusion that ethanol

facilitates social behavior in chronic alcoholic subjects, while

the few studies which have failed to show this positive correlation

(e.g., Nathan and O’Brien 1971; Mortanero 1974) used procedures

which tended to suppress the occurrence of socializing altogether

(see also Griffiths et al. 1978). Comparison of studies with chronic

alcoholics and nonalcoholic volunteers suggests that the effects of

ethanol on social behavior may be similar for these two groups,

but that chronicity of ingestion is a factor which may influence

drug effects on social behavior in nonalcoholic subjects.

Secobarbital

Only one previous study is available in which the effects of barbiturate sedatives have been examined on human social behavior (Reiss

and Salzman 1973). This study showed marginal facilitation of

verbal interaction when secobarbital (175 ml) was administered to

the adolescent member of a three-member family group during a group

problem-solving task. Secobarbital has recently been studied in

dyadic social interaction pairs using procedures developed at

Baltimore City Hospitals, as previously described for studies of

134
FIGURE 2

Effect of oral seccbarbital on seconds

of speaking in a

dyadic social interaction pair. Data

are shown in the

lefthand column for

six individual subjects who received

placebo (pl) and

several doses of

secobarbital. Shown

in the righthand

column are data for

partners, who received placebo only

on days when subjects

received active drug.

See Figure 1 legend

for other features

of data presentation.

From Stitzer et al.

in press. @ ANKHO

International, Inc.

Reprinted with permission.

135
FIGURE 3

Effect of oral chlorpromazine on seconds of speaking in a dyadic

social interaction pair. Data are shown in the lefthand column

for four individual subjects who received placebo (pl) and three

doses of chlorpromazine. Shown in the righthand column are data

for partners, who received placebo only, on days when subjects

received active drug. See Figure 1 legend for other features of

data presentation. From Stitzer et al. in press. @ ANKHO

International, Inc. Reprinted with permission.

136
ethanol (Stitzer et al. in press). The results of this study are

presented in Figure 2. It can be seen that secobarbital in doses

of 30-300 mg produced dose-related increases in vocalization in

all six of the pair members who received active drug, while having

no consistent effect on speaking by the partners who received

placebo only. The appearance of behavioral facilitation following

administration of a barbiturate drug is noteworthy since these

drugs frequently produce only sedation and performance decrements

(Epstein and Lasagna 1968; Idestrijm and Cadenius 1963; Frankenhaeuser

et al. 1964 ; Loomis and West 1958). Furthermore, although subject

history and expectations of drug actions (e.g., Lang et al. 1975)

are frequently involved in interpretation of behavioral effects of

ethanol, such history and expectation variables should not be

significant determinants of barbiturate effects in Subjects who

are relatively inexperienced with the drug. Thus, the similar

behavioral effects of secobarbital and ethanol suggest that facilitation of social conversation represents a behavioral pharmacological

effect of these drugs which is relatively independent of subject

history or expectations.

Chlorpromazine

One previous study, which examined effects of 50 mg chlorpromazine

on social conversation in normal volunteers (Lennard et al. 1967),

reported that the drugged subject in a three-person group initiated

less conmunication and had less communication directed toward him.

Chlorpromazine has also been studied recently at Baltimore City

Hospitals in the dyadic social interaction situation previously

described for studies of ethanol and secobarbital (Stitzer et al.

in press). Doses of 25-100 mg were administered to a single member

of the interaction pair three hours prior to the social session.

Figure 3 shows that the amount of vocalization was reduced in a

dose-related manner for pair members who received active drug, and,

in this case, talking by the partner who received placebo only was

also generally reduced on days when the subject received active

drug. These results are consistent with previous observations of a

depressant effect of chlorpromazine on social conversation in normal volunteer subjects (Lennard et al. 1967). Chlorpromazine serves

as a negative control in the social interaction studies conducted at

Baltimore City Hospitals by demonstrating that social conversation

does not invariably increase after drug administration, but rather

that pharmacological specificity exists with regard to drug effects

on social conversation in the dyadic interaction situation.

d -Amphetarmine

Clinical case reports and survey studies suggest that normal social

behavior is markedly disrupted during periods of chronic high dose

use of amphetamines, while repetitive stereotyped actions which do

not involve other people are typically observed during periods of

chronic use (Schiørring 1977). In contrast, acute administration of

modest doses of stimulants such as d-amphetamine can produce dramatic

137
increases in verbal and social behavior. One study by Griffiths

et al. (1977b) used behavioral observation to assess amounts of

socializing in which study participants engaged. The study, which

was conducted in an inpatient research unit with subjects who had

histories of alcoholism, showed reliable dose-related increases

in amounts of socializing after acute oral doses of d-amphetamine.

Effects of d-amphetamine have also been studied in the dyadic

social interaction situation using procedures developed at Baltimore City Hospitals, as previously described (Griffiths et al.

1977b). Acute doses of 5 to 30 mg were administered two hours

prior to the daily social session to a single member of the interaction pair. Figure 4 shows that the drug produced a dose-related

increase in vocalization in five of seven pair members who received active drug, while talking by the partner who received

placebo only was generally unaffected. While there are apparently

individual differences in response to d-amphetamine, with a certain

portion of subjects showing no effect,-facilitation of social conversation after acute doses of d-amphetamine is very dramatic and

consistent for most subjects.

Overall, the studies described in this section have shown that drugs

can influence the amount of social conversation and social interaction observed in human subjects. The ability of drugs to modify

social behavior appears to have considerable generality across drug

classes, having been observed for stimulants (Griffiths et al. 1977b),

sedatives, major tranquilizers and ethanol (Stitzer et al. in press),

as well as opiates (Babor et al. 1976) and marijuana (Babor et al.

1974a 19741, 1978b). Drug effects on social behavior also have considerable generality across subject populations, having been observed

in both chronic users of the drugs under study and volunteer

nonabuser subjects; furthermore, these effects have been observed

across a wide range of doses in both acute dosing studies and chronic

drug self-administration paradigms. It seems clear that the ability

to modulate human social behavior is an important behavioral property

of a wide variety of psychoactive drugs.

MODULATION OF DRUG EFFECTS BY SOCIAL STIMULI

As discussed in the previous section, evidence has now accumulated

that drugs from several pharmacological classes modulate human behavior in social contexts. The question addressed in this section

is whether the reciprocal relationship can also be demonstrated--

that is, whether there is any evidence that social context can

modulate other physiological, behavioral, or subjective effects of

drugs. Although only a limited amount of research has addressed this

question, results of available studies suggest that some of the subjective effects attributed to drugs can differ markedly depending on

the social context in which the drug is administered. Pliner and

Cappell (1974) studied subjective effects of ethanol 0.5 gm/kg

(3-4 oz 80 proof) in normal volunteer subjects who were either alone

or in a three-person group. In both situations, subjects worked

during 20 min sessions on a “creative” task, which involved

133
FIGURE 4

Effect of oral d-amphetamine on seconds

of speaking in a

dyadic social interaction pair. Data are

shown in the lefthand

column for four individuals who received

placebo (pl) and one

or more doses of

d-amphetamine. shown

in the righthand

column are data for

partners, who received

placebo only on days

when subiects received

active drug. See Figure 1 legend for other

features of data presentation. From

Griffiths et al. 1977b.

@ ANKHO International, Inc. Reprinted

with permission.

139
composing cartoon captions. Mood reports completed after the

session (Clyde Mood Scale) showed that subjects who experienced

the drug effect in an isolated situation reported feeling less

clear thinking, more dizzy and more sleepy as a result of the drug,

while subjects who experienced drug effects in the group situation

became less bored and more elated as a result of drug. Estimates

by the subjects of their degree of intoxication, on the other hand,

did not differ in the social and nonsocial conditions. Thus, there

was a distinction in this study between qualitative aspects of the

subjective drug effect which were modulated by social context, and

quantitative estimates of intoxication which were not modulated by

social context.

Results remarkably similar to those reported by Pliner and Cappell

(1974) were also obtained in a study of marijuana effects conducted

by Jones (1971). In this study, subjects smoked marijuana cigarettes

containing 9 mg THC during two experimental sessions spaced one week

apart. In one session, subjects smoked alone; in the other session

they were in a four-person group. While smoking alone, subjects

generally reported feeling relaxed and drowsy. In the group situation, however, subjective reports indicated elated mood and a lack

of sedation. Global ratings of the degree of intoxication, however,

were similar across the two situations. This study therefore confirms the observation made by Pliner and Cappell that qualitative

aspects of the subjective reports after drug were modulated by

social setting, while quantitative estimates of degree of intoxication were unaffected by setting.

In a final study of this type by Warren and Raynes (1972), the

direction and magnitude of mood change as revealed by subjective

report did not differ significantly during social and nonsocial conditions, but there was a tendency for mood effects to be more

extreme in the social setting.

Studies by Jones (1971) and Pliner and Cappell (1974) demonstrate

nicely that social context may alter the qualitative nature of subjective effects reported after drug ingestion. This finding is

supported by less systematic observations of other investigators

who have noted that subjective reports of drug effects can depend

to a large extent upon the specific social and affective context in

which the effects are experienced (Schachter and Singer 1962;

Nowlis and Nowlis 1956, Sice et al. 1975). Since subjective effects

attributed to drugs can differ qualitatively in different social

contexts, we may assume that these subjective effects are not

immutable properties of the drug but rather effects which can be

determined or modulated by social context and other environmental

variables.

MODULATION OF DRUG SELF-ADMINISTRATION BY SOCIAL STIMULI

Since social stimuli can modulate certain subjective effects of

drugs, as discussed in the previous section, these stimuli may also

140
modulate the propensity to ingest drugs. For example, social

stimuli could function as discriminative stimuli which control

drug ingestion, in which case, presence of social cues would increase the likelihood of drug Ingestion. Alternatively, social

stimuli could actually alter the reinforcing properties of drugs,

making it either more or less likely that drugs would be ingested

in social situations. Finally, access to social stimuli could act

as a reinforcer or punisher to enhance or suppress drug self-administration. Irrespective of the possible mechanisms involved,

it is of interest to determine the extent to which social stimuli

modulate rates and patterns of drug self-administration by humans.

The studies which will be reviewed in this section have in common

a behavioral measure of drug ingestion as the primary dependent

variable. Social conditions are then manipulated to determine the

effect on amount and pattern of drug self-administration. In fact,

information about social modulators of drug self-administration has

all been derived from studies which employ ethanol as the drug to be

self-administered. This is not too surprising in view of the relative ease with which this drug can be studied in a variety of settings.

Although ethanol can be considered a prototypic drug for studies of

the influence of social variables, the generality of results obtained with ethanol remains to be determined.

Social versus Nonsocial Context

The few studies which directly compared ethanol self administration

in social and nonsocial contexts have not found consistent differences in drug self-administration in these two contexts. One study

by Nathan and coworkers (Nathan et al. 1970) examined ethanol selfadministration in chronic alcoholic subjects under conditions of

free socialization or enforced isolation. Although most subjects

claimed that they enjoyed drinking more during the social condition

than during the isolation condition, there were no consistent

differences in amount of drinking during socialization and isolation.

In subsequent studies conducted by these investigators (e.g., Nathan

and O’Brien 1971), subjects were allowed to determine the social

context of drinking by buying their way out of isolation using the

same points which purchased ethanol. This procedure clouded the

distinction between social and isolated conditions and precluded an

analysis of drinking rate as a function of social context.

Fox and Simon (1978) studied drinking topography as a function of

solitary versus social context. Chronic alcoholic subjects participated in 30 min sessions during which they drank their preferred

beverage either alone or in a three-person group. In this study,

the alcoholic subjects tended to consume all available ethanol, and

drinking patterns in the social setting did not differ significantly

from drinking patterns in the solitary setting.

The fact that chronic alcoholics will tend to drink all available

ethanol in experimental situations poses a methodological barrier

141
to demonstrating environmental influences that increase drinking.

It is possible that longer sessions (e.g., Caudill and Lipscomb

1980) or other methodological refinements which suppress baseline

drinking rates (Bigelow et al. 1975) would enhance sensitivity to

effects of social cues. It is also possible, however, that social

context per se may play an inslgnificant role in drinking by

alcoholics. This might be predicted if the reinforcing properties

of the drug itself were so prominent in these individuals that they

overwhelm the Influence of relatively subtle environmental modulators such as social context. Social modulation of ethanol selfadministration might be more easily demonstrated in nonalcoholic

social drinkers or in situations in which baseline drinking is

suppressed below maximal levels.

One recent study (Tomaszewski et al. 1980) examined the influence of

social cues on ethanol consumption in college student beer drinkers.

During experimental sessions subjects were randomly assigned to

drink beer with a partner who had soft drinks but no ethanol available (social setting), with a partner who also drank beer (social

drinking), or alone (control). Paired subjects were matched for

rate and amount of beer drinking as determined during a baseline

session. Subjects in the social setting condition but not those in

the social drinking condition consumed more beer than control subjects who drank in isolation. This study, while providing some evidence for enhanced drinking in a social context, failed to demonstrate a robust and reliable effect of social cues on drinking. It

should be noted that the college student beer drinkers in the

Tomaszewski et al. study, as well as alcoholic subjects in other

studies (e.g., Nathan and O’Brien 1971), consumed substantial amounts

of ethanol under isolated conditions. It is clear therefore that

social cues are not necessary for the maintenance of drinking in

these situations. While social cues may, under some conditions,

modulate the amount of ethanol consumed, a clear demonstration of

this effect remains elusive at the present time.

Modeling

Although there is no strong evidence at present that social context

per se has a marked impact on the self-administration of drugs or

ethanol, compelling evidence has accumulated that modeling can play

an important role in modulating rates and amounts of ethanol consumption. The initial demonstration of a modeling effect was made

by Caudill and Marlatt (1975). The college student volunteers in

this study were told that they would be taking part in a wine

tasting test in which they would sample and rate two decanters of

wine on various subjective dimensions. The real dependent variable

of interest, however, was the amount of ethanol consumed during a

15 min taste test. Subjects were randomly assigned to complete the

taste test with a high consumption model (700 ml consumption) , a

low consumption model (100 ml consumption) or no model. While there

was no difference in the average amount of wine consumed by subjects

who drank alone and by subjects exposed to the low consumption

142
model, subjects exposed to the high consumption model consumed

significantly more wine than those in either of the other groups.

Garlington and Dericco (1977) have demonstrated the modeling effect

using a within-subject experimental design. Subjects drank beer

during a one-hour session in the company of a confederate model.

Models were trained to match their drinking rate to that of the

subject, or to drink at rates one-third higher or one-third lower

than the ongoing rates of the subject. Each condition (baselinematched drinking, high rate drinking, low rate drinking) was in

effect during successive sessions and each continued until a

criterion of stability had been achieved. Figure 5 shows stable

drinking rates of subjects and confederates as recorded by independent observers present in the experimental room. It is clear

that subjects’ drinking rates tracked those of the confederate

model with a high degree of accuracy.

The generality of modeling effects has been extended to female

subjects and to subjects with higher drinking histories (Lied

and Marlatt 1979). Finally, modeling effects have recently been

demonstrated in alcoholic subjects during both taste test and

free drinking procedures (Caudill and Lipscomb 1980).

A series of studies has demonstrated that modeling can exert a

powerful and systematic influence on rates and patterns of drinking

within an experimental social drinking setting and that the influence

of modeling is apparent in both social drinkers and chronic alcoholics. Modeling could clearly be an important regulatory mechanism

controlling drug intake in naturally occurring social situations.

It will be of Interest in future studies to determine the generality of modeling effects across a variety of drugs and to delineate

the conditions under which modeling factors operate (e.g., Dericco

and Garlington 1977; Dericco and Niemann 1980; Hendricks et al.

1978).

Contingent Access to Social Interaction

Positive social reinforcement is presumed to operate in the etiology

of drug use since such use is typically associated with peer models

and friendship groups (Hughes and Crawford 1972; Kandel et al. 1978).

Facilitation of drug ingestion through contingent access to social

stimuli has never been demonstrated in laboratory situations. On

the other hand, studies conducted at Baltimore City Hospitals by

Griffiths, Bigelow, and colleagues have clearly demonstrated that

contingent access to social stimuli can be used to suppress ethanol

self-administration in chronic alcoholics.

A case study reported in a review by Griffiths et al. (1978) illustrates the potentially powerful impact of contingent access to

social stimuli on alcoholic drinking. The subject, a chronic

alcoholic, had 12 drinks (1 oz 95 proof ethanol) available daily

during his participation in an inpatient research unit. Under base143
FIGURE 5

Drinking rates in ounces per minute of subjects and confederates

during successive one-hour experimental sessions. From Garlington

Qnd Dericco 1977. @ Journal of Applied Behavior Analysis.

Reprinted with permission.

144
line conditions, he consumed all available ethanol. Subsequently,

he could earn visiting privileges for his girlfriend by restricting

his drinking to a moderate amount (no more than 5 drinks in a day).

The subject fulfilled the moderate drinking requirements on five of

six days during which the contingency was in effect. During another

study phase, the subject could receive an overnight pass to visit

his girlfriend by restricting his drinking to 5 drinks per day or

less for 10 consecutive days. He was successful in doing so, and

earned the pass. This case study illustrates that drinking by an

alcoholic subject can be precisely modulated by reinforcement

techniques which involve contingent access to social stimuli.

A series of studies was subsequently undertaken by this group of

investigators to examine contingent access to social stimuli as a

modulator of ethanol self administration in chronic alcoholic subjects . In the first study of this type (Bigelow et al. 1974) , ten

chronic alcoholic subjects had access to one oz (95 proof) drinks

during daily 16 hr sessions. The number of drinks available varied

from 12 to 24 for individual subjects. Following a baseline assessment period during which subjects consumed all available ethanol,

subjects were required to sit for 10 or 15 min in a small isolation

booth each time they chose to take a drink. This contingent isolation procedure resulted in marked suppression of drinking (to an

average of 50 percent of baseline) in 7 of the 10 subjects.

Physical isolation in a booth removes subjects from social stimuli

as well as social interaction and also greatly restricts activity

levels. A study by Griffiths et al. (1974b) was undertaken to

separate the influence of some of these factors. In this study,

six chronic alcoholic volunteers had access to seventeen 1 oz

(95 proof) drinks daily during an 11-hr session. Under baseline

conditions of availability subjects did not generally consume all

available drinks, although they typically consumed at least nine

drinks and as many as 16 drinks. During the contingent time-out

intervention, subjects were required to spend 40 min in a time-out

from social interactions each time they chose to drink. During

social isolation subjects could remain in the day-room of the research

unit but could not talk to other ward residents. They could engage

in activities (TV, reading, cards, pool) as long as these did not

involve participation by another person. Figure 6 summarizes results of this experiment, and shows that contingent social isolation

under these conditions initially did not result in a consistent

suppression of drinking. The experiment was repeated in some of

the subjects under slightly different conditions. During these

replications, certain ward privileges were restricted during the

entire experimental session whether or not the subject chose to

drink. During restricted privileges I, subjects were not allowed

to watch television; during restricted privileges II, subjects

were not allowed to read or to watch television. It is clear

from Figure 8 that the contingent social isolation procedure

became more effective as alternative activities were more severely

restricted.

145
FIGURE 6

Effect of contingent timeout from social interactions on amount of

drinking in six individual study participants during three conditions of available privileges: Full Privileges; Restricted Privileges I (no television); Restricted Privileges II (no television,

no reading). From Griffiths et al. 1974b. @ Pergamon Press.

Reprinted with permission.

FIGURE 7

Effects of three different timeout procedures on drinking of 14

chronic alcoholic subjects. Different symbols represent different

study participants. See text for explanation of social and activity

timeout procedures. From Griffiths et al. 1977a. @ Pergamon Press.

Reprinted with permission.

146
A final study by Griffiths et al. (1977a) compared the efficacy of

contingent social time-out and contingent activity time-out in suppressing drinking of alcoholics. Throughout the study, 17 drinks

(1 oz 95 proof) were available to alcoholic subjects in the research

unit during daily 11-hr sessions. Eight subjects were exposed to

three different time-out conditions presented either on several consecutive days or under a procedure in which conditions changed on a

daily basis . During social time-out, subjects could stay in the

dayroom and engage in activities as previously described, but could

not talk or interact with other ward residents. During activity

time-out subjects had to spend 40 min Following each drink sitting

in a specified chair located near the nursing station. They could

not participate in ward activities, but could talk and socialize

with ward residents and staff. A third procedure examined was a

combination of the social and activity time-outs. Figure 7

presents a summary of results for this experiment. Overall, the

response of individual subjects to the social time-out contingency

was highly variable: social time-out alone suppressed drinking in

about half of the subjects exposed to this condition. In subjects

exposed to both social and activity time-out conditions, the two

procedures were frequently about equivalent in suppressing drinking,

although the activity time-out was more effective in some subjects.

The combined social and activity time-outs, on the other hand, were

generally more effective than either one alone, and about equally

as effective as contingent time-out in the isolation booth had been

in a previous study (Bigelow et al. 1974).

It can be concluded from these studies that while contingent timeout from social interaction may produce variable effects in indiviual subjects, the procedure was generally quite effective in suppressing drinking of many alcoholic subjects. Furthermore, the

efficacy of contingent time-out from social interaction was improved

by restricting the other activities which were available to the

subject. Finally, other types of contingent restrictions such as

activity time-out were also effective in suppressing drinking, so

that contingencies which employed time-out from social interaction

were not unique in their ability to suppress drinking.

Experiments reviewed in this section have shown that social stimuli

play important roles in modulating ethanol self-administration under

some conditions but not under other conditions. On the basis of

limited data available, social context per se does not appear to

modify amounts or patterns of ethanol self-administration. Bather,

drinking may occur at high rates under both social and isolated

conditions . Modeling influences within a social context, on the

other hand, are potent and reliable determinants of amounts and

patterns of ethanol self-administration in both alcoholic and

nonalcoholic sub] ects . Contingent tune-out from social interaction

is also a potent modulator of ethanol self-administration, acting

to suppress drinking in chronic alcoholics. Since the presence of

social stimuli and the opportunity to interact socially do not

appear to be critical for maintenance of ethanol self-administration,

it is likely that the efficacy of contingent social time-out repre147
sents a direct suppression of drinking by contingent application

of an aversive event rather than a unique interaction between

ethanol and social stimuli.

SUMMARY AND CONCLUSIONS

It is clear that the relationships between drugs and social stimuli

are myriad and complex. Furthermore, the state of our current

knowledge about these relationships is quite rudimentary. Nevertheless, studies of social factors in drug effects have revealed

several potent and intriguing relationships. These include facilitation of social behavior by drugs of abuse, modulation of subjective and behavioral drug effects by social context, modeling

effects on rates and patterns of consumption and suppression of

ethanol self-administration by contingent access to social stimuli.

Studies of social factors in drug effects may ultimately contribute

greatly to our understanding of the relationship between reinforcing properties of drugs and their other behavioral actions. For

example, many drugs which are abused by humans have been shown to

enhance or facilitate human social interaction (Drug Effects on

Human Social Interactions section). It is possible that drug-produced facilitation of social behavior may constitute one component

of the reinforcing properties of drugs of abuse. If this were the

case, drugs should be better reinforcers and hence more readily

self-administered in social as opposed to isolated contexts. To

date, there is no clear demonstration that social cues or social

context per se facilitate drug self-administration. However, very

little research has been focused on this particular question, and

more self-administration studies which manipulate social cues would

be desirable . Another type of study which would bear on this issue

is one in which subjects self-administer drugs in a social context

but instructions or other interventions are used to prevent the

normal drug- produced increases in social behavior. If this manipulation were to reduce drug self-administration, this result would

suggest that the behavioral drug effect was contributing to the

maintenance of self-administration and hence contributing to the

reinforcing properties of the drug.

It has long been supposed that subjective effects of drugs are an

integral part of their reinforcing properties (Jasinski 1973, 1977;

WHO 1975). More recent studies, on the other hand, have suggested

that subjective and reinforcing properties of drugs may be relatively

independent (Johanson and Uhlenhuth 1978). The fact that social context may alter qualitative subjective drug effects poses intriguing

possibilities for distinguishing the contribution of specific subjective effects to the reinforcing properties of drugs. For example,

self-administration could be compared in social situations which

produce different affective states and hence different qualitative

reports of subjective drug effect. If the quality of subjective

effects attributed to drugs is important in determining reinforcing

properties (e.g., elation versus depression), then self-administration should differ in these situations. If degree of intoxication

148
is a primary determinant, on the other hand, the specific context

or affective milieu may have little impact on rates and patterns

of self-administration. An illustration of this approach is found

in a recent study by Pihl and Yankofsky (1979). In this study subjects were given contrived feedback about their performance on an

“intelligence test.” The feedback indicated that they had performed

either very well or very poorly on the task. Demonstrable changes

in affect occurred as a result of these manipulations. In an

alcohol taste test which followed, subjects exposed to the positive

feedback drank significantly more than subjects who had been exposed to the negative feedback. In the case of chronic alcoholic

Subjects, on the other hand, a change in affective state from

elation to depression, which is commonly observed during periods

of chronic ethanol self-administration, does not appear to influence

rates and patterns of drinking (Mendelson 1964; McNamee et al. 1968;

Nathan et al. 1970; Tamerin and Mendelson 1969). Further research

along these lines would be desirable to clarify the interaction

between affective states, subjective drug effects, and the reinforcing properties of drugs.

Other powerful social modulators of drug self-administration, such

as modeling and contingent access to social stimuli, may operate

relatively independently of the reinforcing properties of drugs.

These factors are clearly important, however, for our understanding

of etiology and maintenance of drug consumption in both abusive and

nonabusive patterns. We might speculate, for example, that initial

exposure to drugs within a social context facilitates drug use via

explicit social reinforcement of drug ingestion combined with

modeling. Once consumption is established, modeling and reinforcement influences would continue to operate in determining rates and

patterns of ingestion and ultimately in determining social versus

abusive patterns of ingestion. The demonstrated potent influence

of social factors on drug consumption is also relevant for developing rational treatment strategies for drug abusers. The use of

modeling as a treatment procedure has received little attention,

while the potential utility of arranging contingent access to

social stimuli is generally recognized (Hunt and Azrin 1973) but

infrequently implemented within treatment programs.

We are just beginning to understand the interactive relationships

between drug effects and social factors. A complete understanding

of the behavioral pharmacology of drugs, as well as an understanding

of the factors which maintain drug self-administration in humans,

will depend upon an eventual unravelling of these interactive relationships. The study of social factors in drug effects promises

to make an exciting and worthwhile contribution to behavioral

pharmacology.

149
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ACKNOWLEDGMENTS

Preparation of this manuscript was supported by USPHS grants

AA-04055 and DA-01022, and by Research Scientist Development

Award DA-00050.

AUTHORS

Maxine Stitzer, Ph.D., Roland R. Griffiths, Ph.D.,

George Bigelow, Ph.D., and Ira Liebson, M.D.

Departments of Psychiatry

Baltimore City Hospitals and

The Johns Hopkins University School of Medicine

Baltimore, Maryland.

154
Discussion

Stimulus Control and Drug

Dependence

Donald R. Jasinski, M.D.

The administration or termination of narcotics and other substances

of abuse to drug-dependent patients alters physiologic functioning

and behavior, as well as feelings, thinking, perception, and mood

(subjective effects) (Martin and Sloan 1977, Jasinski 1977). For

the most part, these alterations are reproducible as to character

and time course and are distinct for classes of drugs (Jasinski

1977). The study of these phenomena in man in conjunction with

operant studies in man and animals has created a "psychology" of

drug abuse. (This is evidenced by the fact that explanations of

the addictive process derive from the study of these phenomena and

that a unique set of psychopharmacologic instruments and techniques

exists for drug abuse.) In my opinion, the most critical of these

phenomena is the alteration of subjective effects. It seems appropriate, therefore, to summarize the concepts explaining the role

of subjective effects in psychopharmacologic studies of abused drugs.

The first set of concepts relates to the opiate withdraw1 syndrome.

In initial studies of addiction to morphine, it was recognized that

characteristic and stereotyped physiologic subjective and behavioral

changes followed termination of morphine-like drugs (Kolb and

Himmelsbach 1938). Among the behavioral phenomena was drug seeking

to relieve the discomfort. An initial and understandable assumption

was that in withdraw1 syndrome the physiologic changes, the subjective effects, and the behavior covaried. Consequently, the more

easily measured physiologic and behavioral changes were utilized

to measure the intensity and time course of the withdrawl syndrome.

The concepts of physical dependence, subjective distress, and

behavior as they related to the addictive process were considered

interchangeable to such a degree that physiologic changes were felt

to be indications of subjective discomfort and drug-seeking behavior

(Jasinski 1977).

Studies of the drug cyclazocine changed this concept (Martin et al.

1965). It was observed that the withdraw1 syndrome of cyclazocine

consisted of physiologic changes similiar to opiate withdraw1 but

without subjective distress or drug-seeking behavior. This observation led to the conclusion that the critical consequences of

physical dependence could be best measured by subjective effects.

155
The second set of concepts relates to the alterations in subjective

effects (apart from relief of withdrawal) following drug administration. Addict subjects given opioids, sedative hypnotics, and

central stimulants discriminate among these drugs and between these

drugs and placebo even when observers cannot discriminate among the

drugs on the basis of behavioral changes (Jasinski 1977). Alterations in feelings, perceptions, and thinking produced by the drugs

have differences and commonalities. The most important commonality

relates to elevation of mood reflected in feeling of well-being,

relaxation, enhanced self-image, and loss of anxiety. These effects

are usually labeled euphoria and are felt to be responsible for the

reinforcing effects of the drug. (This discriminability among drugs

and the measurement of euphoria have been utilized to classify drugs

and measure their reinforcing properties for the purpose of assessing abuse potential.) In summary, some 40 years of clinical

research at the Addiction Research Center in drug-dependent patients

has led to the conclusion that subjective alterations induced by

the administration or withdrawal of drugs of abuse are among the

most sensitive and specific psychopharmacologic measures.

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AUTHOR

Donald R. Jasinski, M.D.

National Institute on Drug Abuse

Addiction Research Center

Baltimore, Maryland 21224

156
Commonalities and

Differences

Among Reinforcers

Differential Drug Effects as a

Function of the Controlling

Consequences

James E. Barrett, Ph.D.

One of the central themes during the initial period in the development of behavioral pharmacology was the issue of whether motivational

factors influence the effects drugs have on behavior. Though seemingly a straightforward question, the translation of this problem

into an experimentally addressable form was, and continues to be,

somewhat difficult. Motivational concepts almost inevitably pose

formidable experimental problems, and studies designed to resolve

those problems have often yielded equivocal results. Typically, however, the question has been approached experimentally by comparing

the effects of various drugs on behavior controlled by different

types of events, e.g., food presentation and escape from electric

shock. Presumably, different events and the behavioral consequences

associated with them engendered different motivational states. The

influence of motivational factors as determinants of drug action

should then be reflected by differential changes in overt behavior

when the organism is given certain drugs.

This approach had one rather substantial problem that was not always

recognized. Behavioral consequences are important in several different ways, not only when they differ on some hedonic dimension,

but also depending precisely on how they are arranged or scheduled

with regard to behavior. Characteristics of behavior such as the

rate, duration, intensity, and temporal distribution of responding

are typically quite distinctive under different schedules even when

only a single consequence is arranged. Further, it has been shown

repeatedly that one of these characteristics, the rate and pattern

of responding, can contribute significantly to the effects many drugs

have on behavior (Dews and DeWeese 1977, Kelleher and Morse 1968a,

McKearney and Barrett 1978). It remains possible that other less

intensively studied factors, quite apart from the type of consequence,

also play an important role in determining the behavioral effects of

drugs.

Because it has been shown that the effects of various drugs on behaviors maintained by only one type of event can depend at least on the

schedule-controlled rate and pattern of responding, experimental

efforts directed towards understanding whether the nature of the

event maintaining responding affects drug action cannot be conducted

arbitrarily (Dews and Morse 1961; Kelleher and Morse 1964, 1968:).

For example, if one is interested in comparing drug effects on behaviors maintained by food and shock, it would be less meaningful to

compare performances under a continuous shock-postponement (avoidance)

159
schedule with those under a fixed-interval food-presentation schedule than it would be to compare drug effects under comparable fixedinterval schedules of food or termination of a stimulus correlated

with shock. In the first comparison, even if overall rates of

responding were similar, it is almost certain that the temporal distribution or the patterning of responding would be quite different.

Consequently, most individuals that have recently examined drug

effects on behaviors maintained by different events have consistently

emphasized the importance of making such comparisons under conditions

as comparable as possible (see reviews by Barrett and Katz 1981,

McKearney and Barrett 1978, Morse et al. 1977).

Figure 1 shows similarities in performances maintained by different

events under comparable schedules of reinforcement. These records

depict responding of squirrel monkeys maintained under 5-minute

fixed-interval schedules of food presentation, shock presentation,

stimulus-shock termination, or intravenous cocaine self-administration.

Despite the marked differences in the nature of these consequent

events, the schedule-controlled rate and pattern of responding maintained by each was remarkably similar. Comparisons of drug effects

under conditions such as these minimize the influence of other variables and permit reasonably straightforward analyses.

This approach was taken in experiments by Kelleher and Morse (1964)

and by Cook and Catania (1964). These investigators studied the

effects of several different drugs (e.g., chlorpromazine, damphetamine, chlordiazepoxide, and imipramine) on behavior maintained

under similar schedules of food presentation, escape from continuous

electric shock, or termination of a stimulus associated with electric

shock. Although Cook and Catania (1964) studied only fixed-interval

schedules, Kelleher and Morse (1964) compared drug effects under both

fixed-interval and fixed-ratio schedules of either food presentation

or stimulus-shock termination. None of the drugs in these experiments had behavioral effects that depended on the type of event

maintaining behavior. However, in the Kelleher and Morse (1964)

study, the effects of d-amphetamine and chlorpromazine were related

to whether responding was maintained under the fixed-interval or

fixed-ratio schedules. These findings were of considerable significance because they suggested that the nature of the event controlling behavior was less important than the schedule under which that

event occurred. Motivational factors, at least as assessed in this

manner, appeared superfluous in attempting to account for the behavioral effects of drugs.

Until recently, there have been very few additional experiments that

focused on comparisons of the effects of drugs on behaviors maintained by different events. Tremendous progress has occurred recently

because of the development and refinement of certain procedures that

have permitted an examination of more diverse events under conditions

where the behavioral performances are often nearly identical. Experimental efforts addressing the question of differential drug effects

as a function of the controlling consequences have incorporated many

of the fundamental principles in behavioral pharmacology. The results

of these studies, therefore, have general implications for principles

160
FIGURE 1

Comparable performances of squirrel monkeys responding under S-minute

fixed-interval schedules with different maintaining events. The pens

react to baseline at reinforcement. Each component was separated by

a one-minute timeout period during which all illumination in the

chamber was extinguished. Food presentation consisted of the delivery of a 300 mg Noyes banana-fLavored pellet; shock presentation was

a 200 msec 9 mA electric shock delivered to the shaved portion of

the monkey's tail which was held motionless by a small stock. Under

the stimulus-shock termination schedule, 9 mA shocks were scheduled

to occur beginning one second after the elapse of the S-minute fixed

interval; a response after the 5-minute interval had elapsed terminated the prevailing stimuli and shock schedule and produced the

timeout period. Cocaine hydrochloride was injected via an indwelling

intravenous catheter connected to a motor-driven syringe; a response

after the S-minute fixed interval produced a 50 ug/kg infusion of

cocaine. Note that performances maintained by the different events

are quite similar despite their various characteristics and means of

administration. (From Barrett and Katz 1991.@ 1981, Academic Press)

161
in this field. In addition, these experiments have also helped clarify and delineate other important environmental determinants of the

behavioral effects of drugs. Continued research, therefore, should

yield valuable information for developing a broad perspective and

better understanding of drugs of abuse.

BEHAVIOR MAINTAINED BY DIFFERENT EVENTS

Recent studies comparing drug effects on behavioral performances

controlled by different events have incorporated a number of developments in the experimental analysis of behavior maintained under

various schedules of reinforcement. These advances have extended

the range of useful consequent events and the specific conditions

under which they can be studied.

Several experiments, to be described below, compared the effects of

various drugs on responding maintained either by the presentation of

food or electric shock. Figure 1 showed that performances maintained

by response-produced shock were indistinguishable from those maintained under similar schedules by food, i.v. cocaine administration,

or by the termination of a stimulus in the presence of which shock

occurred. Although a great deal has already been written about the

maintenance of behavior by shock presentation (McKearney and Barrett

1978; Morse and Kelleher 1970, 1977), a few brief summary points are

necessary for much of the material that is to follow in this chapter.

Noxious events, such as shock, have typically been used either as

punishing stimuli that, when presented, suppress responding or as

stimuli that maintain responding by their termination or postponement.

However, several studies now indicate that response-produced shock

presentation can also maintain responding and that both reinforcing

and punishing effects of shock presentation can be obtained in the

same organism at the same time (Barrett 1977a, Barrett and Glowa 1977,

Kelleher and Morse 1968b, McKearney 1972). Recent experiments have

also demonstrated that behavior can be maintained simultaneously

under concurrent schedules when one schedule programs responseproduced shock and the second consists either of stimulus-shock termination (Barrett and Spealman 1978) or shock avoidance (Barrett and

Stanley 1980a). In these studies responses on one lever produced

shock; at the same time, responses on a second device, either a lever

or chain, were maintained by the postponement of shock or by the

termination of the stimulus-shock schedule. Thus, animals were

responding to produce a shock that, at the same time, they were also

responding to terminate or postpone. Performances maintained under

each concurrent schedule were comparable to those obtained when these

schedules have been arranged individually.

Taken together, these several findings indicate that the reinforcing

or punishing properties of behavioral consequences are not invariant

features of an event, but depend on other factors such as the schedule under which that event is presented and the history of the organism. Significantly, these factors not only determine the effects

that consequent events have on behavior, but also appear to influence

the effects of a variety of drugs. For example, the effects of

162
amphetamine are different depending on whether responding is suppressed or maintained by shock delivery. Punished behavior is typically

decreased by amphetamine, whereas behavior maintained by shock is

increased (Barrett 1977b, Hanson et al. 1967, McKearney 1974,

McKearney and Barrett 1975). These results reaffirm the view that

the schedule can be a critical aspect in determining the effects both

of events and of drugs on behavior.

The finding that animals respond to produce shock by no means implies

that the physical properties of the shock have changed. The same

intensity of shock that increases responding under one condition will

continue to suppress performance of the same animal under another

condition. It is also apparent that this is not a feat obtained only

by means of experimental deceit and that the organisms in these studies are insensitive to the prevailing contingencies. Performances

simultaneously maintained under concurrent schedules of shock avoidance and fixed-interval shock presentation, for example, are characteristic of those maintained when these behaviors are studied in

isolation, thereby indicating precise differential control by the two

schedules in effect.

Dual behavioral effects have been found with stimuli other than shock

(Spealman 1979, Wise et al. 1976, Woods et al. 1975), indicating that

a variety of other consequent events do not have static, immutable

behavioral effects. Stimuli have multiple effects on behavior. More

extensive investigation of the generality of these effects and an

exploration of their implications will undoubtedly provide a more

meaningful understanding of processes controlling behavior. Eventually, such efforts may help in clarifying some of the problems

involved in apparently anomalous habitual behaviors such as substance

abuse.

DRUG EFFECTS ON BEHAVIOR MAINTAINED BY FOOD, ELECTRIC-SHOCK

PRESENTATION AND STIMULUS-SHOCK TERMINATION

Although early experiments did not find differences in drug effects

depending on the type of event, more recent studies have reported

several instances in which the maintaining event appeared to influence the effects of several drugs on behavior. For example, morphine,

methadone, and the narcotic antagonists naloxone and nalorphine

decreased responding maintained under 5-minute fixed-interval foodpresentation schedules at doses that increased responding comparably

maintained by the presentation of an electric shock (McKearney 1974,

1975). Under similar schedule conditions, both amphetamine

(McKearney 1974) and cocaine (Barrett 1976) increased responding

maintained by these two events. However, appropriate doses of pentobarbital, ethanol, and chlordiazepoxide increased responding maintained by food, while only decreasing responding under shockpresentation schedules (Barrett 1976).

These findings suggested that there were several conditions under

which certain drugs appeared to affect similar performances maintained under comparable schedules in an event-dependent manner.

Further, as shown in Figure 2, at least the differential effects of

163
FIGURE 2

Effects of chlordiazepoxide on different control rates of responding

under S-minute fixed-interval schedules of food or shock presentation. The event pen was defected downward during the shockpresentation component. The top record of each pair represents control performance and the lower record the effects of Chlordiazepoxide.

Panel A: top record: comparable rates of responding maintained by

food and shock; lower record: effects of 5.6 mg/kg chlordiazepoxide.

Panel B: top record: substantially higher control rates of shockmaintained responding; lower record: effects of 17.0 mg/kg chlordiazepoxide. Shock intensity was 4 mA in panels A and B. Panel C:

control response rates maintained by food were higher than those

maintained by 1 mA shock; lower record shows changes in performance with 17.0 mg/kg chlordiazepoxide. Although control rates of

responding maintained by shock differed widely, chlordiazepoxide

consistently decreased shock-maintained responding, while responding

maintained by food was only increased. (From Barrett 1976. © 1976,

American Society for Pharmacology and Experimental Therapeutics)

164
chlordiazepoxide appeared to be relatively independent of the control rate of responding maintained by the presentation of food and

shock (Barrett 1976).

In subsequent research the effects of several different drugs were

studied on comparable rates and patterns of responding of squirrel

monkeys maintained under 5-minute fixed-interval schedules by food

presentation or by the termination of a stimulus associated with

shock (Barrett et al. 1977). Responding under both consequent events

was decreased with promazine and increased by d-amphetamine. However, chlordiazepoxide produced effects that depended on the type of

event: food-maintained responding was increased at doses that

decreased responding under the stimulus-shock termination schedule.

Chlordiazepoxide also differentially affected responding maintained

under concurrent variable-interval and concurrent fixed-interval

food- and shock-presentation schedules. In these experiments

responses on one lever produced shock while responses on a second

lever produced food. Despite the fact that these performances were

occurring simultaneously, chlordiazepoxide selectively increased

responding maintained by food while decreasing that maintained by

shock (Barrett et al. 1981c). Figure 3 illustrates this effect under

the concurrent variable-interva1 schedule. Finally, in a recent

study with rats, where comparable rates and patterns of responding

were maintained under variable-interval food-presentation and shockcancellation schedules, chlordiazepoxide increased responding maintained by food but decreased responding under the shock-cancellation

schedule (Ator 1979).

Evidence indicating that the nature of the event could be a factor

determining the effects of certain drugs under interval schedules

prompted additional work in which responding was maintained by different events under fixed-ratio schedules. In one experiment similar

rates and patterns of responding of squirrel monkeys were maintained

under a multiple fixed-ratio loo-response schedule of food presentation or stimulus-shock termination. In contrast to the differential

effects found under fixed-interval schedules with these different

consequent events, chlordiazepoxide, pentobarbital, and ethanol

decreased responding under both fixed-ratio schedules regardless of

whether food or stimulus-shock termination maintained responding

(Katz and Barrett 1978a).

The finding that the different behavioral effects of drugs are

related to the maintaining event under one schedule but not another

reaffirmed the importance of schedule factors. In addition, the

result that differential drug effects occur under one schedule but

not another, implies that unitary motivational accounts of the

effects of drugs based simply on the type of consequent event are

implausible.

Although only decreases in responding were obtained under the fixedratio schedules with pentobarbital, chlordiazepoxide, and ethanol,

other experiments have reported increases in responding maintained

under fixed-ratio stimulus-shock termination schedules with

165
FIGURE 3

Control performances and effects of Chlordiazepoxide under concurrent variable-interval schedules of food (1.5 minute) or shock (6

minute) presentation (MS-58). Abscissae: time; ordinates: cumulative responses. Recordings of food-maintained (left panels) and

shock-maintained (right panels) responding were made simultaneously.

On the records showing food-maintained responding diagonal marks on

the upper tracing denote food delivery and the marks on the lower

line represent shock delivery. On the records showing shockmaintained responding diagonal marks on the upper tracing denote

shock delivery and marks on the lower line represent food delivery.

Pens reset to base after 1100 responses. Note that chlordiazepoxidee

increased responding maintained by food but only decreased responding maintained by shock. (From Barrett et al. 1981c (in press).

© 1981, American Society for Pharmacology and Experimental

Therapeutics)

166
d-amphetamine (Barrett et al. 1981a, Johanson 1978, Katz and Barrett

1978b). Increases in responding maintained by food did not occur

with d-amphetamine, however, in those studies that examined these

effects under comparable schedules. Since these results differed

from those reported earlier by Kelleher and Morse (1964). several

other experiments were conducted in which the effects of damphetamine were examined under a broad range of fixed-interval and

fixed-ratio parameter values, as well as under multiple fixed-ratio

fixed-interval schedules (Barrett et al. 1981a). Over a range of

fixed-ratio values, from 30 to 300 (30 to 170 for food-maintained

monkeys) and a range of response rates from approximately 1.5 to 3.0

responses per second, most doses of d-amphetamine consistently

increased responding maintained by stimulus-shock termination, but

only decreased responding under the food schedule (figure 4).

Under fixed-interval schedules, however, that were varied from 30

seconds to 10 minutes, and over a range of response rates, damphetamine usually increased responding maintained by both-food and

stimulus-shock termination (figure 4). The differential effects of

d-amphetamine on responding under fixed-ratio schedules with different events, but not under the fixed interval, were also found when

these schedules were studied together as components of a multiple

schedule (figure 5).

These studies suggest quite convincingly that d-amphetamine differentially affects responding maintained by food and stimulus-shock

termination under fixed-ratio schedules. Under fixed-interval schedules, however, the effects of d-amphetamine are largely independent

of the event that maintains responding. Significantly. the different

effects of amphetamine on responding maintained by food and stimulusshock termination occur over a wide range of parameter values and

response rates. The results, therefore, cannot be regarded as being

of limited generality; the type of event can play a more significant

role than was apparent in early studies.

Sweeping generalizations about the relative independence of drug

effects and consequent behavioral events are not possible. A number

of different drugs have shown effects that depend on the event; the

specific outcome, however, depends on the drug, the schedule, and the

event. Under some conditions drug effects may also depend on the

parameter value of the schedule. For example, figure 6 shows that

pentobarbital increased responding under 40-response fixed-ratio

schedules of food presentation but not under comparable schedules of

stimulus-shock termination (Barrett et al. 1981a); in the study

described above (Katz and Barrett 1978&),pentobZrbital decreased

responding maintained by both events under higher-valued fixed-ratio

schedules. Other studies have indicated that drug effects under one

component of a multiple schedule can be dramatically modified by

changing the parameter value in another component, even when performance in the unchanged component is not affected (Barrett and Stanley

1980b). The conclusion that the event can play an important function

in determining the behavioral effects of many drugs is inescapable;

the conclusion that such effects are exclusively dependent on the

type of event, independent of other factors, however, is clearly

167
FIGURE 4

Effects of d-amphetamine on responding under different parameter values of fixed-ratio (top) or fixed-interval (bottom) schedules of food

presentation or stimulus-shock termination. Each point represents

the mean usually of at least two determinations. The points on the

left represent the mean of control observations + 1 S.E. Note that

at all of the fixed-ratio parameter values studied, d-amphetamine

decreased responding maintained by food but markedly-increased responding under the stimulus-shock termination schedule. Under the fixedinterval schedules, a broad range of doses of d-amphetamine increased

responding under all parameter values of the fixed-interval stimulusshock termination schedule. Increases in response rate were slightly

less or did not occur under the food-presentation schedule at the

30-second value, whereas at the 3- and lo-minute values rates were

markedly increased. Note the different ordinates for the two graphs

in the lower figure. (Figure from Barrett et al. 1981a)

168
FIGURE 5

Effects of d-amphetamine on responding under a multiple 40-response

fixed-ratio 3-minute fixed-interval schedule of food presentation or

stimulus-shock termination. Figures shown are percent changes in

control rates of responding. Circles denote responding under the

fixed-interval schedules, triangles responding under the fixed-ratio

schedules. Points with vertical lines on the extreme left of each

curve represent control observations + 1 S.E.; where there are no

vertical lines, this measure of variability fell within the area

encompassed by the point. Average control rates under the fixedinterval food-presentation schedule were 0.412 and 0.606 responses

per second for MS-6 and MS-13, respectively; under the fixed-ratio

schedule these rates were 3.799 (MS-6) and 3.851 (MS-13) responses

per second. When responding was maintained by stimulus-shock

termination schedules, rates under the fixed-interval were 0.651

(MS-9) and 1.605 (MS-25); under the fixed-ratio schedule these

rates were 2.903 (MS-9) and 2.336 (MS-25) responses per second.

(Figure from Barrett et al. 198la)

169
FIGURE 6

Effects of pentobarbital on responding under a multiple 40-response

fixed-ratio 3-minute fixed-interval schedule of food presentation

or stimulus-shock termination. Details are the same as in figure 5.

Note that pentobarbital increased responding under both fixedinterval and fixed-ratio schedules of food presentation, but only

decreased responding under these schedules when the maintaining

event was stimulus-shock termination. (Figure from Barrett et al.

1981a)

170
wrong. The same drug will produce similar effects on responding

maintained by different events under one schedule, but dissimilar

effects under another schedule. Although the findings described in

this section suggest that certain modifications are necessary in

existing views of the role of the event, they also reaffirm the

fundamental importance of schedule-controlled responding in determining the behavioral effects of drugs.

Response Duration and the Effects of d-Amphetamine

The effects with d-amphetamine were unexpected and somewhat difficult

to reconcile with-earlier work. As reproducible results accumulated

and response rate appeared to play a less important role in determining some of these effects (see figures 4 and 5), it seemed reasonable

to examine a dimension of the response other than rate. Recordings

were made, therefore, of response duration under the 30-response

fixed-ratio schedules of food presentation or stimulus-shock termination with squirrel monkeys. Subsequently, the effects of damphetamine on both response rate and response duration measures were

examined. Figure 7 shows data from these experiments. Average

response duration was considerably longer under the stimulus-shock

termination (MS-31) schedule than under that maintained by food

(MS-51 and MS-39); response rates maintained by food were slightly

higher than those maintained by termination of the stimulus associated

with shock.

Even though there were initial differences in response duration, the

effects of d-amphetamine on this measure under the two schedules were

similar: duration decreased at low to intermediate doses (.Ol-0.1

mg/kg) and increased at the higher doses (0.3-1.0 mg/kg). As in the

work described above, however, response rates were affected differentially; sizeable increases in rates occurred under the termination

schedule at doses that did not affect or decreased food-maintained

responding. Thus, whether differential or comparable effects of damphetamine are obtained under fixed-ratio schedules utilizing different consequent events depends on whether the experimental focus

is on response rate or response duration. Different conclusions

would be drawn depending on which response characteristic was examined.

Although response rate has been the traditional measure used in

behavioral studies and in behavioral pharmacology, other dimensions

may also provide beneficial information. As has been the case with

response rate, however, further research would necessarily have to

examine conditions where response duration maintained by the different events was comparable or was manipulated over a wide range.

Although these several findings are somewhat difficult to summarize,

it clearly appears that the type of maintaining event can influence

the specific effects a drug will have on behavior. At the present

time it is not possible to provide a general framework within which

these several different findings can be easily placed and evaluated.

Such problems are often true initially when newer findings do not

confirm earlier results. Different events can unquestionably produce

different behavioral effects. At the present time it is difficult

to determine which, if any, of these multiple effects contribute to

171
FIGURE 7

Effects of d-amphetamine on response rate and response duration

under fixed-ratio 30-response schedules of stimulus-shock termination (MS-31) or food presentation (MS-51 and MS-39). Note that

response duration was longer under the termination schedule than

under the food schedules but that at low to intermediate doses

this measure decreased for all animals regardless of the maintaining event. Response rates were higher under the food schedules

and were not increased with d-amphetamine; responding under the

stimulus-shock termination schedule, however, was increased substartiatly with d-amphetamine. (Figure from Barrett et al. 1981a)

172
the differential behavioral effects of drugs. Further experiments

addressed to this issue, which may eventually help in formulating

general principles, are summarized below.

Second-Order Schedules

In the experiments described thus far, all of the procedures involved

schedules where the completion of each schedule requirement produced

the consequent-maintaining event. Within the past ten years several

experiments have been conducted in which responding has been maintained by stimuli paired with consequent events such as food or drug

administration (Goldber 1975, Kelleher 1975). Formally termed

second-order schedules Kelleher 1966), such procedures arrange for

responding to produce a brief, usually visual, stimulus according to

a particular schedule; responding under that schedule is then treated

as a unitary response that is then also reinforced according to a

specific schedule.

The control performances in figure 8 illustrate characteristic rates

and patterns of responding of squirrel monkeys under second-order

schedules of food or shock presentation [fixed-ratio 10 (fixedinterval 3-minute:S)]. Under these schedules the first response

after 3 minutes produced a 3-second change in the color of the visual

stimulus illuminating the experimental chamber; after completion of

ten fixed intervals, the brief stimulus was followed by the delivery

of ten food pellets (MS-43) or ten 8 mA shocks (MS-29). The presentation of food or shock occurred only once, at the end of the complete session. This aspect of arranging the consequent events to

occur at the end of the entire session may be particularly advantageous in experiments where one is interested in examining the effects

of presession drug administration on drug-maintained responding. It

has not always been possible to prevent interactions between the drug

given prior to the session and the maintaining drug because of the

occurrence of repeated injections throughout the session which were

required to maintain performance. Second-order schedules, where

responding is maintained by brief stimuli only eventually paired with

drug injection at the end of the session, eliminate most direct interactions with the presession drug and provide a convenient means for

assessing several experimental issues (see below).

Similar interactions between presession drugs and consequent events

could also exist when events other than drugs maintain responding

and are presented intermittently throughout the session. For example, during an experimental session in which a drug is given as a

pretreatment, the recurrence of shock or food could produce changes

in behavior and in drug effects which may differ from those obtained

when the maintaining event is presented only once at the end of the

session.

Several studies conducted over the past few years have examined these

possibilities using second-order schedules of food or shock presentation, stimulus-shock termination, or intramuscular cocaine administration as maintaining events. Figure 8, for example, in addition to

depicting performances under second-order schedules of food or shock

173
FIGURE 8

Control performances and effects of chlordiazepoxide on responding

maintained under second-order schedules of brief stimuli paired with

either food or electric shock when those events occurred only at the

completion of each daily session. Abscissae: time; ordinates:

cumulative responses. The diagonal marks on each record denote the

occurrence of the 3-second visual stimulus. The recording pen was

reset with the presentation of either food (MS-43, left) or shock

(MS-29, right) at the end of the session. Note that chlordiazepoxide

increased responding maintained by food but only decreased responding

maintained by shock. (From Barrett et al. 1981c (in press). © 1981,

American Society for Pharmacology and Experimental Therapeutics)

174
presentation, also shows that chlordiazepoxide increased responding

maintained under second-order food-presentation schedules but only

decreased comparable responding maintained under similar schedules

by the presentation of shock (see also dose-effect curves in figure

9). These differential effects are similar to those found under

single-component fixed-interval schedules described earlier and suggest that those effects are not influenced substantially by the

recurring delivery of food or shock. Together with the effects of

chlordiazepoxide on responding maintained under the concurrent

variable-interval schedules (figure 3) and under stimulus-shock termination schedules, these several experiments provide rather compelling evidence for the event-dependent effects of chlordiazepoxide on

responding maintained under interval schedules of reinforcement.

In the studies using basic schedules summarized previously the

effects of c-amphetamine under fixed-interval schedules were largely

independent of the type of maintaining event. C-Amphetamine also

produced similar effects under second-order schedules of food or

shock presentation, stimulus-shock termination or intramuscular

cocaine administration (Barrett et al. 1981b, Katz 1980). Both

promazine (Katz 1980) and chlorpromazine (Valentine et al. 1981)

decreased responding under second-order schedules where responding

was maintained by food or by intramuscular cocaine administration.

Other experiments comparing the effects of drugs on performances

maintained by food and drug administration under similar secondorder schedules have not typically found differential effects with

pentobarbital, cocaine or chlordiazepoxide (Herling et al. 1979;

Valentine et al. 1981).

These several experiments indicate that, at least thus far, the

effects of drugs on behaviors under basic schedules are similar to

those obtained when those same events occur under second-order

schedules. It is interesting that drugs such as pentobarbital and

chlordiazepoxide which produce different effects on responding maintained by food and shock, appear to affect responding maintained by

food and cocaine administration in a similar manner. Further experiments that examine a wider variety of different maintaining and

pretreatment drugs, as well as different experimental procedures

(e.g., termination of a stimulus associated with naloxone administration in morphine-dependent monkeys), will undoubtedly help clarify

these issues.

SUMMARY AND CONCLUSIONS

This chapter has reviewed much of the recent experimental information

pertaining to our current understanding of the role of the consequent

event as a determinant of the behavioral effects of drugs. Although

it appeared at one time that the nature of the consequences controlling behavior were less important than other factors, such as the

schedule-controlled rate and pattern of responding, this conclusion

no longer seems true. Several experiments described in the preceding

sections provide overwhelming evidence that the type of event controlling behavior can be an important aspect of the environment

contributing to the behavioral effects of a number of drugs.

175
FIGURE 9

Effects of chlordiazepoxide on responding maintained under the FR 10

(FI 3-minute:S) second-order schedules of food (left panels) or shock

fright panels) presentation. Abscissae: chlordiazepoxide dose;

ordinates: response rate, percent of control. Unconnected points

on the left of each panel are means (+ 1 S.E.) of at least five control observations. Connected points are means of at least two

observations per dose. Note that across the rage of doses that

increased food-maintained responding, responding maintained by shock

was only decreased. (From Barrett et al. 1981c (in press). © 1981,

American Society for Pharmacology and Experimental Therapeutics)

176
Despite the fact that the event can be an important factor, other

features of the behavioral situation such as the schedule under which

the event is presented can also play a role. This was clearly seen

with d-amphetamine which increased responding maintained by food

or stimulus-shock termination under fixed-interval schedules; when

these same events controlled responding under fixed-ratio schedules,

however, d-amphetamine decreased food-maintained responding but

increased responding maintained under the termination schedule. Differential effects were also obtained with chlordiazepoxide under

fixed-interval but not fixed-ratio schedules. These findings point

to the increasing level of complexity involved in behavioral pharmacology as progress is made in attempting to characterize determinants

of the behavioral effects of drugs.

It has been clear for some time that environmental factors can play

an exceedingly influential role in determining the effects of a wide

variety of abused drugs. Environmental factors also exert tremendous

control over behavior and unquestionably influence its distinctive

nature. Many of the factors that are responsible for the subtle

idiosyncratic characteristics of behavior, as well as its more global

features, can be traced directly to the interaction of behavior with

the environment. Ongoing and newly emerging behavior has inevitable

consequences which not only affect that behavior directly and immediately, but also that of future behavior as well.

Drugs of abuse also produce extremely powerful effects on behavior.

It is significant that many of the variables that control behavior

also determine the behavioral effects of drugs. This natural reciprocity between the study of behavior and the behavioral effects of

abused drugs is beneficial because research on drug abuse advances

knowledge in both fields. Despite the fact that the effects of drugs

on ongoing behavior represent a vast integration of changes occurring

at several different levels, many of the principal determinants of

the behavioral effects of abused drugs can be attributed directly to

specific aspects of the environmental conditions under which that

behavior has occurred or is occurring. It has been shown repeatedly

that the same drug can have completely opposite effects on behavior

depending on any of several influential environmental variables.

An emphasis on the clarification and significance of environmental

variables, such as the role of the maintaining event, in attempting

to understand the behavioral effects of abused drugs is not meant

to deny or negate the importance of other factors. Changes in behavior produced by drugs, however, are often most conspicuous because

of the excessive nature, intensity, and disruption that typically

occurs. Drugs of abuse produce a variety of pharmacological effects

that are usually physiologically consistent. Yet, at the level of

behavior, there are often noteworthy discrepancies, particularly in

what seems to be a drug's abuse potential. Many abused drugs, for

example, produce marked uniform effects on psychomotor activity,

physiological and sensory processes that are reasonably consistent

from individual to individual. However, many of these drugs are

not ubiquitously abused nor do they produce entirely uniform behavioral effects. This suggests that perhaps many of the changes in

177
behavior produced by drugs of abuse, as well as a drug's abuse

liability, may be related more directly to environmental than to

pharmacological variables. Future research will hopefully identify

and provide a balanced account of the importance and generality of

both environmental and pharmacological determinants of the behavioral effects of abused drugs.

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AUTHOR

James E. Barrett, Ph.D.

Department of Psychiatry

School of Medicine

Uniformed Services University

of the Health Sciences

4301 Jones Bridge Road

Bethesda, Maryland 20014

181
Predicting the Dependence

Liability of Stimulant Drugs

Roland R. Griffiths, Ph.D., Joseph V. Brady, Ph.D., and

George E. Bigelow, Ph.D.

Over the last 15-20 years, methods have been developed and refined

for examining the self-administration of drugs by animals (e.g.,

Spealman and Goldberg 1978, Griffiths et al. 1980). One interesting issue which can be addressed with these methods involves differentiating between drugs with respect to their relative efficacy

in maintaining self-administration. Initial interest in this scientific pursuit was stimulated when it was recognized that there

is a good correspondence between those drugs self-administered by

laboratory animals and those abused by man. In 1970, interest was

further augmented when Congress passed the Controlled Substances

Act which required that drugs be classified under a five-tier

schedule system which differetitiated between drugs on the basis of

several criteria, including their actual or relative potential for

abuse.

This paper will review animal drug self-administration methods and

describe their usefulness in providing information about the dependence liability of psychomotor stimulant drugs. Specifically,

animal self-administration results with a wide range of psychomotor

stimulants will be reviewed (section I), and approaches for measuring the relative reinforcing efficacy of different drugs in animals will be described (section II). A third section will discuss

the relationship between the reinforcing and anorectic properties

of appetite suppressant drugs. The final section will discuss the

correspondence of the animal drug self-administration results to

clinical information relevant to human drug abuse.

I. SELF-ADMINISTRATION OF PSYCHOMOTOR STIMULANTS BY ANIMALS

The most common and reliable procedure for determining whether a

drug will maintain self-administration is the substitution procedure (Johanson and Balster 1978). The procedure involves establishing self-administration using a dose of a standard drug which

is known to maintain reliable self-administration behavior. After

this behavior baseline has stabilized, a dose of the test drug is

substituted for the standard compounds to determine whether the

test drug will maintain self-administration.

182
Using this basic approach, our laboratory has examined the intravenous self-administration of a ran e of psychomotor stimulants

and structurally related compounds (Griffiths et al. 1976,

Griffiths et al. 1979b) These studies were conducted with male

baboons weighing 15-24 kg and having histories involving selfinfusion of a variety of drugs.

The availability of an intravenous infusion was indicated by a 5-

set tone and illumination of a light directly over a lever on the

intelligence panel. When the light was illuminated, each response

produced a brief feedback tone. Upon completion of a 160-response

fixed-ratio schedule requirement (FR 160), the light over the

lever was extinguished and the drug infusion began. Also at this

time a light was illuminated in the upper left-hand corner of the

intelligence panel for a 1-hr period. A time-out period of 3 hrs

followed each infusion, permitting a maximum of eight infusions

per day.

Self-infusion performance was first established with cocaine at a

dose of 0.4 mg/kg per infusion. After a minimum of 3 consecutive

days of cocaine availability during which six or more infusions

were taken each day a specified dose of a test drug or saline was

substituted for the cocaine. Self-administration testing involved

access to the test drug for at least 12 days. After exposure to

each dose of test drug, cocaine was reinstated, and when the criterion of a minimum of 3 consecutive days of six or more infusions

per day had been met, another dose or drug was again substituted.

This procedure of replacing cocaine with a test drug was continued

throughout the experiment. The order of exposure to drugs, saline,

and different doses was mixed.

Figure 1 presents mean levels of self-infusion for the 14 phenylethylamines. Of all the drugs examined, d-amphetamine was the

most potent, maintaining levels of self-administration above saline

at doses of 0.05 and 0.1 mg/kg. Phentermine, diethylpropion, phenmetrazine, phendimetrazine, benzphetamine, and MDA all maintained

levels of self-administration above saline at doses of 0.5 or 1.0

mg/kg. d-Ephedrine, clortermine, and chlorphentermine were the

least potent of the drugs which maintained performance, supporting

self-infusion rates above saline control levels at doses of 3.0

and 10.0 mg/kg (-ephedrine), 3.0 and 5.0 mg/kg (clortermine), and

2.5 and 5.0 mg/kg (chlorphentermine). In contrast to most of the

other phenylethylamines which maintained self-infusion behavior,

the pattern of self-administration with L-ephedrine was particularly unstable, characterized by either an erratic or cyclic pattern over days. Finally, in contrast to all of the other phenylethylamines tested, fenfluramine, PMA, DOM, and DOET were not selfadministered at a level greater than saline at any of the doses

studied (means of the determinations at each dose did not exceed

the range of saline values). Three animals exposed to 1.0 mg/kg

per infusion of DOET died within the first three days.

183
FIGURE 1

Average number of infusions per day day with 14 phenythylamures. Intravenous

infusions were delivered upon completion of 160 lever presses, a 3-lvr. a timeout followed each infusion, permitting a maximum of eight infusions per day.

C indicates mean of all the 3-day periods with cocaine which immediately 

preceded every substitution of a phenylethylamine or saline. S indicates

mean of days 8-12 after substitution of saline (two saline substitutions in

each of 15 animals). Brackets indicate ranges of individuals animals means.

Drug data points indicate mean of 6 days 8-12 after substitution of a drug for

individual animals. Lines connect means at indicated doses of drug. (From

R.R. Griffiths, J.V. Brady and L.D. Bradford. In Thompson, T. and Dews,

P.B., eds. Advances in Behaviorol Pharmacology. Vol. 2. New York © Academic press. 1979b. pp. 163-208. Reprinted by permission.)

184
Figure 2 shows mean levels of self-infusion for three additional

central nervous system stimulant compounds which are not phenylethylamines: cocaine, caffeine, and nicotine. Cocaine maintained

high levels of self-infusion performance through a broader range

of doses than any of the 16 other drugs tested (0.032-3.2 mg/kg).

Figure 2 shows that mean levels of self-infusion of both nicotine

and caffeine were within the saline control range. Inspection of

the day-to-day data revealed that the caffeine dose of 3.2 mg/kg

was sometimes associated with variable daily patterns of selfadministration.

The preceding findings are derived from one specific drug substitution procedure. Obviously in such self-administration testing,

many methodological variations are possible. The overall reliability of animal drug self-administration testing is indicated by

the replicability of results across a range of methodological and

procedural variations. Assessments of drug self-administration

have been conducted using different species, routes of administration, response requirements, durations of availability, behavioral

or pharmacological histories, etc. with remarkably consistent results. For example, a comprehensive review of published studies

with psychomotor stimulants (Griffiths et al. 1979b) indicated

there were 36 published experiments across five different species

and three different routes of administration, in which d-amphetamine maintained self-administration, whereas there was only one

published report which described a failure to obtain self-administration. This same replicability across published studies holds

true for drugs which do not maintain self-administration. For

instance, with fenfluramine, eight different studies in three different species uniformly failed to demonstrate self-administration.

Data from drug self-administration testing provide information for

making the relatively dichotomous discrimination about whether or

not a drug maintains self-administration. Table 1 summarizes the

results of a large number of studies of psychomotor stimulant drug

self-administration in animals (Griffiths et al. 1980). Drugs were

selected for inclusion in the table if they had been available

through licit or illicit channels for human use or abuse. Maintenance of self-administration by each drug in the table was rated

as "yes,' 'no,' or "equivocal," based on the conclusions of the

published reports. Drugs were also rated as maintaining "equivocal" self-administration if different studies reported conflicting

results.

II. ASSESSING THE RELATIVE REINFORCING EFFICACY OF DRUGS IN

ANIMALS

Data from substitution procedures such as that described above for

the phenylethylamines permit a relatively gross discrimination

about whether or not a drug will serve as a reinforcer. In recent

years increasing experimental attention has been directed toward

developing more sensitive drug self-administration procedures to

make more refined and graded discriminations of the relative reinforcing efficacy of different drugs. Behavioral procedures for

185
FIGURE 2

Average number of infusions per day with cocaine, caffeine

and nicotine. Datails of figure identical to Figure 1. (From

R.R. Griffiths, J.V. Brady and L.D. Bradford. In. Thompson, T.

and Dews, P.B., eds. Advances in Behavioral Pharmacology. Vol.

2. New York © Academic Press, 1979b. pp. 163-208. Reprinted

by permission.)

186
TABLE 1

Summary of Results from Animal Drug Self-Administration Studies

187
assessing the relative reinforcing efficacy of drugs are derived

from procedures which have been used for evaluating the behaviormaintenance properties (i.e., reinforcing properties) of a variety

of environmental stimuli (e.g., food, water, drugs, etc.). Observed variation in this performance-maintenance property has been

assumed to reflect the "strength," "efficacy," or "value" of stimuli as reinforcers, although the hypothetical status of such intervening processes requires interpretative caution (as discussed in

detail by Griffiths et al. 1979b).

Comparison of Different Cocaine Doses: In a variety of studies,

methods that may assess relative reinforcing efficacy have been

used to examine the effects of a range of cocaine doses. In spite

of wide procedural differences, a clear generalization has emerged

from this research: higher doses of cocaine are associated with

higher measures of reinforcing efficacy than lower doses, except

that doses exceeding 0.1 or 0.5 mg/kg are usually shown to be

equally reinforcing. This relationship has been demonstrated with

discrete-trial choice procedures (Johanson and Schuster 1975, Brady

and Griffiths 1977). concurrent schedules (Ialauer and Woods 1974.

Llewellyn et al. 1976), fixed-interval schedules (Balster and .

Schuster 1973, Goldberg and Kelleher 1976, Bradford and Griffiths

1980), second-order schedules (Kelleher and Goldberg 1977), progressive-ratio schedules (Yanagita 1973, Bedford et al. 1978,

Griffiths et al. 1978a, 1979a), and fixed-ratio schedules

(Grlffiths et al. 1979a).

Comparison of Different Drugs: Fewer studies have attempted to

compare the reinforcing efficacy of different stimulant drugs

(Yanagita 1973, Griffiths et al. 1975, Griffiths et al. 1978a,

Johanson and Schuster 1975, 1977). One study (Griffiths et al.

1978a) used a progressive-ratio schedule for comparing performance

maintained by cocaine and three amphetamine derivatives (diethylpropion, chlorphentermine, and fenfluramine) over a substantial

range of doses. Infusions of drug were contingent upon completion

of a FR response requirement, with a 3-hr time-out period following

each infusion. Prior to testing each dose of drug, stable selfinfusion performance was first established with cocaine when the FR

requirement was 160. Subsequently, a test dose of drug was substituted for the standard dose of cocaine. If the dose of drug

maintained a criterion level of self-infusion performance, the

ratio requirement was systematically increased every day until the

"breaking point" at which the self-infusion performance fell below

a criterion level (one or zero infusions per day). A breaking

point was defined as the ratio value at which criterion performance

disruption occurred.

Figure 3 shows the results in five baboons. Within-animal comparison of the maximum breaking points maintained by the different

drugs indicates that cocaine maintained the highest breaking

points, followed in order by diethylpropion, chlorphentermine, and

fenfluramine. More specifically, within-animal comparison of the

data presented in Fig. 3 reveals doses of cocaine that maintained

higher average breaking points than all the doses of diethylpropion,

188
chlorphentermine, and fenfluramine tested. Similarly, there were

doses of diethylpropion that maintained higher average breaking

points than all doses of chlorphentermine and fenfluramlne, and

finally, there were doses of chlorphentermlne that maintained

higher average breaking points than all doses of fenfluramine.

Breaking point values for doses of fenfluramine, chlorphentermine, diethylpropion, and cocaine in 5 baboons. Each point represents a single breaking

point observations. Lines connect the menas of the breaking point observations at different doses of drug. Closed circles indicated data obtained

during the first exposure to a drug dose. Open circles indicate data

obtained during a second exposure to a drug dose. (From R.R. Griffiths,

J.V. Brady and J.D. Snell. Psychopharm, 56.5-13, 1978a. Reprinted by permission. © Springer-Verlag New York, Inc.)

189
Johanson and Schuster (1977) provided additional information about

several of these same compounds in a study which examined drug

choice performance in rhesus monkeys. Using a two-lever discrete

trial choice procedure, these investigators compared cocaine (0.1

and 0.5 mg/kg) and diethylpropion (0.5 and 1.0 mg/kg), and showed

that cocaine was generally preferred to diethylpropion. These

results are compatible with the previously cited progressive-ratio

study, and suggest that, under these conditions, cocaine is a more

efficacious reinforcer than diethylpropion.

III. ASSESSMENT OF THE RELATIONSHIP BETWEEN ANORECTIC AND REINFORCING PROPERTIES OF APPETITE SUPPRESSANT DRUGS

The previous sections have focused on the reinforcing properties

of stimulant drugs. It has been argued that a balanced assessment

of dependence liability should not consider the reinforcing properties of a drug independently of the therapeutic properties;

rather, it is important to consider the relationship between the

reinforcing properties and therapeutic properties. Knowledge about

this relationship provides information about the extent to which

therapeutic applications of a drug will necessarily involve exposure to the drug's reinforcing effects (Griffiths et al. 1979b)..

Using baboon drug self-administration data Griffiths et al. (1978b)

developed a quantitative measure of this relationship between the

reinforcing and therapeutic properties of a series of anorectic

compounds. It was reasoned that, in terms of minimizing dependence

liability, the most desirable anorectic drug would be more potent

as an anorectic than as a reinforcer; while an undersirable anorectic drug would be more potent as a reinforcer than as an anorectic. Existing anorectic drugs may fall anywhere on the continuum defined by these parameters. A quantitative measure of this

continuum is provided by the anorectic-reinforcement ratio which

compares the relative potency of a drug as an anorectic with its

relative potency as a reinforcer (Griffiths et al. 1978b).

A standardized drug self-administration substitution procedure with

baboons (Griffiths et al. 1976) similar to that described in an

earlier section of this chapter was used to determine the lowest

drug dose which maintained intravenous self-administration above

saline control levels. This dose provided the denominator for

calculation of the anorectic-reinforcement ratio. A measure of

anorectic effects in the baboon was also obtained by determining

the dose of drug which suppressed daily food intake to 50% of control levels. This dose provided the numerator for calculation of

the anorectic-reinforcement ratio.

The filled bars of Figure 4 show the resulting anorectic-reinforcement ratios (based upon adjustment to an arbitrarily assigned damphetamine value of 1.0) derived from the relationship between

food suppression dose (numerator) and lowest reinforcing dose

(denominator) for each of nine drugs. The ratio values range

from a low of zero for fenfluramine and phenylpropanolamine to a

a high of 14.81 for cocaine, and reflect the fact that compounds

190
with high ratio values are more potent reinforcers (relative to

their anorectic potency) than compounds with lower ratio values.

FIGURE 4

Anorectic-reinforcedment ratios for cocaine and eight anorectic drugs. Filled

bars show data derived entirely from baboon experiments. Striped bars show

data derived from both human clinical information and baboon experiments.

Compounds with high ratio values are more potent reinforcers (relative to

their anorectic potency) than compounds with lower ratio values (From R.R.

Griffiths, J.V. Brady, and and L.D. Bradford. In. Thompson. T., and Dews, P.B.,

eds. Advances in Behavirol Pharmacology. Vol. 2. New York: © Academic

Press, 1979b. pp. 163-208. Reprinted by permission.)

Since the measure of anorectic potency as determined with the

baboon could be confounded by nonspecific psychopharmacological

effects such as drug-induced sensory or motor decrements, an

alternative set of values was derived by utilizing as the ratio's

numerator the lowest recommended daily human anorectic doses.

This alternative method of calculation provided a comparative set

of ratio values. Comparison of the striped bars vs. the filled

bars in Figure 4 shows the correspondence between the ratios based

upon these two independent measures of anorectic potency. Since

cocaine is not used clinically as an anorectic, no striped bar

appears in the figure for cocaine.

IV. CORRESPONDENCE OF ANIMAL DRUG SELF-ADMINISTRATION RESULTS

TO CLINICAL INFORMATION

Relationship Between Animal Data and Human Drug Abuse: In general,

there is a good correspondence between those drugs self-administered by laboratory animals and those abused by man. This section

will involve a discussion of self-administration results summarized

in Table 1 in relation to subjective-effect information obtained

in clinical studies, and in relation to the incidence of clinical

191
case reports describing abuse obtained from thorough reviews of

the literature (Griffiths et al. 1979b; Griffiths et al. 1980).

Amphetamine, diethylpropion, cocaine, methylamphetamine, methylphenidate, and phenmetrazine are all associated with numerous

clinical case reports involving abuse. Furthermore, all of these

drugs plus benzphetamine and e-ephedrine have been evaluated on

subjective-effect questionnaires (Addiction Research Center

Inventory, ARCI) in drug abuser subjects and have been shown to

produce a similar constellation of "euphoric" effects presumed to

reflect abuse potential. This information concerning the abuse

and subjective effects of these drugs corresponds with the fact

that all of these drugs maintain self-administration in animals,

as shown in Table 1.

In contrast, Table 1 shows that neither phenylpropanolamine nor

fenfluramine maintained self-administration in animals. This

corresponds well to the available clinical information about these

anorectic phenylethylamines. Both of these drugs are associated

with a relatively low incidence of abuse. There are no reports of

human abuse of phenylpropanolamine in spite of its wide availability as a nonprescription anorectic sold on an over-the-counter

basis. There have been only two reports describing the nonmedical

misuse of fenfluramine, and in both instances, the drug was apparently used for its hallucinogenic effects. As discussed elsewhere

(Griffiths et al. 1979b), animal drug self-administration does not

provide accurate predictive information about hallucinogens.

Furthermore, fenfluramine was evaluated on questionnaire ratings

and the ARCI, and produced a subjective-effect profile which was

unlike that produced by amphetamine and which has been interpreted

to indicate dysphoria.

Table 1 shows that chlorphentermine is associated with equivocal

self-administration in animals which indicates that chlorphentermine is a less robust reinforcer than drugs such as cocaine,

amphetamine, and phenmetrazine. Available information about chlorphentermine provides no basis for differentiating this drug from

fenfluramine or phenylpropanolamine: the incidence of case reports

involving abuse is extremely low, and evaluation of subjective and

objective effects indicated that the drug was dissimilar to amphetamine.

Table 1 also indicates that both caffeine and nicotine produce only

equivocal self-administration in animals, indicating that these

drugs are less robust reinforcers than some of the other drugs

listed. This finding does not adequately predict the fact that

human self-administration and dependence on these compounds are

ubiquitous. It seems probable that wide social acceptance and

availability of these compounds are responsible for greatly

potentiating their use and abuse.

Finally, Table 1 shows that pemoline is not self-administered by

laboratory animals. This information corresponds to the fact that

192
there are relatively few clinical case reports describing its

abuse as a psychomotor stimulant.

Relationship Between Animal and Human Drug Self-Administration

Data: The preceding discussion describes the relationship between

the animal self-administration results and existing clinical and

experimental information about the abuse and subjective effects of

the psychomotor stimulants. There have been several recent experimental reports which have directly examined the human self-administration of several psychomotor stimulants. In a study by Bigelow

et al. (1980), human self-administration of d-amphetamine, fenfluramine, and placebo were compared under double-blind conditions

in the context of an outpatient weight-control program. Overweight

women were randomly assigned to a medication group and given substantial self-control over the amount of anorectic medication they

could take over a four-week period while enrolled in a behavioral

self-management treatment program for overweight. The medication

groups differed in the persistence of drug self-administration.

Figure 5 shows the percentage of patients in each drug group who

continued to use their assigned medications over consecutive days.

FIGURE 5

Human self-administration of d-amphetamine, fenfluramine and placebo over consecutive days. Subjects were overweight women enrolled in an outpatient weightcontrol program and randomly assigned to a medication group. d-amphetamine (N.

17), fenfluramine (N-27), placebo N = 21), Use of d-amphetamine was significantly better maintained than use of fenfluramine. (From

Bigelow and J.E. Henningfield. In: Mello, N.K. ed. Advances in Substance

Abuse , Greenwich, Conn. © Jai press, Inc. 1980. pp. 1-90. Reprinted by permission.)

193
Patients were considered to have continued medication use through

the day they took their last dose, even if they had temporarily

suspended use prior to that time. Fenfluramine use fell off most

rapidly; placebo use fell off next most rapidly; and d-amphetamine

use was most strongly maintained. Statistical comparison revealed

that the mean duration of d-amphetamine use was significantly

longer than that for placebo, and that the mean duration of fenfluramine was significantly less than that for placebo. Other

recent studies by Johanson and Uhlenhuth (1978, 1980) have

described human self-administration of the psychomotor stimulants

d-amphetamine and diethylpropion. On three days each week, normal

volunteers, who were blind to the type of drug available, were

permitted to choose between differently colored capsules containing placebo or various doses of drug. The results showed that subjects generally preferred the psychomotor stimulant drugs to placebo

on the maioritv of trials. As with the other clinical and experimental information about abuse and subjective effects, the results

of these three human drug self-administration studies correspond to

the animal drug self-administration results by demonstrating that

both d-amphetamine and diethylpropion maintain higher levels of

self-administration than placebo in contrast to fenfluramine which

does not maintain self-administration above placebo levels.

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cocaine reinforcement: Effect of dose and infusion duration. J

Exp Anal Behav,20:119-129, 1973.

Bedford, J.A., Baily, L.P. and Wilson, M.C. Cocaine reinforced

progress-ratio performance in the rhesus monkey. Pharmacol

Biochem Behav, 9:631-638, 1978.

Bigelow, G.E., Griffiths, R.R., Liebson, I. and Kaliszak, J.E.

Double blind evaluation of reinforcinq and anorectic actions of

weight control medications. Arch Gen-Psychiat, 37:1118-1123, 1980.

Bradford, L.D. and Griffiths, R.R. Responding maintained by

cocaine or d-amphetamine under fixed-interval schedules in baboons.

Drug and Alcohol Dependence, 5:393-400, 1980.

Brady, J.V. and Griffiths, R.R. Drug maintained performance and

the analysis of stimulant reinforcing effects. In: Ellinwood,

E.H. and Kilbey, M.M., eds. Cocaine and Other Stimulants. New

York: Plenum Press, 1977. pp.599-613.

Goldberg, S.R. and Kelleher, R.T. Behavior controlled by scheduled

injections of cocaine in squirrel and rhesus monkeys. J Exp Anal

Behav,25:93-104, 1976.

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in animal and human drug-taking behavior. In: Mello, N.K., ed.

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abuse liability of drugs with animal drug self-administration

procedures: Psychomotor stimulants and hallucinogens. In:

Thompson, T. and Dews, P.B., eds. Advances in Behavioral Pharmacology. Vol. 2. New York: Academic Press, 1979b. pp. 163-208.

Griffiths, R.R., Brady, J.V. and Snell, J.D. Relationship between

anorectic and reinforcing properties of appetite suppressant drugs:

Implications for assessment of abuse liability. Biol Psychiat,

13:283-290, 1978b.

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performance maintained by drug infusions: Comparison of cocaine,

diethylpropion, chlorphentermine, and fenfluramine. Psychopharm,

56:5-13, 1978a.

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43:81-83, 1975.

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in baboons. Psychopharm, 50:251-258, 1976.

Iglauer, C. and Woods, J.H. Concurrent performances: Reinforcement by different doses of intravenous cocaine in the rhesus monkey. J Exp Anal Behav, 22:179-196, 1974.

Johanson, C.E. and Balster, R.L. A summary of the results of

self-administration studies using substitution procedures in primates. Bull Narcotics, 30:43-54, 1978.

Johanson, C.E. and Schuster, C.R. A choice procedure for comparing

drug reinforcers: Cocaine and methylphenidate in the rhesus monkey.

J Pharmacol Exp Ther, 193:676-688, 1975.

Johanson, C.E. and Schuster, C.R. A comparison of cocaine and

diethylpropion under two different schedules of drug presentation.

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

Stimulants. New York: Plenum Press, 1977. pp. 545-570.

Johanson, C.E. and Uhlenhuth, E.H. Drug self-administration in

humans. In: Krasnegor, N., ed. Self-Administration of Abused

Substances: Methods for Study. National Institute on Drug Abuse

Research Monograph 20. DHEW Pub. No. (ADM)78-727. Washington,

D.C.: supt. of Docs., U.S. Govt. Print. Off., 1978. pp. 68-85.

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humans: d-Amphetamine. Psychopharm, 71:275-279, 1980.

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second-order schedules of food presentation or cocaine injection.

J Exp Anal Behav, 28:221-231, 1977.

Llewellyn, M.E., Iglauer, C. and Woods, J.H. Relative reinforcer

magnitude under a non-independent concurrent schedule of cocaine

reinforcement in rhesus monkeys. J Exp Anal Behav, 25:81-91, 1976.

Spealman, R.D. and Goldberg, S.R. Drug self-administration by

laboratory animals: Control by schedules of reinforcement. Ann

Rev Pharmacol Toxicol, 18:313-339, 1978.

Yanagita, T. An experimental framework for evaluation of dependence liability in various types of drugs in monkeys. In: Pharmacology and the Future of Man. Proceedings of the Fifth International Congress of Pharmacology. San Francisco, 1972. Basel:

Karger, 1973. pp. 7-17.

ACKNOWLEDGEMENTS

Preparation of this manuscript was supported in part by National

Institute on Drug Abuse grants DA-01147, DA-01022, and Research

Scientist Awards K05 DA-00018 and K02 DA-00050.

AUTHORS

Roland R. Griffiths, Ph.D.

Joseph V. Brady, Ph.D.

George E. Bigelow, Ph.D.

Department of Psychiatry and Behavioral Sciences

The Johns Hopkins University School of Medicine

Baltimore, Maryland 21205

196
Establishment of Orally Delivered

Drugs as Reinforcers for Rhesus

Monkeys: Some Relations to

Human Drug Dependence

Richard A. Meisch, M.D., Ph.D., and Marilyn E. Carroll, Ph.D.

The study of drug-seeking behavior in laboratory animals was made

possible by the development of techniques that permit an animal

to intravenously self-administer drugs (Deneau et al. 1969,

Thompson and Schuster 1964, Weeks 1961). These intravenous techniques have been used in many subsequent studies; on the other

hand, the oral route has not often been used. Over the last 10

years, procedures have been devised that result in orally delivered drugs serving as reinforcers (Meisch 1975; Samson and Falk

1974).

A major problem in studies of oral drug intake is that animals

reject most drug solutions, probably because they have an aversive taste. One way to overcome this problem has been to induce

the drinking of large volumes of water and then to substitute

drug solutions at low concentrations for the water.

Specifically, in the initial studies water drinking was induced

by intermittent delivery of food pellets to food-deprived rats.

When water was replaced by ethanol solutions, the rats drank

large amounts of ethanol (Falk et al. 1972; Freed et al. 1970;

Holman and Myers 1968; Meisch and Thompson 1971; Senter and

Sinclair 1967). When deliveries of food pellets were

discontinued, water drinking diminished, whereas ethanol drinking

persisted at rates that far exceeded water drinking (Freed et

al. 1970; Meisch and Thompson 1971). Thus, ethanol was

functioning as a reinforcer. Results of subsequent studies

demonstrated that several different procedures could be used to

establish ethanol as a reinforcer (Meisch 1975). This research

has been extended to rhesus monkeys (Meisch et al. 1975) and to

other drugs (Carroll and Meisch 1978, 1979a, b, 1980b; Meisch and

Stark 1977).

In the last three years orally delivered etonitazene,

pentobarbital, and phencyclidine have been established as

reinforcers for rhesus monkeys (Carroll 1981; Carroll and Meisch

1978, 1980b; Meisch et al. 1981). The procedures used in these

studies were derived from procedures used in the earlier studies.

197
This paper concerns features common to the procedures used to

establish orally delivered drugs as reinforcers and variables

that control drug-reinforced behavior. Some implications of

these results for an analysis of human drug dependence are

mentioned.

METHODS

Animals

Male adult rhesus monkeys (Macaca mulatta) are housed in individual experimental chambers. The monkeys are reduced to and

maintained at 70 to 85 percent of their free-feeding weights.

Apparatus

Stainless steel primate cages (Labco #ME 1305 or Hoeltge #HB-108)

with three solid walls and one barred wall serve as the experimental chambers. A response lever for food, a drinking spout,

and corresponding stimulus lights are mounted on one solid wall.

A red stimulus light, 14 cm above the food lever, is illuminated

when food is available. One-g Noyes banana-flavored pellets are

delivered to a small tray recessed in the wall beneath the food

lever. The drinking spout is electrically nonconductive, 1 cm in

diameter, and protrudes 2.7 cm into the cage. A small brass contact plate (0.5 cm in diameter) is recessed 1 cm from the tip of

the spout and is wired to a lip-sensitive drinkometer. A lip

contact activates a solenoid for a maximum duration of 0.25 sec,

thereby delivering approximately 0.5 ml of liquid through the

spout. A break in lip contact during liquid delivery immediately

terminates solenoid operation; this arrangement prevents

spillage. Lip contact with the brass plate on the spout results

in illumination of one of two pairs of stimulus lights. The

lights are mounted at the 2, 4, 8, and 10 o'clock positions on a

3.2 cm radius measured from the center of the drinking spout.

Each light within a pair is 180 degrees from the other light.

The white pair of lights is illuminated for the duration of each

lip contact response when water is present; the green pair of

lights is illuminated for the duration of a response when the

drug is present. In addition to the two pairs of feedback

lights, a larger yellow light is 9 cm above the drinking spout.

This light is illuminated when water is available during sessions

and intersessions, and it blinks at a rate of 10 Hz when drug is

available. Liquids are contained in covered stainless steel

reservoirs. There is no measurable evaporation. Solid state

equipment or computers for scheduling and recording events are

located in an adjacent room. Details concerning the apparatus,

control equipment and drinking devices have been presented

elsewhere (Carroll et al., 1981b; Henningfield and Meisch 1976a;

Meisch and Henningfield 1977).

198
Procedure

Food-induced drinking of water. Daily sessions are 3 hours in

length and are preceded and followed by a l-hour stimulus

blackout so that data can be recorded and liquids changed. Water blackout so that data can be recorded and liouids changed. Water

is continuously available via the drinking spout during the

remaining 19 hours.

Water deliveries occur under a fixed-ratio 1 schedule (FR 1);

that is, each lip-contact response produces one delivery of

approximately 0.5 ml of water. Initially, water intake during

the sessions is measured in the absence of within-session food

availability; the daily food ration is given during the 19-hour

intersession period. Subsequently, access to food is shifted to

the beginning of the second hour of the 3-hour session. Food

availability is signaled by illumination of a light above the

food lever. In the presence of the food light, lever presses

produce food pellets according to various schedules. An FR 1

schedule was used with pentobarbital and a DRL (Differential

Reinforcement of Low Rates) 30 sec was used with etonitazene and

phencyclidine. After the fixed number of pellets is obtained,

the food light is turned off.

During the 3-hour session, each lip-contact response results in

water delivery. After water drinking is stable for five consecutive sessions, water is replaced by a low drug concentration

(e.g., 0.0078 mg/ml of sodium pentobarbital). In all experiments

behavior is judged stable when visual inspection of the data

reveals no systematic trends in either the rate or pattern of

responding over five consecutive sessions.

Increases in drug concentration are made by doubling the concentration. Each concentration is presented until five sessions of

stable behavior are obtained.

Termination of access to food within sessions. Access to food

within sessions is permanently terminated either when drinking

becomes dissociated from eating (e.g., drinking during the first

hour of the session) or when drinking results in pronounced

effects (e.g., severe ataxia). When access to food within

sessions is stopped, the maintenance feedings of food are given

at least 1 hour after the session.

Increases in fixed-ratio size. After drug intake is stable in

the absence of inducing conditions (i.e., food available during

the session) the fixed-ratio size is gradually increased. Fixed

ratios are increased in the sequence FR 1, 2, 4, 8, . . . .

Comparisons of drug- and water-maintained behavior. Rates of

drug responding are compared with rates of vehicle (water)

responding either by substituting water for drug solutions or by

making water concurrently available via a second drinking spout.

When water is concurrently available, the locations of the drug

and water are reversed from session to session to control for

possible side preference.

199
Effects of drug concentration. Drug concentrations are presented

in either an increasing ( e.g., ethanol) or decreasing (e.g.,

etonitazene, pentobarbital) series of concentrations. Each concentration is present until five sessions of stable behavior are

obtained.

Effects of food deprivation and satiation. Drug and water

sessions occur on alternate days. After 10 sessions of stable

behavior (5 drug and 5 water sessions), the food-deprived monkeys

are satiated by rapidly increasing the amount of food available

between sessions until not all available food is consumed. This

phase lasts for 30 sessions. The monkeys are again food

deprived.

RESULTS

Acquisition

Water drinking. During 3-hour sessions in which only water is

variable, food-deprived rhesus monkeys usually drink less than

150 ml. The water drinking occurs in an irregular pattern.

In the next phase, the daily food allotment is made available

within the session either intermittently or in a single meal.

Both ways of presenting food generate substantial water drinking

that ranges among monkeys from 300 to 1000 ml per session. When

food pellets are presented intermittently, a pattern of scheduleinduced drinking develops; and when food is given in a single

meal, a high rate of drinking occurs for about 30 minutes after

the meal (see figure 1).

Induced drug intake. In the next phase a low drug concentration

e.g., 0.0078 mg/ml of sodium pentobarbital) replaces water

during the session. Between sessions water is freely available.

After five sessions the concentration is doubled. However, if a

trend emerges over a block of five sessions, the concentration is

held constant until behavior is stable.

Drug intake (mg/kg of body wt/session) generally increases with

increases in drug concentration (figure 2). Figure 3 shows that

higher drug concentrations and under intermittent schedules 'of

food reinforcement, the pattern of food-reinforced lever pressing

is disrupted (Carroll and Meisch 1980b). Thus, the animals consume quantities of the drug sufficient to alter ongoing behavior.

Removal of food. Access to food is shifted from within the

session to after the session either when drug intake becomes

dissociated from food intake or when drug intake produces marked

behavioral effects such as anesthesia. In the absence of food,

drug intake persists but usually at a lower level than in the

presence of food (figure 2).

200
MONKEY M-HW

Figure 1. Cumulative records for monkey M-HW shoving represelltative performances under several conditions. since the monkey

was responding under an FR 1 schedule, vertical increments in the

records represent both liquid responses and deliveries. The records labeled l No FID. are from sessions when only water (0

mg/ml) or pentobarbltal (0.25 mg/ml) was present. Records

labeled FID. are from sessions when the daily food ration was

given to the monkeys one hour after the start of the session.

All food was generally consumed within 10 minutes, and this point

is indicated by the arrows. Note the high rate of drinking after

eating. Also, note that in the absence of food, pentobarbital deliveries maintained higher response rates than did water deliveries

(from Renningfield et al. 1978).

Figure 2. Pentobarbital

intake (mg/kg/3-hour session)

as a function of pentobarbital concentration. Bach

point is a mean of the last

five sessions at each

concentration. Not illustrated is monkey Pi's foodinduced intake at .35 mg/ml;

at this concentration his

intake was considered

dangerously high and foodinduced drinking was discontinued after two sessions at

this concentration (from

Renningfleld et al. 1978).

201
Figure 3. Cumulative records are presented for four rhesus

monkeys during 3-hour sessions. Phencyclidine (PCP) was

available on an FR 1 schedule throughout the 3 hours and food (lg

banana pellets) was available during the last 2 hours of the

session according to a DRL 30 sec schedule. A maximum of 75

pellets was available, and the numbers in parentheses refer to

the actual number of pellets obtained. The upper record for each

monkey was taken from the first session at a particular PCP

concentration. The lower record was taken five sessions later.

Food pellet deliveries were marked by the event pen at the lower

edge of each record. Lip contact responses were recorded by the

stepping pen which stepped once with each lip contact response.

Downward deflections of the stepping pen represent deliveries of

0.5 ml of drug solution. In three of the four monkeys (M-R, U-B,

M-P) the food maintained behavior was less disrupted five

sessions after the inital exposure to the PCP concentration,

suggesting the development of tolerance, (Carroll, unpublished

data).

Maintenance

Increases in fixed-ratio size. To determine if the drug is functioning as a reinforcer, comparisons are made between rates of

drug deliveries and water deliveries. Before these comparisons

are made, the size of the fixed-ratio schedule is increased in

order to amplify differences in drug- and water-maintained

behavior. Earlier work with rhesus monkeys showed that occasionally ethanol drinking did not exceed water drinking at low

fixed-ratio values (Henningfield and Meisch 1976b). At low

fixed-ratio values, increases in the ratio usually produce

202
increases in response rates and no changes in the number of

liquid deliveries (figure 4).

FIXED RATIO VALUE

Figure 4. Responses and liquid deliveries as a function of

fixed-ratio value. Note the increases in response rate with

increases in the fixed-ratio value (from Carroll et al. 1978).

Comparisons of drug- and water-maintained response rates. If a

drug is serving as a reinforcer, it should be possible to obtain

rates of drug-reinforced behavior that exceed rates of waterreinforced behavior. Three ways of comparing rates have been

used. One is to compare blocks of water sessions with blocks of

drug sessions. Figure 5 shows that the number of liquid deliveries decreases when water is introduced and that the number of

liquid deliveries increases when the drug is reintroduced. A

second way to compare drug and water response rates is to alternate drug and water sessions. With this procedure, drugmaintained behavior exceeds water-maintained behavior. A third

procedure consists of providing concurrent access to both drug

and water and alternating the side positions of the liquids.

Under these conditions monkeys reliably choose drug over water

(Carroll 1981; Henningfield and Meisch 1979).

203
Figure 5. Liquid deliveries per 3-hour session as a function of

liquid delivered: 4.0 mg/ml pentobarbital or water. Note that

the ordinate scales and fixed-ratio values differed among the

monkeys (from Henningfield et al. 1981).

DRUG CONCENTRATION

Figure 6. Liquid deliveries as a function of drug concentration.

"N" specifies the number of animals in each group. Values for

each animal are from the last five sessions at each

concentration. Closed circles refer to the initial concentration

series; open circles are retest points obtained after the initial

series, in the opposite sequence of the initial series. Ethanol

was presented in an ascending series for both rats and monkeys.

The other drugs were given in a descending sequence for both rats

and monkeys (from Carroll et al. 1978).

204
Effects of drug concentration. Figure 6 shows an inverted Ushaped function relating drug concentration to number of liquid

deliveries. Initially, as drug concentration is increased, the

number of liquid deliveries also increases. Further increases in

concentration result in decreases in the number of deliveries.

However, total drug intake per session (mg of drug per unit of

body weight) generally increases directly with drug

concentration.

Effects of food deprivation and satiation. Another variable that

affects drug-maintained behavior iS food intake. Figure 7 shows

that food satiation decreases pentobarbital deliveries whereas

food deprivation increases drug deliveries. Similar findings

have been reported with phencyclidine (Carroll 1981; Carroll and

Meisch 1980b). Also, food deprivation increases oral and intravenous drug intake in rats (Carroll and Meisch 1979b, 1980a,

1981; Carroll et al. 1979, 1981a; Meisch and Kliner 1979). With

ethanol it is generally known that food deprivation increases

intake (for a review see Meisch 1977); however, the increases in

ethanol drinking with food deprivation have usually been attributed to the caloric value of ethanol.

Figure 7. Liquid deliveries of pentobarbital (1.0 mq/ml; closed

circles) or water (0 mg/ml; open circles) across consecutive

daily 3-hour sessions for monkey Pl. The arrows along the

abscissa mark where changes occurred in the food conditions. The

first arrow shows the change from limited food access (food

deprivation) to unlimited food access (food satiation) during the

Id-hour intersession period. The second arrow shows the change

from unlimited food access (food satiation) to limited food

access (food deprivation) during the intersession period (Kliner

and Meisch, unpublished data).

205
DISCUSSION

Orally delivered ethanol, etonitazene, pentobarbital, and phencyclidine have been established as reinforcers for rhesus monkeys

(Carroll 1981; Carroll and Meisch 1978, 1980b; Meisch et al.

1981; Henningfield and Meisch 1978). The procedures used with

each drug have certain features in common. The monkeys were food

deprived, usually to 80 percent of their free feeding weight and

in some cases to 70 percent. During daily 3-hour sessions water

drinking was induced by feeding the monkeys. Once high rates of

water drinking occurred, a low drug concentration replaced the

water. The drug concentration was gradually increased across

sessions. When high levels of drug intake were reached, the time

of feeding was shifted from within the session to after the

session. In the absence of inducing conditions, rates of drugmaintained responding consistently exceeded rates of watermaintained responding.

The establishment of orally delivered drugs as reinforcers is one

facet of a more general program to analyze drug-reinforced

behavior. Variables affecting behavior maintained by drug

drinking have just begun to be examined. Results obtained so far

appear consistent with results of intravenous drug studies. It

is now apparent that high rates of responding can be sustained in

rhesus monkeys with drugs such as ethanol, pentobarbital, and

phencyclidine. In experienced organisms the taste of drug solutions may function as both discriminative and conditioned reinforcing stimuli in maintaining extended sequences of drugreinforced behavior (Carroll and Meisch 1979a).

Although there is a substantial delay between drinking a drug

solution and onset of the effects that occur once the drug is

absorbed, learning occurs in spite of the delay, for the drugs

come to serve as reinforcers. In taste-aversion conditioning

there is also learning over long temporal delays. Both

situations have in common the drinking of chemical solutions with

subsequent onset of drug-produced interoceptive effects.

In medicine, progress has been made in analyzing disease states

by producing them in animals. Thus, when drugs function as reinforcers for animals, one has an experimental preparation that

reproduces the most critical feature of human drug dependence;

namely, that for drug-dependent humans a drug serves as a

reinforcer. Since the oral route is a common mode of human drug

abuse, it is desirable to have an animal oral self-administration

preparation. As in other areas of medicine, experimental studies

with a valid animal model should ultimately result in improved

clinical treatment.

206
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ethanol-dependent animals. J Pharmacol Exp Ther, 190:365-376,

1974.

Senter, R.J., and Sinclair, J.D. Self-maintenance of intoxication in the rat: A modified replication.

9:291-292, 1967.

Psychonom Sci,

Thompson, T., and Schuster, C.R. Morphine self-administration,

food-reinforced, and avoidance behaviors in rhesus monkeys.

Psychopharmacologia, 5:87-94, 1964.

Weeks, J.R. Experimental morphine addiction: Method for automatic intravenous injection in unrestrained rats.

138:143-144, 1961.

Science,

ACKNOWLEDGEMENTS

This work was supported by NIDA grant #DA-00944 and by NIAAA

grant #AA-00299 to Richard A. Meisch. This work was also supported by NIOA grant #DA-O2486 and by a grant from the Committee

on Problems of Drug Dependence to M.E. Carroll. R.A. Meisch is a

recipient of a NIDA Research Scientist Development Award

#DA-00007.

AUTHORS

Richard A. Meisch, M.D., Ph.D.

Marilyn E. Carroll, Ph.D.

Psychiatry Research Unit

Box 392 Mayo

University of Minnesota 55455

209
Human Dependence on Tobacco

and Opioids: Common Factors

Jack E. Henningfield, Ph.D., Roland R. Griffiths, Ph.D., and

Donald FL Jasinski, M.D.

Recent years have seen increasing acceptance of the notion that tobacco is an addictive or dependence-producing substance, particularly as it is used in cigarette smoking. This idea is supported by the observations that tobacco serves as a reinforcer

(i.e., it maintains behavior leading to its use) and that most people who smoke cigarettes would like to quit but cannot, even in the

face of well documented health risks and economic sacrifices

(Surgeon General’s Report 1979). The term “drug dependence"

suggests that (1) the drug serves as a reinforcer, (2) behavior

occurs which is maintained by the opportunity to take the drug,

and/or (3) other reinforcers are sacrificed as a consequence of

taking the drug (Kalant et al. 1978). Many cigarette smokers in

some degree satisfy these criteria for drug dependence (Russell

1976; Jaffe and Kanzler 1979).

Since cigarette smoking has only recently been conceptualized as an

instance of drug dependence, it should be useful to systematically

compare cigarette smoking with another more thoroughly studied dependence process such as opioid dependence or narcotic addiction.

At first blush, cigarette smoke and opioid drugs appear to produce

vastly differing pharmacological and behavioral effects: large

doses of opioids can produce a debilitating sedation that is not

produced by heavy cigarette smoking. However, these differing direct drug effects may be only marginally relevant to the ongoing

dependence processes per se, and certain functional similarities in

the two forms of dependence suggest that opioid dependence may, in

fact, provide a useful and valid conceptual model to which

cigarette smoking may be compared.

The purpose of this chapter is to compare the functional similarities between tobacco and opioid dependence. Relevant experimental data, clinical observations, and epidemiological findings will be discussed under the organizational framework shown in

table 1.

210
TABLE 1

Patterns of Use

Personality Characteristics and Social Factors

Physiologic Dependence

Deprivation Effects

Tolerance

Dose Effects on Drug Intake

Reinforcing Efficacy and Dependence Liability

Response Requirement

Conditioning Factors

Antagonist Administration Effects

Preloading Effects

Relapse Patterns Following Abstinence Treatment

Feeding Behavior Effects

PATTERNS OF UK

In both cigarette smoking and opioid dependence, use of the respective drug occurs on a regular daily basis and, given adequate

supplies, self-imposed abstinence is infrequent. This overall pattern of use is distinct from that of many other drugs of abuse

(e.g., the sporadic use of the hallucinogens or the use of psychomotor stimulants in which periods of self-administration are broken

by periods of abstinence, cf. Jaffe 1975). With bath tobacco and

opioids, simple exposure to the drugs (“experimentationl

") frequently leads to chronic use (Bejerot and Bejerot 1978). In fact,

while exact figures vary, it has been estimated that 85% of adolescents who smoke one or more cigarettes become compulsive smokers

(Russell 1971). Similarly, with opioids, it has been found that a

high percentage of experimental users become dependent users, e.g.,

97 percent in a study by Robins and Murphy (1967). From this perspective, both drugs have a high "dependence liability" or "addictive potential." A difference in this regard is that most cigarette smokers are compulsive daily users (about 95%, Russell 1971)

whereas current data suggest that a substantial portion of the

total population of opioid users are not compulsive daily users

(that is, they are "chippers," Zinberg 1979). With both tobacco

and opioids, certain routes of administration are preferred

(smoking and injecting, respectively) but other routes or forms of

the drug will be substituted if the preferred one is precluded.

For example, most tobacco users are cigarette smokers (Surgeon

General’s Report 1979) but some smokers will change to chewing

tobacco or snuff if their occupation does not permit smoking

(Russell 1971). With individual opioid users for whom the intravenous route is preferred, other routes and drug forms also will

suffice (e.g., oral methadone, Jaffe 1975, and smoking of opioids,

Way 1964).

211
Finally, when asked to give reasons for their smoking behavior, the

answers obtained from most cigarette smokers may be categorized as

follows: (1) smoking for the "pleasurable-relaxing" effects is the

most common reason; (2) smoking for the stimulating effects is next

most common; (3) smoking to "reduce negative feelings" or to

“relieve anxiety" is the third most common (Green 1977). This

constellation is more similar to that reported by opioid users (cf.

Dr. Charles Haertzen, personal communication) than it is, for

instance, to that reported by amphetamine users, in which

stimulation is the foremost reason for drug-taking behavior.

PERSONALITY CHARACTERISTICS AND SOCIAL FACTORS

Social pressure from both peers and family members is critical in

initiating and terminating the process of dependence to both tobacco and opioids. Specifically, there is a high probability that

friends and family users will share the same pattern of drug use

(cf. Reeder 1977; Evans et al. 1978; Kozlowski 1979; Nurco 1979).

Additionally, a prime indicator of treatment success for both cigarette smoking and opioid dependence is the presence of friends

and/or peers who have been successfully treated for their

dependency (Levitt 1971; Kozlowski 1979; Nurco 1979). That there

are commonalities in the personalities of tobacco and opioid users

is suggested by the fact that most opioid users (about 95 percent)

are also cigarette smokers (O'Donnell 1979). As groups, users of

different drugs may be characterized by particular constellations

of social and personality variables, and these constellations show

greater overlap across certain drug classes than others. In this

respect, psychological characteristics of opioid users (Kissin

1972) show considerable overlap with those of cigarette smokers

(Eysenck 1973; Kozlowski 1979). Particular points of similarity

include an increased prevalence of antisocial and psychopathic

tendencies, rebelliousness, anxiety, repressed hostility, and extroversion. Additionally, in both cigarette smokers and opioid

users, there is evidence that experimentally elicited aggressive

responses are attenuated by use of cigarettes in cigarette smokers

(Hutchinson and Emley 1973; Jaffe and Jarvik 1978) and opioids in

opioid users (Wallace 1979).

PHYSIOLOGIC DEPENDENCE

Physiologic dependence is a factor of significance in opioid dependence and of suspected significance in cigarette smoking. There

are three primary aspects of physiologic dependence. The first is

important in the maintenance of opioid-taking behavior, in which

the emergence of the withdrawal syndrome is correlated with increasingly intense craving scores (Wikler 1961). Some analogous

findings in animal studies are that the onset of the opioid withdrawal syndrome is correlated with increased rates of drug-taking

behavior (Wikler et al. 1963) and increases in the reinforcing

212
efficacy of opioid drugs (Thompson and Schuster 1964). The second

aspect of physiologic dependence to opioids is the increasing propensity of a person in withdrawal to become anxious and to emit aggressive and antisocial acts (Kissin 1972; Brill and Laskowitz

1972). The third aspect of physiologic dependence is the phenomenon of protracted abstinence (cf. Martin et al. 1978), which, in

the most rigorous use of the term, refers to physiologic withdrawal

signs that are present for more than six months following the onset

of opioid abstinence (Himmelsbach 1941; Martin 1978). Protracted

abstinence to opioids has also been well documented in animal

studies (Martin et. al. 1978). With regard to cigarette smoking,

it has been recently postulated that withdrawal phenomena occur and

are similar in certain respects to those which characterize opioid

dependence (e.g., Schachter 1979; Fagerstrom 1980). Specifically

(1) the onset of withdrawal increases desire to smoke and also increases the probability of smoking, thus helping maintain patterns

of smoking (e.g., Schachter et al. 1977; Jaffe 1978); (2) the

emergence of withdrawal is associated with an increase in levels of

anxiety (Nesbitt 1973) and an increase in the propensity of the

person to emit aggressive or antisocial acts (Heimstra 1973;

Perlick 1977); (3) there is a protracted withdrawal syndrome whose

main characteristic is a long-term recurrent craving (cf. Eisinger

1971; Shiffman 1979).

While it is becoming more widely accepted that a withdrawal

syndrome can emerge during tobacco abstinence, there has been

relatively little systematic study or quantification of such a

syndrome (Surgeon General’s Report 1979). Available data suggest

that measurable physiological changes such as decreased heart rate

and blood pressure, and decreased excretion of catecholamines occur

within hours after smoking is terminated and last up to 30 days;

symptoms such as sleep disturbance, headache, and gastrointestinal

discomfort occur and may persist for several days after abstinence

ensues; weight gain is a frequent concomitant to abstinence;

finally, the most prevalent symptom, desire to smoke, occurs and

may recur for many years (cf. review by Shiffman 1979). Such a

synopsis of possible withdrawal signs and symptoms is somewhat misleading, however, since the kinds of symptoms which have been

reported and the temporal patterns of the emergence of these

symptoms are not consistent across studies or even across individuals within studies. An important series of human studies would be

one similar to those done by the Addiction Research Center on

opioids, sedatives, and ethanol, in which the hypothesized withdrawal syndrome is characterized and quantified. If a quantifiable

syndrome is verified, then factors could be studied which are of

known importance in determining the magnitude of other kinds of

drug withdrawal syndromes (e.g., factors such as the preabstinence

dosing regimen). Classic substitution procedures could also be

done to identify which specific factors attenuate or block the syndrome (e.g., a preliminary study by Fagerstrom, 1980, suggests that

nicotine-containing chewing gum is partially effective in blocking

cigarette withdrawal symptoms, cf. also Johnston 1942).

213
Another line of research that must be pursued is abstinence studies

using animals. Animal studies would be of particular interest

since, to date, there have been no demonstrations of either

nicotine or tobacco withdrawal in animals, even following prolonged

exposure to nicotine (e.g., Stolerman, Fink and Jarvik 1973) or tobacco (Jarvik 1967). However preliminary studies have revealed

some physiological rebound effects which occur when chronic nicotine administration is terminated in rats (e.g., Wenzel and Azmeh

1970), suggesting the possibility that a withdrawal syndrome may be

produced.

DEPRIVATION EFFECTS

Deprivation of opioids and tobacco increases the tendency of humans

and animals to self-administer opioids and of humans to smoke cigarettes. While deprivation of opioids in an opioid user, and

possibly deprivation of tobacco in a cigarette smoker usually results in the onset of a withdrawal syndrome, deprivation is, operationally, a temporal manipulation which may increase the reinforcing efficacy of a substance regardless of whether or not a

withdrawal syndrome also happens to occur. In clinical studies, a

sensitive measure of the deprivation effect is the probability

that the drug will be self-administered. With cigarettes this

effect was demonstrated in our laboratory when cigarette smokers

were deprived 0, 1, or 3 hours and then given access to cigarettes

(Henningfield and Griffiths 1979). Figure 1 shows that latency to

the first puff following access to cigarettes was inversely related

to the duration of the deprivation period. Curiously, a subsequent

study showed that “anticipated deprivation” did not produce measurable changes in the smoking of a single cigarette when subjects

were given a cigarette and were informed that after smoking that

cigarette they would be required to abstain for 0, 1, or 3 hours

(Griffiths and Henningfield 1981a). One measure of deprivation is

desire to smoke, and several cigarette smoking studies have shown

(as noted in the Physiologic Dependence section) that strength of

the desire to smoke is a direct function of the deprivation period

(e.g., Shiffman 1979; Shiffman and Jarvik 1980). With the opioid

drugs it is well known clinically that the probability of selfadministration is a direct function of the deprivation period,

though this effect is usually considered to reflect the onset of

physiologic withdrawal symptoms (Wikler 1952; Jaffe 1975). Similarly , several human studies on opioid withdrawal effects have

shown that self-reported craving strength is a direct function of

the deprivation period (Wikler 1978).

TOLERANCE

Tolerance to toxic or aversive effects of both tobacco and opioids

is thought to be important in the ontogeny of dependence.

Tolerance may also be a determinant of levels of drug intake. When

tolerance is suspected to have occurred at the cellular level it is

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CIGARETTE DEPRIVATION

(HOURS)

Figure 1. For each of three subjects the man number of seconds from

the start of the session until the first puff occurred is shown as a

functions of hours of deprivation of smoking. © The

Pbychonomic Society. From Behavior Research Methods and Instrumentation, Vol. 11, No. 6, 1979. Reprinted with permission.

of additional significance since it may be part of the phenomenon

of physical dependence (cf. Kalant et al. 1971), and hence share a

role in the maintenance of the self-administration behavior (cf.

Physiologic Dependence section). Tolerance to the various effects

of opioids has been extensively studied in both animals and humans

(cf. Way and Glasgow 1978). Tolerance to the effects of nicotine,

and to a lesser extent, cigarette smoke, have also been studied in

both humans and animals (cf. Goodman et al. 1980; Domino 1973;

Jarvik 1979). The extent to which there are similarities and differences in the development of tolerance to tobacco as compared to

the opioids must await further studies. However, it is possible

that tolerance to certain effects of smoking may occur more rapidly

than opioid tolerance. For example, it is known that tolerance to

cardiovascular effects of nicotine can develop within a few hours

when nicotine is injected intravenously every 20-30 minutes and

that the development of this tolerance is more pronounced in

smokers than in nonsmokers (Jones et al. 1978). In our laboratory

215
at the Addiction Research Center, preliminary data indicate that

tolerance to certain effects of cigarette smoking, (e.g., attenuation of the patellar reflex and subjective responses) may be lost

overnight and gained after a few hours of smoking, while tolerance

to other effects may be more slowly acquired and more slowly lost.

Interestingly, while tolerance to the initial nausea and dysphoria

are thought to be important in the acquisition of smoking, even

chronic cigarette smokers whom we have tested usually show these

symptoms when they are given a high nicotine cigarette to smoke as

their first cigarette of the day and only to a lesser extent when

given an identical cigarette to smoke after several hours of normal

smoking.

DOSE EFFECTS ON DRUG INTAKE

Drug dose is an important pharmacologic variable that can determine

rate of self-administration and quantity of drug obtained. If the

rate of drug self-administration is an inverse function of the unit

dose, and total drug intake remains constant across doses, then the

organism is "regulating" its drug intake and "titration" or "compensation" is said to have occurred. In animal studies of both

intravenous opioid self-administration (e.g., Stretch and Gerber

1977) and intravenous nicotine self-administration (Hanson et al.

1979), drug intake is a direct function of drug dose. That is,

except at high doses which have "rate-limiting" effects, drug intake regulation is poor at best. This relationship is distinct

from that obtained in studies of intravenous psychomotor stimulant

self-administration (e.g., amphetamine or cocaine) where dose regulation is more precise (e.g., Yokel and Pickens, 1974).

In clinical studies on the effects of drug dose, findings with tobacco are mixed. When nicotine content of cigarettes is varied,

findings are similar to those obtained in the animal studies

described. That is, nicotine intake increases as a direct function

of nicotine dose except at the highest doses, at which rate of

self-administration declines sharply (cf. Schachter 1979; Russell

1976, 1979; Gritz 1980). Dose compensation is much more striking

when amount of cigarette smoke is manipulated as may be

accomplished by varying cigarette size (Gritz et al. 1976; Jarvik

et al. 1978) or the concentration of the cigarette smoke is varied

(Sutton et al. 1978; Henningfield and Griffiths 1980). Figure 2

shows that when tobacco product concentration was decreased across

sessions, from 100% (no. 0) to 10% (no. 4), number of puffs taken

per 3-hour session doubled in 3 subjects tested. Expired air

carbon monoxide levels confirmed that measured changes in puff parameters plus unmeasured but likely changes in inhalation parameters

resulted in good tobacco smoke dose compensation by these

subjects. Thus, while manipulations of cigarette dose may produce

good titration, manipulations of nicotine content do not produce

reliable changes in rate of self-administration and hence titration

(cf. Gritz 1980). Comparable studies of the effects of dose manip216
ulations on rate of opioid self-administration in humans have not

been conducted. However, clinical studies in which humans are

permitted to self-regulate their analgesic drug (opioid) intake

indicate that humans are sensitive to drug dose manipulations and

suggest that moderate intake compensation occurs (Keats et al.

1969; Sechzer 1971).

REINFORCING EFFICACY AND DEPENDENCE LIABILITY

Retrospective analyses suggest that cigarettes and opioids have

high dependence liability; that is, a single exposure to either

cigarettes or opioids is often followed by the development of a

pattern of compulsive use (a notable exception being therapeutic

administration of opioids in clinical settings). Furthermore, once

compulsive use develops, users of both opioids and tobacco emit

large amounts of work, spend considerable sums of money, and endure

sacrifices in health and other areas to maintain their self-administration behaviors. A historical perspective illustrates a similarity with regard to the abuse potential of tobacco and opioids:

Cocteau's dictum regarding opium smoking, that "he who has smoked

will smoke" is equally true with regard to tobacco (Russell 1976).

217
One approach to providing information about the relative dependence

liability of drugs is to examine their efficacy in maintaining drug

self-administration behavior in laboratory animals. Studies to

date suggest that both opioids and nicotine (as well as cigarette

smoke) do maintain self-administration in animals; however, opioids

appear to be more efficacious reinforcers than nicotine or tobacco

smoke. Specifically, while many studies have shown that opioids,

delivered intravenously, intramuscularly, and orally, serve as effective reinforcers for animals (cf. Johanson 1978; Carroll and

Meisch 1979), studies involving intravenous self-administration in

rats, monkeys, and baboons suggest nicotine to be an equivocal reinforcer when compared to other drugs of abuse, including opioids

(Griffiths et al. 1979). However, it would be premature to pass

final judgement on the results of the animal studies of nicotine

and/or tobacco smoke self-administration, firstly, because the

route of administration that is preferred by humans (inhalation)

has not been extensively used with animals. Just as it required

many years to develop a preparation in which orally delivered

ethanol served as a potent reinforcer for animals (cf. Meisch

1977), it may take a long time to develop the appropriate

procedures for studying tobacco use in animal preparations (cf.

Ando and Yanagita, 1981, for a promising development in tobacco

smoke self-administration by monkeys). Secondly, the animal

nicotine self-administration data are of questionable relevance to

the reinforcing efficacy of cigarettes since it is clear that

nicotine is not the sole determinant of smoking rates (Russell

1979; Gritz 1980) and that noninhalation routes of nicotine administration are not equivalent to nicotine administration via cigarette smoking (Russell and Feyerabend 1978). Finally, there have

been no clear demonstrations that intravenously delivered nicotine

is an effective reinforcer for humans (see below).

Another approach to providing information about the dependence

liability of drugs is to conduct human studies and systematically

evaluate self-reports of subjective "likingw or “drug satisfaction"

(Jasinski 1977). The validity of this approach is suggested by the

similarities in the human findings, animal self-administration

findings, and in the epidemiological reports of drug abuse

(Griffiths and Balster 1979; Griffiths et al., this volume;

Yanagita 1980). Intravenous injections of opioids in most addict

subjects (Jasinski 1977), or of nicotine in cigarette smokers

(Johnston 1942; Jones et al. 1978) are reported to be pleasurable.

With both opioids and tobacco, studies have demonstrated an additional similar relationship: as dose of opioids, intravenous

nicotine or cigarettes is increased, subjective reporting indicates

that satisfaction also increases (e.g., Kay et al. 1967; Goldfarb

et al. 1976; McClane and Martin 1976; Jarvik et al. 1978; Griffiths

and Henningfield 1981b).

218
RESPONSE REQUIREMENT

Response requirement, also referred to as “response cost,” may be

defined as the amount of behavior reauired to obtain a reinforcer.

With regard to drug self-administration by humans, response cost

can be defined as the amount of effort required to obtain the drug,

or as the monetary value of the drug when monetary earning is proportional to work output. Economic theory uses the concept of

“elasticity” to describe the extent to which consumption of a

commodity varies with the price of that commodity. From a common

perspective of drug addiction, opioids and cigarettes might be

viewed as relatively inelastic commodities in dependent persons,

i.e., that as price increases, consumption would remain relatively

constant. In fact, however, both opioid demand and cigarette

consumption have proved to be relatively elastic in that consumption decreases when price increases (cf. Peto 1974; Marco 1979).

This is not to say that increasing the price or response repuirement for cigarettes and opioids does not result in an increase in

net expenditure or response output. Response output does increase

--it just does not keep pace with the requirements for maintaining

a constant level of intake.

A clear experimental demonstration of the interactions between

response requirement and intake of methadone or cigarettes was

shown in preliminary studies by Bigelow and his co-workers. In

these studies, response requirement was defined as the number of

lever pulls per delivery of a methadone dose (Bigelow 1978) or a

cigarette (Griffiths et al. 1980). As response requirement increased, for either cigarettes or methadone doses, response rate

was an increasing or inverted U-shaped function, and the number of

cigarettes or methadone doses obtained decreased. These findings

are consistent with epidemiological findings which showed that for

both opioids and cigarettes, increased prices result in increased

spending but decreased intake (Peto 1974; Nurco 1979). Analogous

results have been obtained in animal drug self-administration

studies using opioids (cf. Griffiths et al. 1980), but these

procedures have not been applied in animal studies of cigarette

smoking or intravenously delivered nicotine.

CONDITIONING FACTORS

Conditioning of both the operant type and the respondent (or

Pavlovian) type is thought to occur as an integral part of the dependence process with both cigarette smoking and opioid dependence.

Specifically, the development of conditioned stimuli, discriminative stimuli, and conditioned responses may contribute to maintenance of the pattern of compulsive use and facilitate relapse

following a period of abstinence. For instance, clinical lore suggests that environmental stimuli previously associated with smoking

are likely to evoke craving responses and increase the probability

of smoking when these stimuli recur (cf. Pomerleau and Pomerleau

219
1977; Danaher and Lichtenstein 1978; Pomerleau 1979). Therefore,

in most smoking treatment programs it is recommended that the

abstaining smoker try to avoid environmental stimuli which are

highly associated with smoking, e.g., having visual access to

cigarettes, social and drinking situations, etc (cf. Oanaher and

Lichtenstein 1978; Pomerleau and Pomerleau 1977; USOHEW 1978).

Systematic studies are needed to determine if these environmental

stimuli elicit withdrawal type responses in a manner similar to the

elicited opioid withdrawal described below. It is known that

desire to smoke cigarettes may persist for several years after

smoking was terminated and that formerly high probability smoking

situations are particularly effective at evoking the craving

responses (Shiffman 1979). Finally, a preliminary study by Gritz

(1977) has shown that sioht and smell of tobacco smoke are important determinants of smoking rate, demonstrating that tobacco

self-administration, like opioid self-administration, may be influenced by external stimulus factors.

With regard to opioid dependence, the evidence that conditioning

factors -play a critical role has grown since the notion was first

postulated by Wikler (1952. 1965. 1978). Recent studies by O’Brien

and his colleagues have demonstrated. that opioid withdrawal can

occur as a conditioned response to administration of placebo in

patients who have previously received naloxone injections (O’Brien

et al. 1980; O’Brien et al., this volume). In another study from

the same laboratory, it was demonstrated that subjective and

physiologic responses which are normally elicited by opioid

administration could also be elicited by presentation of heroinrelated stimuli or by the self-administration of placebo in

patients with histories of hydromorphone injections (Ternes et al.

1980; Sideroff and Jarvik 1980). Analogous findings have been

obtained in animal studies (cf. Thompson and Schuster 1964;

Schuster and Woods 1968; Davis and Smith 1976; Wikler 1978). These

studies are important in that they demonstrate that stimuli

previously associated with drug administration or drug withdrawal

may attain functional roles in the dependence process via conditioning (learning) mechanisms. While further experimental data are

required for a more definitive conclusion, it is clear that conditioning factors may be important controlling variables which are

common to both opioid and cigarette dependence.

ANTAGONIST ADMINISTRATION EFFECTS

One factor that distinguishes cigarette smoke from substances such

as alcohol, barbiturates, and food is that the primary pharmacologically active constituent (nicotine) has a specific cellular

site of action (viz., nicotinic receptors). It is well known that

opioids are also receptor-specific. Self-administration of both

opioids and cigarette smoke may be influenced by administration of

pharmacologic antagonists. Clinical administration of opioid antagonists (e.g., naltrexone) to human opioid users decreases opioid

220
self-administration (Mel10 and Mendelson 1978; Meyer and Mirin

1979). The limited available data regarding nicotine antagonist

administration showed that mecamylamine (a centrally acting

nicotinic blocker) administration to human cigarette smokers

produced increases in smoking during weekly 2-hour sessions: it

was not determined whether or not continuous antagonist

administration ultimately would have reduced smoking rates

(Stolerman, Goldfarb, Fink and Jarvick 1973). Pentolinium (a

peripherally acting nicotinic blocker) did not affect smoking

rates. In a study of cigarette smoking by monkeys, mecamylamine

(but not the peripherally acting hexamethonium) reduced overall

levels of smoking over the course of several weeks (Glick et al.

1970). A caveat with regard to the interpretation of results of

antagonist administration in cigarette smoking studies is that,

strictly speaking, there is not a tobacco antagonist; rather, there

are nicotine antagonist drugs. Administration of nicotine

antagonists (e.g., Goldberg and Spealman 1981) or of opioid

antagonists (Moreton et al. 1975; Davis and Smith 1976) to animals

which are intravenously self-administering nicotine or intravenous

opioids, respectively, decreases the self-administration behaviors.

The effects of opioid antagonists in blocking or reversing the

responses produced by opioids have been extensively studied and

reviewed for both humans (e.g., Jasinski 1978) and animals (e.g.,

Way and Glasgow 1978). Preliminary studies of antagonism of the

effects of nicotine in animals (cf. Domino 1973) and the effects of

smoking in humans (Jarvik 1973) indicate similar antagonist

blockade and reversal of effects. A noteworthy difference is that

opioid antagonists may precipitate withdrawal in opioid-dependent

organisms, while no similar phenomenon has been demonstrated in

organisms chronically exposed to tobacco smoke or nicotine.

PRELOADING EFFECTS

In human research, acute preload administration of opioid drugs or

tobacco products (e.g., nicotine or cigarette smoke) decreases

subseauent administration of opioids or cigarettes, respectively.

A good clinical example of this opioid preload effect is the use of

methadone to treat illicit opioid dependence (cf. Kreek 1979).

Jones and Prada (1975) showed that methadone administration to

patients who were given the opportunity to obtain intravenous

hydromorphone (Oilaudid) produced decreases in self-administration

of the opioid. Of six subjects tested, 3 completely stopped

working for hydromorphone while the other 3 worked intermittently

for hydromorphone. These findings are compatible with those

obtained in studies of cigarette smoking in which preloading

subjects with cigarette smoke produces a decrease in subseauent

smoking (e.g., Kozlowski et al. 1975; Kumar et al. 1977). Nicotine

preloading given either orally (Jarvik et al. 1970) or intravenously (Lucchesi et al. 1967) also may produce decreases in

smoking, although these kinds of preloading manipulations produce

221
weaker and less consistent decrements in smoking than when cigarette smoke preloading is done (cf. Kumar et al. 1977). These

results show that nicotine is not the sole determinant of cigarette

smoking. Consistent with these experimental findings are the

modest rates of therapeutic success of preload types of treatment

for cigarette smoking (e.g., nicotine-containing chewing gum) which

are similar to the modest rates of success of methadone programs

for opioid dependence when methadone is dispensed to a heterogeneous population of opioid users.

These drug preloading effects have also been studied in animals

where it has been demonstrated that opioid preloads usually (e.g.,

Wurster et al.

(Jones and Prada 1977), reduce subsequent opioid

1977; Jones and Prada 1975) but not invariably

self-administration by animals -- these opioid findings are

consistent with those obtained in human studies. Similarly, one

study has demonstrated decreases in cigarette smoking rates in

monkeys which occurred when nicotine was added in the monkeys'

drinking water (Jarvik 1973).

RELAPSE PATTERNS FOLLOWING ABSTINENCE TREATMENT

Hunt and his co-workers have shown that patterns of relapse to drug

use following abstinence are similar for cigarette smoking, opioid

dependence, and alcoholism (Hunt et al. 1971; Hunt and General

1973; Hunt and Bespalec 1974). During the first few months,

roughly 70% of patients relapse. Subsequently, the rates of

relapse approach asymptotically a level at which about 75% have

relapsed, and the rest are still abstaining. These findings suggest an important commonality, but one whose mechanisms are not

clear. Perhaps the protracted abstinence syndrome (Physiologic

Dependence section), conditioned craving (Conditioning Factors

section), or social and personality variables (Personality Characteristics and Social Factors section) are significant.

FEEDING BEHAVIOR EFFECTS

Roth opioids and tobacco can reduce feeding behavior and produce

weight loss, and intake of both opioids and tobacco may be increased by food deprivation. The effects of food intake on opioid

and nicotine self-administration have been experimently studied

using animals. Meisch and his co-workers (e.g., Meisch and Stark

1977; Carroll et al. 1979; Meisch and Kliner 1979) showed that oral

or intravenous etonitazine intake by rats was inversely related to

body weight when body weight was manipulated by varying size of the

daily food ration. A similar finding was obtained in rats which

drank morphine solutions (Nichols 1972). In a study of intravenous

nicotine self-administration, nicotine was self-injected at significant levels when the animals were at 80 percent of their normal

weights but not when the animals were at 100 percent body weight

and allowed free access to food (Lang et al. 1977).

222
In a clinical study of the effects of severe food deprivation, it

was found that cigarette smokers smoked much more and that nonsmokers learned to smoke. A similar finding was obtained with

regard to coffee drinking (Keys et al. 1950). Similarly, addicts

sometimes report that when they are hungry (for food) they have a

stronger craving for opioids and cigarettes and that they smoke

more. Clinically, it has been observed that opioid dependence is

frequently accompanied by nutritional deficiency, though it is not

clear whether this effect is mediated pharmacologically or sociologically (Kreek 1979). With regard to cigarette smoking, epidemiological data have shown that cessation of cigarette smoking is

frequently accompanied by a gain (often excessive) in weight

(Garvey et al. 1974; Heyden 1976; Schacter 1979). The possibility

of a direct interaction between nicotine obtained by cigarette

smoking and appetite has been experimentally demonstrated by

Perlick (1977) who showed that subjects who were given low- or nonicotine cigarettes to smoke ate twice as many jelly beans as

subjects who were given high nicotine cigarettes to smoke.

DISCUSSION AND CONCLUSIONS

The behavior of cigarette smoking, as it occurs in many cigarette

smokers, may be properly regarded as an instance of drug dependence

or as an addiction. As a form of drug dependence, cigarette smoking bears striking similarities in its functional characteristics

to the prototypic form of drug dependence--opioid dependence or

narcotic addiction. The extent to which similar controlling variables pervade tobacco and opioid dependence may not be readily

apparent when only the commonly described features of cigarette

smoking and opioid dependence are considered. However, the idea

that these two seemingly diverse kinds of drug dependence share

some common features is not a new one: comnonalities between

tobacco smoking, opioid use (e.g., opium smoking), and alcoholism

have been noted for several hundred years (Jaffe 1978; Austin

1978). The present paper has extended these observations by systematically comparing functional relationships found in cigarette

smoking and opioid dependence which are empirically based on laboratory and clinical data. The research reviewed shows that many

fundamental commonalities exist between tobacco and opioid dependence, adding further support to the notion that cigarette smoking

is an instance of drug dependence.

Some of the common functional relationships reviewed in this paper

are not uniquely shared by cigarette smoking and opioid dependence. For instance, most forms of drug and substance abuse can

probably be reduced by increasing the response requirement necessary to maintain the dependence (Griffiths et al. 1980). Other

commonalities are less widely shared: the similarities in cigarette

smoking and opioid dependence noted in the pattern of chronic daily

use, receptor specificity, and the role of physical dependence do

not appear to be shared with most other forms of drug or substance

abuse.

223
In this paper we have explicitly avoided equating cigarette smoking

with nicotine dependence or nicotine self-administration. This

approach is consistent with a conservative evaluation of the available data which show that, while nicotine accounts for many of the

effects produced by cigarette smoking, clinical and experimental

manipulations of nicotine administration do not affect cigarette

smoking to the degree that would be predicted if nicotine were the

only factor controlling cigarette smoking.

The comparison of the functional similarities between tobacco and

opioid dependence has been made possible largely by the application

of the methodology of behavioral pharmacology to the analysis of

drug dependence. Future basic science research will undoubtably

point out further functional similarities and dissimilarities

between cigarette smoking and other forms of drug and substance

abuse. Such research will ultimately provide a thorough analysis

of the dependence process, per se, and will have important implications for the treatment of drug dependence.

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Addiction and the U.S. Public Health Service. Washington, D.C.:

Supt. of DOCS., U.S. Govt. Print. Off., 1978. pp. 63-88.

Wikler , A. Recent progress in research on the neurophysiological

basis of morphine addiction. Am J Psychiatry, 105: 329-338, 1948.

233
Wurster, R.M.; Griffiths, R.R.; Findley, J.D.; and Brady, J.V.

Reduction of heroin self-administration in baboons by manipulation

of behavioral and pharmacological conditions. Pharm Biochem Behav,

7: 519-528, 1977.

Yanagita, T. Self-administration studies on psychological dependence. Trends in Pharm Sci, 161-164, 1980.

Yokel, R.A., and Pickens, R. Drug level of d- and l-amphetamine

during intravenous self-administration. Psychopharmacologia, 34:

255-264, 1974.

Zinberg, N.E. Nonaddictive opiate use. In: DuPont, R.L.; Goldstein,

A.; and O’Donnell, J., eds. National Institute on Drug Abuse.

Handbook on Drug Abuse. Washington, D.C.: Supt. of Docs., U.S.

Govt. Print Off., 1979. pp. 303-314.

ACKNOWLEDGMENT

Dr. Griffiths’ work on this project was supported in part by USPHS

Grant No. DA-01935.

AUTHORS

Jack E. Henningfield, Ph.D. NIDA Addiction Research Center,

Clinical Pharmacology Section, and The Johns Hopkins University

School of Medicine, Department of Psychiatry and Behavioral

Sciences.

NIDA Addiction Research Center, P.O. Box 5200, Baltimore, Maryland

21224.

Roland R. Griffiths, Ph.D. The Johns Hopkins University School of

Medicine, Department of Psychiatry and Behavioral Sciences,

Baltimore, Maryland 21205.

Donald R. Jasinski, M.D. Director, NIDA Addiction Research Center.

P.O. Box 5200, Baltimore, Maryland 21224.

234
Discussion

Commonalities and Differences

Among Reinforcers

Chris E. Johanson, Ph.D.

Since I entered the field of behavioral pharmacology, there has been an

enormous increase in the number of studies in the area of drug selfadministration and a utilization of these techniques in the development

of an animal model for the assessment of abuse potential of drugs. I

often forget that although there were some isolated self-administration

studies before 1960, the field really began in 1962 with a publication

by Weeks (1962) and later in 1964 with a publication by Thompson and

Schuster (1964). Since I entered the area in 1970, it is not surprising

that I have the feeling that there has been a logarithmic increase in

the number of studies in the field because this 10-year period makes

up well over 50% of its total life. I make this comment not to show

you that I, too, am a pioneer in the field but that the field iS very

young and that we should be very encouraged by the enormous progress

that we’ve made in assessing the determinants of drug self-administration

in animals and now humans during a relatively short period of time.

The present conference could not illustrate this progress more clearly.

I fully appreciated this enormous increase in knowledge when Bob

Schuster and I were asked last year to write a review article; the fact

that it was completed 6 months late indicates that we had a great deal

of trouble trying to summarize the vast amount of research on drug

self-administration in animals. We concentrated in the review on studies

of maintenance variables, i.e., determinants of drug self-administration.

We noted in our review that early research was concerned primarily

with the type of drug that would maintain responding and the

investigators simply marched through the pharmacopeia using the same

simple behavioral preparations (e.g., low fixed ratio schedules) for every

drug. This perseveration was most likely the consequence of the

researchers being continually impressed, even amazed, that animals would

self-administer the same drugs that humans abused without any clever

coercion. Unfortunately, this led some investigators to the premature

conclusion that drug abuse was a totally pharmacological problem. In

recent years, there has been a shift in emphasis to environmental

determinants of the reinforcing properties of drugs. In my opinion this

shift has led some investigators to the equally inappropriate conclusion

that the pharmacological properties of the drug itself have little to do

with its behavioral effects. Clearly, as this conference has shown, drug

self-administration is determined by a complex interaction between both

pharmacological and behavioral variables. In addition, the variables

235
which control responding maintained by drugs operate in a similar manner

to variables that control other types of behavior. This similarity has

led researchers and clinicians to conclude that it is appropriate to search

for commonalities in the determinants of substance abuse or excessive

behavior.

Although the primary application of drug self-administration studies is

the understanding of the determinants of drug abuse in humans, the

procedures and techniques which have been developed are also useful for

a variety of other purposes. First of all, there is a special set of

manipulations which decrease rate of drug self-administration and

therefore have relevance for treatment approaches. These variables are

both behavioral, such as punishment, and pharmacological (e.g.,

drug treatments such as methadone maintenance). Self-administration

studies can also be useful for understanding certain problems encountered

in the treatment of drug abuse patients. For instance, an understanding

of conditioned drug effects, such as those described by O’Brien,

incorporated within the context of actual drug self-administration studies,

can help us elucidate mechanisms of relapse in exdrug users. Studies

of drugs as negative reinforcers may help us understand that essential

medications are often not taken by patients because they have aversive

properties. However, as with positive reinforcers, the aversive properties

of a drug are not immutable and can be affected by the context of

their administration.

There are also studies that use drug self-administration methodologies

to elucidate biochemical mechanisms of action of a specific drug. While

this approach has great appeal, investigators should exercise caution in

Interpreting their findings and should be especially careful in recognizing

the multiple determinants of responding. Self-administration studies can

also be used to study drug toxicity. It is far more important in the

determination of a drug’s abuse potential to study this toxicity within

the range of doses that are self-administered rather than at some

arbitrarily chosen dose range.

Finally, but first in some sense, drug self-administration methods are

useful for screening new compounds for abuse potential. In this

application, it may appear that we are retreating to an emphasis on

the pharmacological properties of drugs. During our break, a member

of this audience pointed out to me that outsiders (I have to include as

outsiders people from funding agencies who are here to learn how drug

self-administration techniques can be used ) might view this field as

schizophrenic. We believe that any event can function as a reinforcer

under some environmental condition. On the other hand, the mission

of screening to predict the abuse liability of a compound implies that

drugs differ in their ability to serve as reinforcers. In my opinion, both

of these views are correct. Clearly psychologists are clever and can

produce conditions under which any drug might serve as a reinforcer.

So then what IS the mission of screening for abuse potential? I believe

it is to determine at a pre-clinical level those drugs for which there is

a high probability that the drug will serve as a reinforcer in a variety

of people under a variety of environmental circumstances. In order to

accomplish this mission, therefore, drugs must be evaluated under a

range of conditions. The abuse liability of a drug simply corresponds

236
to the extent of the conditions under which this drug maintains

responding. Drugs which are positive reinforcers under only a very

limited number of conditions are less likely to be abused to a serious

extent by humans than drugs that are self-administered no matter what

the environmental situation. The assessment of the abuse liability is a

drug is a complex question, and while researchers are often prone to

promise simple answers, it is clear that if we are to make progress in

decreasing the abuse of drugs, our efforts must continue.

REFERENCES

Thompson, T. and Schuster, CR. Morphine self-administration and foodreinforced and avoidance behaviors in rhesus monkeys.

Psychopharmacologia, 5: 87-95, 1964.

Weeks, J.R. Experimental morphine addiction: Method for automatic

intravenous injections in unrestrained rats. Science, 138: 143-144, 1962.

AUTHOR

Chris E. Johanson, Ph.D.

The University of Chicago

Department of Psychiatry

950 Fast 59th Street

Chicago, Illinois 60637

237

Complex Schedules and

Maintenance of

Drug Dependence

Second-Order Schedules:

Extended Sequences of Behavior

Controlled by Brief Environmental

Stimuli Associated with Drug SelfAdministration

Steven R. Goldberg, Ph.D., and Michael L. Gardner, Ph.D.

INTRODUCTION

A factor common to all conceptualizations of drug dependence is

the persistent maintenance of behavior that leads to drug

self-administration. Vivid descriptions of the complex, often

protracted, sequences of activities involved in obtaining and

administering various drugs are contained in both the lay and

scientific literatures on human drug abuse. Such a sequence

might, for example, consist of breaking into a home, stealing

property, converting the property to money, and finally purchasing, preparing, and administering a drug--the effects of

which are often short-lived. Although the terminal event, administration of the drug, is ultimately responsible for those

behaviors, the environmental stimuli occurring in specific

temporal relations throughout the sequence must also contribute

heavily to the maintenance of both the individual components of

the sequence and the overall pattern of behavior (Wikler, 1965,

1973; Goldberg, 1970, 1975; O'Brien, 1975). An experimental

analysis of the functions of environmental stimuli in the maintenance of extended sequences of behavior terminating in drug

injection is of obvious interest.

Over the last 20 years this kind of analysis has been pursued in

the laboratory using the preparation, techniques, and theoretical framework developed by Skinner (1938) and Ferster and

Skinner (1957) in the study of operant conditioning. Requirements for the basic preparation consist of an experimental

Subject, response manipulandum, method of drug delivery, and

means of presenting exteroceptive stimulus changes within a controlled environment. Studies of drug self-administration usually employ rats or monkeys as Subjects and a lever press as the

response. Drug solutions are typically infused through chronlcally implanted venous catheters and can be delivered

241
automatically according to specified relations between responding and environmental events (i.e., according to given schedules). Lights and tones most often are used as exteroceptive

stimuli in addition to drug injections.

Generally, responding by laboratory animals has been maintained

under relatively simple schedules of drug injection. Drugs have

most often been injected following a fixed number of responses,

an arrangement designated a fixed-ratio (FR) schedule. Although

occasional experiments have used FR schedules requiring 100 or

more responses per injection (FR 100), most have not exceeded FR

30, and by far the most common schedule has been FR 1.

Fixed-interval (FI) and variable-interval (VI) schedules also

have been used. Under an FI schedule, the first response after

a fixed period of time produces an injection; under a VI schedule the period of time before a response can produce an injection is not fixed but varies from one injection to the next.

These simple schedules have been used with many drugs to determine if responding that results in the injection of a drug will

be initiated, and, if so, to study the effects on rate of responding and drug intake of variations in dose of the drug and

parameter value of the schedule. Results of these studies have

provided useful parametric information and have demonstrated the

validity of applying a behavioral analysis to the problem of

human drug abuse (see Goldberg, 1976; Johanson, 1978; Spealman

and Goldberg, 1978 for reviews). Under appropriate conditions,

injections of drugs from diverse pharmacological classes have

been shown to control rates and patterns of responding in much

the same manner as more frequently studied maintaining events

such as food or water presentation.

Although laboratory experiments on responding maintained under

simple schedules of drug injection have contributed much to an

analysis of the ways in which different drugs interact with ongoing behavior to produce a given effect, a more complete

understanding of the complex patterns of behavior involved in

human drug self-administration necessarily requires the use of

correspondingly complex laboratory preparations. It is up to

laboratory investigators to develop experimental procedures for

the generation of response sequences that closely resemble, in

terms of complexity and persistence, the patterns of behavior

characteristic of human endeavors. To the extent that we can do

so, our confidence in the relevance of those procedures as components of animal models of human drug self-administration will

be increased. In recent years a growing number of studies have

employed second-order scheduling procedures to gain experimenta

control over long and orderly sequences of behavior terminating

in drug injection.

SECOND-ORDER SCHEDULES OF DRUG INJECTION

Under second-order schedules, completion of an Individual component (or unit) schedule, rather than an individual response,

produces the terminal event according to another overall

242
schedule. Thus, they are appropriately considered "schedules of

schedules" (cf., Kelleher, 1966a. b). Second-order schedules

have been used extensively in behavioral preparations to study

the unitary properties of complex patterns of behavior, the

generality of schedule processes, and stimulus functions in

extended behavior sequences. The rates and patterns of responding maintained under second-order schedules are of wide

generality with respect to the species of SubJect, type of

response, and type of maintaining event (cf., Findley, 1962;

Kelleher, 1966a; Goldberg et al., 1975; Marr, 1979).

Figure 1 serves to illustrate some of the terminology, procedures, and results common to studies of second-order schedules

of drug self-administration. Cumulative records of lever pressing by squirrel monkeys under two second-order schedules of intravenous cocaine injection are shown. In the top panels, lever

presses produced a 2-sec illumination of amber stimulus lights

(S) according to a 30-response fixed-ratio component schedule

(FR 30: S); and, component completions produced the amber lights

and an injection of 100 pg/kg of cocaine according to an overall

5-min fixed-interval schedule (FI 5-min). The entire secondorder schedule is abbreviated: FI 5-min (FR 30: S), and is read:

"a fixed-interval 5-min schedule of fixed-ratio 30 components."

Diagonal marks of the response pen in each record indicate

brief-stimulus presentations; resetting of the response pen to

baseline indicates cocaine injection. In the bottom panels, the

component schedule remained FR 30, but the overall schedule was

lengthened to FI 15-min. With S-254 and S-60, the response pen

now occasionally reset automatically after 1100 responses as

well as with cocaine injection. Overall rates of responding in

excess of one response per second were maintained under both

schedules. The inserts (a and b to the right of the figure)

show that patterns of responding-typical of FR schedules were

maintained within individual components that terminated Only

with brief stimulus presentations (see also, Goldberg, 1973a. b;

Goldberg et al., 1975). In further experiments, discussed

below, the functions of stimuli paired with response-produced

injections of morpnine or cocaine under second-order schedules

have been examined. Results of these studies provide important

information on the role of drug-paired stimuli in the acquisition, maintenance, and extinction of long and orderly sequences

of behavior terminating in drug self-administration.

EFFECTS OF DRUG-PAIRED STIMULI DURING ACQUISITION

Two experiments have demonstrated enhanced control over responding as the result of presenting brief drug-paired stimuli during

acquisition (Kelleher, 1975; Goldberg and Tang, 1976). In the

first experiment, lever presses by a rhesus monkey (R-529) produced intravenous injections of 30 pg/kg of cocaine under an FI

10-min schedule; each injection was preceded by a 2-sec illumination of amber stimulus lights. The top panel in figure 2

shows a cumulative record of responding under this schedule from

early in the animal's history. Rate of responding was low, and

243
FIGURE 1

FIG. 1.

(S-461,

High rates of responding maintained in squirrel monkeys

S-254 and S-60) under two second-order schedules of

cocaine injection. Completion of each 30-response fixed-ratio

component schedule produced a 2-sec presentation of amber stimulus lights (FR 30: S); the first FR 30 component completed after

5 min elapsed [top records; FI 5-min (FR 30: S)] or 15 min

elapsed [lower records; FI 15-min (FR 30: S)] produced both the

amber lights and an intravenous injection of 100 ug of cocaine

hydrochloride per kg. Abscissae: time. Ordinates: cumulative

number of lever-pressing responses. Short diagonal deflections

of the response pen indicate brief stimulus presentations. The

response pen reset to the bottom of the record whenever 1100

responses cumulated and when cocaine was injected; downward deflections on the horizontal event lines also indicate injection

of cocaine. After each injection there was a 1-min timeout

period during which the recorder was stopped. Each session

ended after the 15th timeout period. A complete experimental

session at the 5-min fixed-interval condition is shown for each

monkey in the top panel; a complete experimental session for

each monkey at the 15-min fixed-interval condition is shown in

the lower panel (from top to bottom). (S. R. Goldberg,

unpublished observations).

244
FIGURE 2

FIG. 2. Increases in responding after the transition from a

lo-min fixed-interval schedule of cocaine injection to a secondorder schedule of cocaine injection with fixed-ratio components

(rhesus monkey R-529). Abscissae: time. Ordinates: cumulative number of lever-pressing responses. First panel: performance under a lo-min fixed-interval schedule of cocaine injection. Each short diagonal stroke on the record indicates 2-sec

presentation of amber lights accompanied by an Intravenous injection of 30 pg/kg of cocaine hydrochloride. Second panel:

first session under a second-order schedule. Completion of each

lo-response (FR 10) or 3-response (FR 3) fixed-ratio schedule

component produced a 2-sec illumination of amber stimulus

lights, indicated by a short deflection of the response pen.

The first FR component completed after a fixed interval of 10

min elapsed produced the amber lights and an injection of 30

pg/kg of cocaine, indicated by the resetting of the pen to the

bottom of the record. Third panel: Second session under a

second-order schedule with FR 3 components; recording as in

second panel. Fourth panel: subsequent performance under a

second-order schedule with FR 10 components: [FI 10-min (FR 10:

S)]; recording as in second panel.

(From Kelleher, R. T. Characteristics of behavior controlled by

scheduled injections of drugs. Pharmacological Reviews, 27: 307-

323. © 1975, American Society for Pharmacology and Experimental

Therapeutics.)

245
no clear indication of the temporal patterning characteristic of

FI schedules was yet evident. The second panel shows the

effects of changing from the simple FI 10-min schedule to a

second-order FI 10-min schedule of FR components. Initially

every tenth response, and later every third response, produced

the brief amber lights; the first FR component completion after

10 min had elapsed produced both the amber lights and cocaine

injection. Rate of responding increased slightly when the ratio

requirement under the second-order schedule was 10 responses and

increased markedly when the requirement was reduced to three

responses. Subsequently, rates of responding in excess of one

response per sec were maintained with either FR 3 or FR 10 components. Although these second-order schedules did not alter

the maximum frequency of cocaine injection, rate of responding

increased greatly within a very short period of time.

A second experiment (Goldberg and Tang, 1976) also showed that

high rates of responding could be rapidly engendered when brief

presentations of drug-paired stimuli were scheduled during acquisition. Another rhesus monkey (AX) was initially exposed to

experimental conditions under which each lever press produced an

intravenous injection of 0.2 mg/kg of morphine accompanied by a

2-sec illumination of red stimulus lights. Record A in figure 3

shows responding from the first session under this FR 1 schedule

of morphine injection. Two or three injections were produced

early in the session; then, approximately midway through the

session, rate of responding increased and over 40 injections

were produced within the next 15 min. In the third session a

fixed ratio of 10 responses was required for every injection.

Only low rates of responding were maintained during the eight

sessions that this FR 10 schedule of morphine injection remained

in effect (Record El). The experimental conditions then were

changed to a second-order FI 60-min (FR 10: S) schedule: every

tenth response produced the 2-sec red lights and the first FR 10

component completion after 60 min produced both the red lights

and intravenous injection of 5 mg/kg of morphine. Under this

schedule, injection of drug was restricted to the end of each

session, and 23 hr or more elapsed before the start of the next

session. Rate of responding increased dramatically during the

first session under this second-order schedule (Record C).

After 40 sessions, the within-component patterns of responding

were characteristic of those maintained by simple FR schedules

and responding over the 60-min interval showed the gradual positive acceleration typical of simple FI schedules. Overall rate

of responding remained at a substantial level (Record D).

The final performance of monkey AX illustrates an important

characteristic of second-order brief-stimulus schedules of drug

injection. Long and orderly sequences of behavior can be maintained when the direct effects of the drug are minimal or

absent. This characteristic can be particularly useful when

studying drugs with pronounced suppressant effects on behavior,

such as morphine.

246
FIGURE 3

FIG. 3. Increases in responding after transition from a simple

fixed-ratio (FR) schedule of intravenous morphine injection to a

second-order schedule with FR units (rhesus monkey AX). Abscissae: time. Ordinates: cumulative number of lever-pressing

reponses. Top records: the first session (A; session 1) when

each response produced a 0.2 mg/kg injection of morphine sulfate

and the third session (B; session 3) when every tenth response

produced a 0.2 mg/kg injection of morphine sulfate. Each injection was accompanied by a 2-sec presentation of red stimulus

lights. A short diagonal deflection of the response pen and the

event pen indicates presentation of the red lights accompanied

by a morphine injection. The session ended after 47 injections

(A) or 19 injections (B). Middle and bottom records: the first

session (C; session 5) and 37th session (D; session 40) under a

second-order schedule, in which completion of every 10-response

(C) or 30-response (D) FR schedule component during a 60-min

interval of time produced only the 2-sec red lights; the first

FR component completed after 60 min elapsed produced the red

lights which remained on until 25 injections of 0.2 mg/kg morphine sulfate were delivered (total dose of 5 mg/kg). Diagonal

deflections of the response pen indicate presentations of the

red lights and downward deflections on the horizontal event line

indicate injections of morphine spaced 10 sec (C) or 2 sec (D)

apart. The response pen reset to the bottom of the cumulative

record whenever 1100 responses cumulated and when the session

ended. (From Goldberg and Tang 1976).

247
EFFECTS OF DRUG-PAIRED STIMULI DURING EXTINCTION

The effects of presenting brief stimuli during periods in which

saline is substituted for drug (extinction) have been shown to

depend on the interaction between the animal's history of stimulus presentations before and during extinction and the ongoing

rates and patterns of behavior (Kelleher and Goldberg, 1977;

Goldberg et al., 1981). When previously drug-paired stimuli

were presented regularly during the time that extinction was

occurring, responding declined rapidly and little evidence for

any effect of the stimulus presentations was found. Figure 4

shows the effects of substituting saline for cocaine on responding by a squirrel monkey (S-461) under a second-order FI 5-min

(FR 30: S) schedule. Responding was maintained at the high rate

typical of this monkey during the early intervals of the first

saline-substitution session. but declined rapidly towards the

end of this session and remained low in subsequent salinesubstitution sessions. These results indicate that the brief

light presentations that were so important in the rapid acquisition of high rates of responding rapidly lost their efficacy

when drug was no longer injected.

Under slightly different conditions, however, presentations of

previously drug-paired stimuli can markedly enhance behavior

undergoing extinction (Kelleher and Goldberg, 1977; Goldberg et

al., 1981). With one squirrel monkey (S-416) that had shown

high overall rates of responding under a second-order schedule

of cocaine injection identical to the one shown in figure 4 with

S-461, the schedule was first modified by increasing the overall

FI length to 180 min (i.e., 10.800 sec) before extinction of

behavior was studied (Goldberg et al., 1981). Every 30th response during the overall 180-min interval produced a brief

illumination of amber stimulus lights; cocaine was injected in

association with the lights only once each day at the end of the

3-hr session (figure 5). Despite the extended session length

and very low frequency of drug injection, high overall rates

continued to be maintained throughout each session. When injections of saline were substituted for cocaine and the brief light

presentations were omitted, rate of responding fell and the

within-component fixed-ratio patterns of responding were

absent. Saline substitution without brief stimulus presentations was continued for eight sessions. In the ninth session,

brief stimulus presentations were reinstated under the component

FR 30 schedule, but saline continued to be injected at the end

of the overall FI 180-min schedule. The original high rate and

fixed-ratio patterns of responding were almost totally restored. Over the next nine sessions of saline substitution with

the brief stimulus presentations, rate of responding gradually

decreased to the level maintained previously without the stimUli. At this point, cocaine was again injected at the end of

the overall FI 180-min schedule, and responding was quickly

restored to pre-extinction levels.

248
FIGURE 4

FIG. 4. Effects of substituting saline injections for cocaine

injections with squirrel monkey S-461. Completion of each 30-

response fixed-ratio (FR 30) component produced a 2-sec presentation of amber lights; the first FR 30 component completed

after 5 min elapsed produced both the lights and intravenous

injection of either 100 μ/kg cocaine hydrochloride or saline.

Recordings as in figure 1 except that the recorder was stopped

during both the timeout periods and 2-sec presentations of the

amber lights. Panel A shows the last session with cocaine injections before substituting saline; Panels B and C show the

first and fourth sessions of saline substitution, respectively;

and Panel D shows a subsequent session with cocaine injections

reinstated. (S. R. Goldberg, unpublished observations).

249
FIGURE 5

FIG. 5. Effects of reinstating brief stimulus presentations during saline substitution after an intervening number of sessions of saline substitution in

which the stimuli were not presented (squirrel monnkey S-416). Abscissae time.

Ordinates cumulative responses. Diagonal deflections of the response pen

indicate brief stimulus presentations. The response pen reset to the bottom of

the record after 1100 responses and at the end of the session The event pen

was displaced downward during the period of time in which repeated injections of

cocaine hydrochloride (total dose of 0.75 mg/kg) or injections of saline were

associated with amber lights. Components were 30-response fixed-ratio schedules the overall schedule was a 10.800-sec (i.e., 180-min) fixed-Interval

schedule. Component completions produced 2-sec presentations of the amber

lights in all records except the one shown in the second panel in which brief

stimuli were presented. The top panel shows rewarding under the second-order

FI lO, 800-sec (FR 30- S) schedule of cocaine injection Saline was then substituted for cocaine and the brief stimuli were omitted for the next eight sessions. the eighth session is shown in the second panel. Next. the brief stlimuli

were reinstated. but saline continued to be injected. the first (session 9) and

last (session 18) sessions under these conditions are shown In the next two panels The last panel shows reinstatement of cocaine injections. Note the immediate restoration of high rates and fixed-ratio patterns of responding when the

brief stimuli were first reinstated during saline substitution (session 9).

(From Goldberg. S.R., Kelleher. R.T., and Goldberg. D.H. Fixed-ratio responding under second-order schedules of food presentation or cocaine injection

J Pharmacol Exp Ther. 218(l) 271-281, 1981. © 1981, American Society for

pharmacology and Experimental Therapeutics.)

250
Very similar results were obtained in a related study with

squirrel monkeys in which completion of 10 consecutive FI 5-min

components resulted in injection of 300 ug/kg of cocaine

(Kelleher and Goldberg, 1977). When saline was substituted for

cocaine and brief light presentations at the completion of each

FI component were omitted, rate of responding fell and the

within-component fixed-interval patterns of responding were

absent. Reinstating brief presentations of previously drugpaired stimuli at completion of the fixed-interval components,

while saline substitution continued, increased the overall rate

of responding and engendered within-component patterns of responding characteristic of simple FI schedules.

These experiments indicate that an animal's history with respect

to brief stimulus presentations during extinction is an important factor in determining the effects of those stimuli on ongoing behavior. When the stimuli were presented throughout the

course of extinction, response rate decreased rapidly and patterns of responding were disrupted. If, however, responding was

allowed to decline during an initial extinction period in which

the stimuli were not presented, subsequent reintroduction of the

stimuli temporarily restored rates and patterns of responding to

pre-extinction levels.

EFFECTS OF DRUG-PAIRED STIMULI DURING MAINTENANCE

Comparisons of Presence Versus Absence of Drug-Paired Stimuli.

Just as brief presentations of drug-paired stimuli can enhance

performance during both acquisition and extinction of behavior,

brief stimulus presentations during long-term maintenance of

responding by consequent drug injections also have pronounced

effects (Kelleher and Goldberg, 1977; Goldberg et al., 1981).

Figure 6 shows the effects of omitting the brief stimulus presentations on responding by monkey S-254 under a second-order FI

15-min (FR 30: S) schedule of intravenous cocaine administration. When every 30th response produced brief illumination of

amber stimulus lights, and the first component FR 30 schedule

completed after 15 min produced both the lights and 100 ug/kg of

cocaine, responding was maintained at a high rate throughout the

overall FI 15-min schedule (panel A). Omitting the brief stimuli, while leaving all other conditions the same, greatly decreased the overall rate of responding and engendered long

pauses at the beginning of many of the intervals (panels B and

C). Reinstating the brief stimulus presentations returned

responding to previous levels (panel D).

Figure 7 summarizes these data on the effects of omitting the

brief stimulus presentations under the FI 15-min (FR 30: S)

schedule, and shows the effects of varying the dose per injection on quarterlife and overall rate of responding. quarterlife

is a measure frequently used to assess the amount of positive

acceleration in responding under FI schedules, and is defined as

the percentage of the interval during which 25 percent of the

responses are made. Thus, a linear rate of responding produces

251
FIGURE 6

FIG. 6. Effects of omitting brief stimulus presentations under

a second-order schedule of cocaine injection in squirrel monkey

S-254. The first 30-response fixed-ratio component completed

after 15 min elapsed produced a 2-sec presentation of the amber

stimulus liqhts and intravenous injection of 100 μg/kg of

cocaine hydrochloride [FI 15-min (FR 30: S)]. Recordings as in

figure 1 except that the recorder was stopped during 2-sec presentations of the amber lights in records A and D (indicated by

downward deflections of the response pen). When the brief stimulus presentations were omitted (records B and C), 2-sec presentations of the amber lights occurred only in association with

the injection of cocaine at the end of each interval (downward

deflections of the response pen indicate FR component completions). Cumulative records are shown from the last session

before omitting the brief stimulus presentations (A), the first

session (B) and the third session (C) in which brief stimuli

were not presented during the intervals, and the second session

(D) after reinstating the brief stimuli. (S. R. Goldberg,

unpublished observations).

252
FIGURE 7

COCAINE

μg/kg/injection)

FIG. 7. Quartet-life values and overall response rates for a

squirrel monkey (S-254) as a function of the dose of cocaine

hydrochloride per injection. Components were 30-response fixedratio schedules; the overall schedule was a 15-min fixedinterval schedule. Component completions produced either a

brief presentation of drug-paired stimulus lights (filled

circles) or no stimulus change (open circles). Abscissae:

dose, log scale. Ordinates: quarterlife values (top) and overall response rates (bottom). Circles represent the mean of the

last three sessions (stimulus) or two sessions (no stimulus) at

a dose; bracketed vertical lines show the range. Each dose of

cocaine was studied for at least four sessions, and the no stimulus condition was studied for three sessions. Note the marked

decrease in overall response rate and increase in quarterlife

when the brief stimuli were omitted. (S. R. Goldberg,

unpublished observations).

253
a quarterlife value of approximately 25 percent; progressively

higher quarterlife values indicate progressively more positive

acceleration (i.e., lower rates at the beginning of the interval

and higher rates at the end of the interval). With monkey

S-254, quarterlife values remained at approximately 30 percent

across a range of cocaine doses from 50 to 400 pg/kg/injection,

indicating a relatively constant rate of responding throughout

the overall interval. Omitting the brief stimulus presentations

at the 100 ug/kg/injection dose (open circle) increased the

quarterlife to over 40 percent, indicating relatively less

responding at the beginning of the interval and more responding

at the end of the interval. Overall rate of responding was

lowest at the 50 ug/kg/injection dose, approximately tripled at

the 100 ug/kg/injection dose, and then remained high at the last

two doses. As previously seen in figure 6, omitting the brief

stimulus presentations greatly decreased the overall rate of

responding. These findings have been replicated in additional

squirrel monkeys with variations in the type and parameter value

of the second-order schedule of cocaine injection (Kelleher and

Goldberg, 1977; Goldberg et al., 1981).

The effects of omitting brief stimulus presentations during

maintenance of responding also have been replicated using both

rhesus and squirrel monkeys responding under second-order scheaules of morphine injection (Goldberg and Tang, 1976, 1977). In

the Goldberg and Tang studies, the schedules were of the general

form FI 60-min (FR 30). Every 30th response produced either a

brief illumination of stimulus lights or no stimulus change; tne

first component completion after 60 min produced repeated morphine injections paired with the stimulus lights. Figure 8

shows the effects on overall response rates of varying the dose

of morphine at the end of the 60-min interval. Rates of responding were lowest at the 0 mg/kg dose (saline) and either

increased steadily or increased to asymptotic levels as the dose

of morphine was increased.

Figure 9 shows the effects of omitting and reinstating the brief

stimulus presentations on overall rates of responding with two

squirrel monkeys (S-369 and S-4O5). When the morphine-paired

brief stimuli were no longer presented, rate of responding

declined over several sessions to approximately half the level

maintained before the stimuli were omitted; responding quickly

recovered to the higher rate when the brief stimulus presentations were reinstated. A comparable effect is shown in figure

10 with a rhesus monkey (AT) responding at two different doses

of morphine (0.5 and 5.0 mg/kg). Although the 5.0 mg/kg dose

maintained higher rates under both stimulus and no stimulus conditions than did the 0.5 mg/kg dose under comparable conditions,

omitting the stimuli at either dose produced large decreases in

rates of responding.

Comparison of Drug-Paired and Nonpaired Stimuli. The experiments up to this point have all investigated the effects of

presence versus absence of brief stimulus presentations. A

254
FIGURE 8

mg/kg MORPHINE

FIG. 8. Overall response rates of three squirrel monkeys

(S-185, S-369 and S-405) and of two rhesus monkeys (AW and AT)

under a second-order schedule of intravenous morphine Injection

as a function of the total dose of morphine sulfate injectea at

the end of the session. Abscissae: dose. Ordinates: mean

response rate. Each bar represents the mean and the brackets

the range of the last five sessions at each dose of morphine and

of the last three (squirrel monkeys) or two (rhesus monkeys)

sessions of saline (0 mg/kg) substitution. Doses of morphine

were studied for eight to sixteen sessions, saline for at least

four sessions. (Based on data from Goldberg and Tang, 1976,

1977).

255
FIGURE 9

FIG. 9. Overall response rates of two squirrel monkeys (S-369

and S-405) under the second-order schedule of intravenous morphone injection as a function of presenting or not presenting

2-sec amber stimulus lights at completion of each 30-response

fixed-ratio (FR 30) component. Abscissae: consecutive sessions. Ordinates: mean response rate. Each bar represents the

mean and the brackets the range of three sessions. Each session

ended with Intravenous injection of a total dose of 1.5 mg/kg

morphine sulfate. Shaded bars represent sessions when the 2-sec

stimulus occurred at completion of each FR 30 component; open

bars represent sessions when no stimulus change occurred at completion of each FR 30 component (the amber lights occurred only

in association with injection of morphine at the end of the session). Note the marked decrease in responding when the brief

stimuli were omitted. (Based on data from Goldberg and Tang,

1976, 1977).

256
FIG. 10. Overall response rates of rhesus monkey AT under the

second-order schedule of intravenous morphine injection as a

function of presenting or not presenting 2-sec red lights (brief

stimulus) at completion of each 30-response fixed-ratio (FR 30)

component. Abscissae: consecutive sessions. Ordinates: mean

response rate. Each bar represents the mean and the brackets

the range of four Sessions. Each session ended with intravenous

injection of a total dose of 0.5 mg/kg or 5.0 mg/kg morphine

sulfate. Shaded bars represent sessions when the 2-sec stimulus

occurred at completion of each FR 30 component and open bars

represent sessions when no stimulus change occurred at completion of each FR 30 component. When the brief stimuli were omitted at the 0.5 mg/kg morphine dose, mean response rate dropped

to such a low rate (session 16). that when the brief stimuli

were reinstated the FR response requirement was initially reduced to one and three (sessions 17 and 18, respectively; not

shown in this figure) and subsequently returned to 30 (FR 30;

sessions 19 to 22). (From Goldberg and Tang, 1976).

257
recent study (Goldberg et al., 1979) examined the extent to

which the pairing of a stimulus with drug injection was responsible for the enhanced performance when brief presentations of

the stimulus were scheduled. Squirrel monkeys responded under

second-order schedules in which completion of component fixedratio schedules produced either morphine or cocaine injection

according to overall fixed-interval schedules. With the group

of monkeys for which morphine injection was the terminal event

(S-667, S-388, S-369 and S-405). the parameter value of the

overall FI schedule was 60 min; with the group for which cocaine

injection was the terminal event (S-334, S-333 and S-411), the

parameter value of the overall FI schedule was 10 min. Components consisted of FR 30 schedules for all monkeys in the morphine group and for one monkey (S-334) in the cocaine group;

components were FR 100 schedules for the other two monkeys in

the cocaine group. With all animals, injections at the end of

the interval were accompanied by illumination of amber StimuluS

lights. Completions of component FR schedules produced, in separate experimental phases: 1) brief illumination of amber

lights; 2) brief illumination of blue lights; or 3) no stimulus

change. Thus, comparisons were made between 1) paired stimulus,

2) nonpaired stimulus, and 3) no stimulus changes at completion

of components.

Figure 11 shows cumulative records of responding by monkeys from

each group under the three conditions. High rates of responding

were engendered by the second-order schedules with paired brief

stimuli. Additionally, within-component patterns of responding

characteristic of simple FR schedules were maintained. When

nonpaired stimuli were presented, overall rates of responding

decreased, and component FR patterns of responding were disrupted. These changes were even more pronounced when the stimuli were omitted altogether.

Figure 12 summarizes the effects of the different methods of

presenting stimulus changes at component completion on local and

overall rates of responding for all monkeys in both groups.

Local rates of responding in figure 12 were calculated as the

average rate from the first to last response in each FR component (i.e., pause time before the first response in each fixed

ratio was not included in the computations). Overall rates of

responding were calculated by dividing the total number of responses by the total time, excluding responses and time in the

presence of the amber or blue lights. Paired brief stimulus

presentations clearly maintained higher local and overall rates

of responding than either nonpaired stimulus presentations or no

stimulus presentations; with monkeys for which the comparison

can be made, nonpaired stimuli maintained higher rates than no

stimuli. Thus, the discriminative control exerted by brief

stimuli occurring regularly throughout sequences of behavior

terminating in drug injection is sufficient to enhance responding somewhat, but pairing the stimuli with drug injection

increases their efficacy.

258
FIGURE 11

FIG. 11. Representative cumulative records showing responding

under the second-order schedules of intravenous cocaine or morphine injection when the completion of every fixed-ratio component during the fixed interval produced either a paired (amber

light) or a nonpaired (blue light) brief stimulus or when the

brief stimuli were omitted. Abscissae: time. Ordinates: cumulative responses. Short diagonal deflections of the response

pen indicate brief stimulus presentations; downward deflections

on the horizontal event lines indicate injection of drug. Left

panels show responding during portions of the session under the

secondorder schedule of cocaine injection (monkey S-411); recordings as in figure 1. Right panels show responding during

the entire session under the second-order schedule of morphine

injection (monkey S-388, paired and nonpaired stimuli; monkey

S-405, no stimulus); recordings as in figure 2.

(From Goldberg, S.R., Spealman, R.D., and Kelleher, R.T. Enhancement of drug-seeking behavior by environmental stimuli associated

with cocaine or morphine injections. Neuropharmacology, 18:1015-

1017, 1979. © 1979, Pergamon Press, Ltd.)

259
FIGURE 12

MORPHINE

FIG. 12. Local and overall rates of responding (responses/sec)

under the second-order schedules of intravenous cocaine or morphine injection when the completion of every fixed-ratio component during the fixes interval produced either a paired or a

nonpaired brief stimulus or when the brief stimuli were omitted. Bars show average rates of responding during the last

three sessions of each successive condition for individual monkeys; brackets show ranges. Each condition was studied for 5 to

20 consecutive sessions.

(From Goldberg, S.R., Spealman, R.D., and Kelleher, R.T. Enhancement of drug-seeking behavior by environmental stimuli associated

with cocaine or morphine injections. Neuropharmacology, 18:1015-

1017, 1979. © 1979, Pergamon Press, Ltd.)

260
Second-Order Schedules of Nicotine Injection. In addition to

providing useful procedures for the study of stimulus functions

in extended behavior sequences, second-order schedules have

enabled other phenomena to be studied under laboratory conditions that might otherwise have been difficult to control experimentally. For example, a number of investigators have noted

that nicotine maintains very low rates of responsing leading to

its injection by laboratory animals under conditions in which

presentation of other drugs maintains high rates of responding

(e.g., Deneau and Inoki, 1967; Yanagita, 1972, 1977; Griffiths

et al., 1979).

have aversive properties that limit human smoking behavior

Indeed, it has been suggested that nicotine may

(Russell, 1976, 1979). However, in a recent laboratory study,

high rates of responding by squirrel monkeys were maintained

under second-order brief-stimulus schedules of nicotine injection (Goldberg et al., 1981; Goldberg and Spealman, 1981a).

The procedures involved were similar to those employed in

previous studies with cocaine and morphine. Squirrel monkeys

responded under second-order schedules in which every tenth

response produced brief illumination of amber stimulus lights;

the first component FR 10 schedule completed after an overall FI

schedule of 1 or 2 min had elapsed produced both the brief

lights and intravenous injection of 30 pg/kg of nicotine. Each

injection was followed by a 3-min timeout period during which

the chamber was dark and responses had no programmed Consequences.

Representative cumulative records of responding by each of three

squirrel monkeys (S-151, S-200 and S-156) under these schedules

are shown in figure 13. Responding was well maintained by 30

ug/kg injections of nicotine at overall rates of approximately

one response per sec. Characteristic fixed-ratio patterns of

responding were controlled by the brief stimuli: responding

during each ratio unit was usually characterized by an initial

pause, followed by an abrupt transition to a high steady rate of

responding that terminated with presentation of the brief stimulus or drug. The average local rate of responding was about

four responses per sec.

These results are especially interesting in view of the fact

that the same doses of nicotine that functioned to maintain

responding under the second-order schedule also can function

effectively to suppress responding maintained under an FR schedule of food presentation (Goldberg and Spealman, 1981b). Thus,

nicotine can have pronounced actions in either maintaining or

suppressing behavior, depending on the environmental context

within which it is studied. Current studies of second-order

performances maintained by nicotine injection are being conducted to determine the range of conditions resulting in rapid

acquisition, prolonged maintenance, and subsequent extinction of

the behavior.

261
FIGURE 13

FIG. 13. Representative performance of three squirrel monkeys

(S-151. S-2OO and S-156) under a second-order schedule of intravenous nicotine injection. Every 10th lever pressing response

(FR 10) during a 1-min (S-151) or 2-min interval (S-200 and

S-156) produced a 2-sec illumination of amber stimulus lights;

the first FR 10 component completed after 2 min elapsed produced

the 2-sec amber light and a 30 pg/kg injection of nicotine

tartrate [FI 2-min (FR 10: S)]. Recordings as in figure 1. (S.

R. Goldberg, unpublished observations).

262
Second-Order Schedules of Intramuscular Drug Injection. Using

second-order schedules, it has also been possible to maintain

long, reproducible sequences of behavior terminating in intramuscular drug injections (e.g., Goldberg and Morse, 1973;

Goldberg et al., 1976; Katz, 1979). Figure 14 shows representative cumulative records of responding by a squirrel monkey

(S-667) under a second-order schedule of intramuscular cocaine

injection. The experimental conditions, and resulting performance, are very similar to those described previously except that

injections of cocaine were given intramuscularly rather than

intravenously. The second-order schedule used in this study was

a 30-min fixed-interval schedule of 30-response fixed-ratio components. Completion of the first FR 30 component after 30 min

had elapsed illuminated amber stimulus lights for 2 min. While

the amber lights were on, the door of the experimental chamber

was opened and 3.0 mg/kg of Cocaine was injected into the

monkey's calf muscle.

Figure 14 shows the effects of substituting saline for cocaine,

and of removing and reinstating brief presentations of the amber

lights at completion of the FR 30 components. The effects of

these manipulations were similar to the effects of comparable

manipulations when drugs were injected intravenously: rate of

responding decreased when saline was substituted for cocaine

(left panel), and rate of responding decreased and component FR

patterns of responding were absent when the brief stimuli were

omitted (right panel). The demonstration that responding can be

maintained under second-order schedules terminating in intramuscular injections of drugs provides a potentially important

technical contribution to the laboratory analysis of drug selfadministration. It may be possible, using these techniques, to

study drugs that are difficult to administer intravenously

because of low solubility or other factors. Also, longer

studies may be attempted since the need to implant and maintain

chronic venous catheters is eliminated.

SUMMARY AND CONCLUSIONS

The present results, and those of other studies of responding

under second-order schedules of drug Injection (e.g., Goldberg

et al., 1975, 1976, 1981; Kelleher and Goldberg, 1977; Katz,

1979), were generally similar to results of studies that have

used food as the maintaining event (for reviews see Gollub,

1977; Kelleher, 1966a; Mart-, 1969, 1979). Rates and patterns of

responding under second-order schedules have been shown to be

controlled by interactions among: 1) the type and parameter

value of the component schedule; 2) the type and parameter value

of the overall schedule; and 3) the manner of presenting exteroceptive stimulus changes at completion of components. When

brief stimuli paired with cocaine, morphine, or nicotine injections were presented at completion of fixed-ratio component

schedules, rates and patterns of responding typical of simple

fixed-ratio schedules were obtained. Presentation of the drugpaired stimuli controlled high rates and characteristic fixed263
FIGURE 14

FIG. 14. Representative performance maintained under a secondorder schedule of intramuscular cocaine injection in squirrel

monkey S-667. Abscissae: time. Ordinates: cumulative leverpressing responses. Short diagonal deflections of the response

pen indicate brief stimulus presentations. The response pen

reset to the bottom of the cumulative record whenever 1100 responses cumulated and at the end of the session. Completion of

each 30-response fixed-ratio (FR 30) component during a 30-mln

Interval produced a 2-sec presentation of amber stimulus lights

(all records except the one at the middle right in which no

brief stimuli were presented). The first FR 30 component completed after 30 min elapsed illuminated the amber lights for 2

min during which time the chamber was opened and the monkey

given an intramuscular injection of 3 mg/kg of cocaine hydrochloride in the calf muscle. The event pen was displaced downward during this 2-min period of time. The effects of substituting saline injections for cocaine injections for 10 sessions

(middle left record) and of omitting the brief stimulus presentations for three sessions (middle right record) are shown.

Upper and lower records show control performance before and

after saline substitution or omission of brief stimuli. (S. R.

Goldberg, unpublished observations).

264
ratio patterns of responding in much the same manner as other

frequently studied consequent events, such as food presentation. When the stimuli were omitted, rates of responding were

lower and component fixed-ratio patterns were absent. Presenting stimuli that were not paired with drug injection produced

intermediate rates of responding and patterns of responding that

were less distinct than those obtained with paired stimuli.

Previous studies that have used fixed-interval rather than

fixed-ratio schedules as components of second-order schedules of

drug injection have found similar effects of presenting or omitting drug-paired stimuli (e.g., Kelleher and Goldberg, 1977;

Katz, 1979).

The experiments reviewed in this paper all used overall fixedinterval schedules under which fixed-ratio component completions

produced drug injections only after fixed periods of time

elapsed. Results of these experiments were generally consistent

with those of previous experiments that have used food presentation as the maintaining event; responding either was maintained

at a high rate throughout the overall interval or consisted of

an initial pause followed by positive acceleration to a high

rate that terminated with drug injection. However, studies of

comparable second-order brief-stimulus schedules of food presentation have sometimes reported more pausing at the beginning of

overall fixed-interval schedules than those reported here under

the second-order schedules of cocaine or nicotine injection

(e.g.. Gonzalez and Goldberg, 1977; Goldberg et al., 1981;

Kelleher, 1966b). The relatively higher rates early in the interval when cocaine or nicotine was used as a maintaining event

might partially have resulted from the direct aftereffects of

previous drug injections (cf., Katz, 1979; Goldberg et al.,

1981). Cocaine (e.g., Gonzalez and Goldberg, 1977; Spealman,

Goldberg, Kelleher, Goldberg and Charlton, 1977) and nicotine

(e.g., Spealman et al., 1981) have both been shown to increase

rates of responding early in the interval under fixed-interval

schedules of either food presentation or termination of a stimulus associated with electric shock. It is important within

this context, however, to note that omitting presentations of

brief drug-paired stimuli decreased rates of responding early in

the overall interval even under the second-order schedules of

cocaine injection. This finding may have implications for programs designed to modify human drug-taking behavior, since presenting drug-paired stimuli not only increased rates of responding maintained by drug injection, but produced these increases

at the time drug injection was least imminent.

When stimuli paired with either cocaine or morphine injections

were introduced early in the experimental histories of rhesus

monkeys, they had profound effects on behavior. Although rates

of responding controlled by the drug injections were low, and

patterns of responding were erratic, introducing drug-paired

stimuli rapidly engendered high rates of responding and a

temporal patterning of responses characteristic of the fixedratio schedules under which they were produced. Thus, even

265
before behavior maintained by drug injection had stabilized,

stimuli associated with the injections could markedly enhance

responding in a manner typifying the process of reinforcment.

Presenting previously drug-paired stimuli during periods of

saline substitution had different effects depending on the conditions under which they were presented. When the stimuli were

presented throughout the period of saline substitution, response

rates declined rapidly and component fixed-ratio patterns of

responding were disrupted. Markedly different effects were

obtained, however, if responding was first allowed to decline

during a period of saline substitution in which the stimuli were

not presented. Subsequent reintroduction of stimulus presentations temporarily restored rates and patterns of responding to

those maintained when drugs had been injected. Thus, previously

drug-paired stimuli can retain their response-maintaining characteristics for a long period of time when they are not repeatedly presented during extinction. Processes similar to

those described here with laboratory animals could play a significant role in human relapse to drug self-administration after

prolonged periods of abstinence (Wikler, 1965, 1971; Goldberg,

1970).

Direct analogies between the control of human behavior and any

given set of laboratory procedures are, of course, tenuous at

best. Sufficient amounts of experimental data simply have not

been collected, especially on human behavior. Nevertheless,

second-order schedules of drug injection appear to resemble in

many respects the conditions under which human behavior outside

the laboratory is maintained by drug self-administration. Drug

injections are not continuously available but are administered

intermittently only after progression through a number of sequential stimulus changes and component behavior patterns. The

orderly patterns of responding by laboratory animals under

second-order schedules of drug injection also compare favorably

in terms of their persistence and complexity to those seen in

humans. These complex patterns of drug self-administration behavior are extremely sensitive to manipulations of environmental

variables and this is another promising field for future research. As yet there seems to be literally no limit to the

amount of behavior that can be maintained by drug injections

using second-order scheduling contingencies.

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AUTHORS

Steven R. Goldberg, Ph.D.

Michael L. Gardner, Ph.D.

National Institute on Drug Abuse

Division of Research

Addiction Research Center

P.O. Box 12390

Lexington, Kentucky 40583

270
The Place of Adjunctive Behavior

in Drug Abuse Research

John L. Falk, Ph.D.

To call a stream of behavior "excessive" is to vilify it. Most

excessive behavior is conceived of as bad, although some is seen

as exceptional, or even the output of genius. A central question

revolves around the sources of unusual amounts of behavior, whether

we consider that behavior good, bad, or indifferent. The study of

this question can elucidate the genesis of particular excessive

behavior that we find obnoxious,

Behavior is labeled and censured as excessive because society finds

its personal, medical, or social consequences repugnant. Again,

this excessiveness is not a quality of the behavior itself, but of

the social sanctions applied. Therefore, perhaps, we should study

all manner of behavioral excesses and how they come about, not just

those which society has decided are outside its bounds of acceptable

behavior. We propose, then, to seek the general sources producing

behavioral exaggeration, not just those regarded as pathological.

Both society and its clinical services consider excessive behavior

to be invasive or intrusive if it interferes with alternative,

adaptive behavior which could and should be occurring in the situation. Much of the current concern with illicit drug seeking and

drug taking revolves around this issue. Other excessive behavior

is considered undesirable because it produces negative consequences:

overeating, cigarette smoking, and child or spouse abuse, for

example.

There are several theoretical notions about how excessive behavior

is generated. One is that there is an intrinsic defect in some

persons. This could be a "bad seed," bad genes, or just a weak will.

Another view is that a person who is basically all right may be

the subject of some sort of demonic possession--if not by a literal

demon, perhaps a demon-like process, such as exposure to a highly

seductive drug. Weakness in the face of overwhelmingly enticing

goods or services is not condoned, but some sympathy is felt for

those temporarily fallen from grace, since some stimuli have a

reputation for being all but irresistible.

271
A third way in which behavioral excess is believed to be generated

is by irritative disinhibition. Some dark and atavistic side of

human nature can be released by indulging in dangerous chemical

substances. Such agents can weaken the "will" or the "cortical

inhibitions," allowing dangerous impulses behavioral egress. These

three notions are not mutually exclusive, and it is not unusual to

find all of them entwined in accounts of putative mechanisms underlying the control of behavior by drugs having abuse liability.

All of these conceptions are genie-in-the-bottle theories. Something inside the person, when it gets out, is behaviorally intrusive.

Environmental conditions, by this view, can trigger or precipitate

behavioral excesses, but they are not really determiners of behavior.

The important determinants of excessive behavior are seen as

structural defects which are innate or are formed by early physical or psychic trauma. There is a kind of internal class struggle:

the good, inhibitory responses hold the bad, impulsive responses in

check. This point of view has led to a set of beliefs about what

will happen when people are given easy access to potent reinforcers

such as drugs. Loss of control will occur because these agents

both activate the primitive reaction patterns and disrupt our

defenses. Some drugs are purported to be like push-pull amplifiers:

they pull you because they are euphorics, and they push you because

they either release aggression or produce a zombie-like state of

carelessness about personal or social consequences. From this

perspective, the only way to keep potent reinforcers from producing

behavioral excesses, then, is to keep people from getting their

hands on them.

In contradistinction to this view, there is an increasing recognition of the socioeconomic determinants of antisocial behavioral

excesses. Environmental determinants are now used explicitly to

maintain desirable behavior and to attenuate unwanted behavior.

Since reinforcing and punishing events have been to some extent

used successfully to control behavioral excesses, the assumption

has been that perhaps similiar events have contingently engendered

the excesses in the first place. While this may be the case, clear

proof is lacking. Excessive behavior, by such a view, would be

maintained because it is followed by reinforcing consequences.

While it cannot be denied that such a mechanism may be an important underlying factor sustaining substance abuse, it is becoming

evident that we also have a different model of excessive and

persistent behavior, one which appears counteradaptive in that it

is not under the control of obvious contingencies of reinforcement.

The phenomenon is called schedule-induced or adjunctive behavior.

SCHEDULE-INDUCED BEHAVIORS

A number of years ago, I found that a rather ordinary experimental

arrangement produced a curious and dramatic result (Falk 1961).

When a normal rat was placed into a chamber for about 3 hours each

day and required to lever-press to earn most of its food ration,

it did so, but it also concomitantly drank inordinate amounts

272
of water. Enough food was permitted each day to maintain the body

weight at about 80 percent of the normal adult free-feeding weight.

The rat was free to move about the chamber and press the lever at

any time, but a press paid off with a 45 mg food pellet only

intermittently, on the average of once per minute. This "variableinterval l-minute" schedule of reinforcement (Ferster and Skinner

1957) produces a moderate, but persistent, rate of pressing.

Among the marks of excessive behavior are that it appears to be

counteradaptive and that it tends to be chronic, or at least to

reappear frequently. Large and useless amounts of water are

drunk by animals as an adjunct to the schedule of reinforcement

described above as well as many other schedules (Falk 1969). In

the initial experiments with the variable-interval schedule, rats

pressed at a moderate rate until a pellet was delivered and then

a burst of drinking ensued, followed by a return to pressing.

Animals drank after eating almost every food pellet. Drinking in

connection with eating is not unusual, but the amount of water

ingested over a 3-hour session was most unusual: Animals drank

close to one-half of their body weights!

In this initial study, 14 rats were exposed to this schedule.

Within a week or two the pressing and drinking pattern had stabilized. with a mean session water intake of 92.5 ml. This was

about-ten times the average intake of the control animals, rats - -

reduced to 80 percent of their normal, free-feeding weights, but

given their food pellets all at once; these drank an average of

only 9.5 ml in 3.5 hours. It should be noted that in none of

these experiments were the animals ever deprived of water. When

they were not in the experimental chambers for their 3-hour session each day, they were housed in individual home cages with free

access to water. Extensive study of the conditions that produce

session overdrinking revealed no traditional physiological or

behavioral considerations which could account for the induction

of this persistent overdrinking, or polydipsia, which lasts month

after month, as long as the distributed-feeding condition remains

in effect.

Unlike drinking produced by the depletion of body water, or by

eating highly salted food, this polydipsia is not mitigated by

intubating water into the stomach before a session (Falk 1969).

Furthermore, the overdrinking does not depend on the intermittent

eating of a dry food pellet; it can be produced by a variableinterval schedule of liquid food portions (Falk 1967). Instead

of listing classic physiological and behavioral variables which

do not account for this schedule-induced polydipsia (for review

see Falk 1969, 1971), let us characterize the crucial factors

which produce the phenomenon. The experimental arrangement

described really contains only two constraints which are not

present in the living conditions of most other normal, laboratorydwelling animals: a limited food ration and a limitation on the

rate at which this ration can be eaten. While the reduced food

ration in itself does not produce overdrinking, somehow the confluence of the two restraints does.

273
A powerful behavioral phenomenon, such as schedule-induced polydipsia, is unlikely to be the only excessive behavior generated

by such ubiquitous schedule conditions as intermittently delivered

food. Indeed, quite similar food intermittency conditions yield

schedule-induced aggression or attack. For example, a pigeon

earning small portions of food intermittently in an experimental

chamber which also contains a semi-restrained second pigeon shows

a pattern of directed attack against this pigeon shortly after the

delivery of each portion of food (Azrin et al. 1966). As in the

case of schedule-induced polydipsia, the attack level is quite

excessive as measured against nonintermittent food conditions

(either no food available or the ration given as a single large

portion). This aggressive behavior can take many forms. For

example, squirrel monkeys will repeatedly bite a rubber hose after

the intermittent delivery of each small food portion (Hutchinson

et al. 1968).

These behavioral excesses are not simply reflexive responses

evoked by the periodic delivery of a bit of food. If the water

or the restrained pigeon is not freely available in the situation,

the animals will work repeatedly to attain access to them (Cherek

et al. 1973, Falk 1966). The behavioral excesses, then, reveal

the animals' considerable motivation to engage in them, since they

will work hard to attain these opportunities.

How widespread are the behavioral excesses produced? Hyperactivity

in animals (Levitsky and Collier 1968) and humans (Fallon et al.

1979), consumption of nonfood materials (pica) (Villarreal 1967),

escape responses (Azrin 1961), and of particular interest in the

present context, the intake of various drugs (Gilbert 1978), have

all been investigated. Thus far, we have only mentioned the production of these phenomena in the rat, pigeon, and squirrel monkey. Other studies have revealed them in the mouse, rhesus monkey, gerbil, chimpanzee, and in humans as well (Falk, in press).

Are these behavioral excesses produced only by food deprivation

and schedules of food delivery? While most of the experimental

work has been done using food schedules, the generation of schedule-induced adjunctive behavioral excesses is not limited to this

condition. Schedule-induced activity in rats has been produced

by intermittent access to water; conversely, overdrinking has

been produced by scheduling running-wheel access. In humans,

hyperactivity, polydipsia, and smoking have been induced by the

scheduled presentation of monetary rewards, the playing of games,

or by problem-solving (Clarke et al. 1977, Fallon et al. 1979,

Muller et al. 1979, Wallace et al. 1975, Wallace and Singer 1976).

Thus, there is a considerable degree of generality both in the

kinds of commodities or behavior sequences whose intermittency

generates adjunctive behavior and in the variety of the resulting

adjunctive, excessive activities. The scheduling of commodities

and activities important to the individual, then, proves to be a

major multiplier or exaggerator of ancillary, unexpected behavioral outputs.

274
IMPLICATIONS FOR SUBSTANCE ABUSE

It is of critical interest, for our present purposes, to establish

whether this excessive behavior bears a homologous relation to

those excesses in humans classed as substance abuse. If such a

homology is to be considered plausible, at least three points need

to be established. First, there must be evidence that adjunctive

behavioral excesses do occur in humans under appropriate scheduleinduction conditions. This has been confirmed. Second, the schedule-induction conditions should be rather nonspecific in terms of

the particular commodity which is being made available on an intermittent basis. That is, it should be sufficient that the commodity

or activity be of importance to the individual in a motivational

sense. Again, available evidence confirms the generality of this

relation: several kinds of scheduled events have been demonstrated

to induce various sorts of excessive behavior in humans. Third,

schedule induction should be able to institute and maintain drug

abuse in animals under conditions that otherwise would not lead to

excessive drug taking. Unless such a relation holds true for animals, the human homology would be a difficult argument to sustain.

Once again, several drug classes are chronically accepted at excessive levels under appropriate schedule-induction conditions. These

include overdrinking of barbiturates, narcotic analgesics, amphetamines, chlordiazepoxide, and ethanol (Gilbert 1978).

Schedule induction can change a weak, oral reinforcing agent into

a very powerful one. For example, ethanol was drunk excessively

by a group of rats exposed continuously to an intermittent feeding

schedule (Falk et al. 1972). On this schedule, a food pellet was

delivered to a rat every 2 minutes for a l-hour feeding period.

Feeding periods were each spearated by 3 hours, making six l-hour

feeding periods for each 24-hour cycle. Five percent ethanol was

the fluid available for 3 months. The mean alcohol intake for

eight animals was 13.1 grams per kilo per day. The blood ethanol

level of these animals remained above 100 mg/dl for the major part

of the 24-hour cycle, and often lay between 150 and 300 mg/dl.

The ethanol solution was preferred to water and some other solutions, and the chronically excessive intake resulted in severe

physical dependence on ethanol. Comparable animals maintained

under similar nutritional conditions, but not fed on an intermittent schedule, did not drink as much alcohol as the scheduled animals nor did they show evidence of physical dependence (Falk and

Samson 1975). A number of studies in animals, using food pellet

schedules, have demonstrated schedule-induced excessive intravenous

drug self-administration with heroin, methadone, cannabis, and

nicotine (Oei et al. 1980, Smith and Lang 1980, Takahashi and

Singer 1980).

Many drugs are reinforcers to both animals and humans (Johanson

1978), but under most circumstances, particularly when taken orally,

they function as weak reinforcing agents. Some schedules can

exaggerate the reinforcing properties of agents, thereby increasing

their oral or intravenous self-administration. Both nature and

society often provide us with an uneven flow of the commodities

275
important to survival or the maintenance of an accustomed style of

life. Environmental situations, then, in many ways constitute a

set of complex, intermittent schedules.

The particular adjunctive behavior that might be induced by such

natural schedules would depend upon the available behavior alternatives. Adjunctive behavior is to some extent a function of the

opportunities present in the environment. In animals, the presence

of a fluid to drink permits excessive drinking. Hyperactivity

often occurs if a running wheel is made available in conjunction

with an inducing schedule. In humans, the alternative opportunities

provided by the environment are probably critical in determining

what behavioral excesses occur, be they drug taking, violence,

exercise, or creative endeavors.

Clearly, however, even with creative or productive alternatives to

drug taking available, there is no assurance that an individual

will take advantage of them. Past history and training are critical

in enabling a person to utilize a potential opportunity. It is

probable that those persons lacking complex behavioral repertoires

will turn more readily to easily consumed adjuncts, such as drug

taking. Society must take care to provide alternative behavioral

repertoires which enable us to make creative and productive choices.

If commodity access is limited, as it often is, in such a way that

adjunctive behavior occurs persistently, then it is desirable that

this excessive behavior be productive, or at the very least, benign.

The induction of excessive, adjunctive behavior by rather simple

schedule conditions demonstrates how commodity constraint in one

realm can result in excessive behavior in a seemingly unrelated

domain. It should be emphasized that these are all normal behavioral processes demonstrable in normal, unselected experimental

subjects. Bizarre or extreme manipulations were not imposed. The

commerce with life's commodities which is arranged in most of the

research described is similiar to that probably encountered by most

subjects attempting to exploit an ecological niche in competition

with other species and their own neighbors or in just working for

a living. From normal sources extreme results can flow. Rather

bland environmental conditions of intermittence can produce persistent and problematic excesses, including drug abuse,

REFERENCES

Azrin, N.H. Time-out from positive reinforcement. Science, 133:

382-383, 1961.

Azrin, N.H.; Hutchinson, R.R.; and Hake, D.F. Extinction-induced

aggression. J Exp Analysis Behav, 9:191-204, 1966.

Cherek, D.R.; Thompson, T; and Heistad, G.T. Responding maintained by the opportunity to attack during an interval food reinforcement schedule. J Exp Analysis Behav, 19:113-123, 1973.

276
Clarke, J.; Gannon, M.; Hughes, I.; Keogh, C.; Singer, G.; and

Wallace, M. Adjunctive behavior in humans in a group gambling

situation. Physiol Behav, 18:159-161, 1977.

Falk, J.L. Production of polydipsia in normal animals by an intermittent food schedule. Science, 133:195-196, 1961.

Falk, J.L. The motivational properties of schedule-induced polydipsia. J Exp Analysis Behav, 9:19-25, 1966.

Falk, J.L. Control of schedule-induced polydipsia: type, size

and spacing of meals. J Exp Analysis Behav, 10:199-206, 1967.

Falk, J.L. Conditions producing psychogenic polydipsia in animals.

Ann N Y Acad Sci, 157:569-593, 1969.

Falk, J.L. The nature and determinants of adjunctive behavior.

Physiol Behav, 6:577-588, 1971.

Falk, J.L. The environmental generation of excessive behavior.

In: Mule S.J., ed.

(in press).

Behavior in Excess. New York: Free Press

Falk, J.L.; Samson, H.H.; and Winger, G. Behavioral maintenance

of high concentrations of blood ethanol and physical dependence

in the rat. Science, 177:811-813, 1972.

Falk, J.L.; and Samson, H.H. Schedule-induced physical dependence

on ethanol. Pharmacol Rev, 27:449-464, 1975.

Fallon, J.H., Jr.; Allen, J.D.; and Butler, J.A. Assessment of

adjunctive behaviors in humans using a stringent control procedure.

Physiol Behav, 22:1089-1092, 1979.

Ferster, C.B., and Skinner, B.F. Schedules of Reinforcement.

New York: Appleton-Century-Crofts, 1957.

Gilbert, R.M. Schedule-induced self-administration of drugs. In:

Blackman, D.E., and Sanger, D.J., eds. Contemporary Research in

Behavioral Pharmacology. New York: Plenum Press, 1978. pp.

289-323.

Hutchinson, R.R.; Azrin, N.H.; and Hunt, G.M. Attack produced by

intermittent reinforcement of a concurrent operant response.

J Exp Analysis Behav, 11:489-495, 1968.

Johanson, C.E. Drugs as reinforcers. In: Blackman, D.E., and

Sanger, D.J., eds. Contemporary Research in Behavioral Pharmacology. New York: Plenum Press, 1978. pp. 325-390.

Levitsky, D.,and Collier,

Physiol Behav, 3:571-573,

Muller, P.G.; Crow, R.E.;

motor activity in humans.

G. Schedule-induced wheel running.

1968.

and Cheney, C.D. Schedule-induced locoJ Exp Analysis Behav, 31:83-90, 1979.

277
Oei, T.P.S.; Singer, G.; and Jefferys, D. The interaction of a

fixed time food delivery schedule and body weight on self-administration of narcotic analgesics. Psychopharmacology, 67:171-176,

1980.

Smith, L.A., and Lang, W.J. Changes occurring in self-administration of nicotine by rats over a 28-day period. Pharmacol Biochem

Behav, 13:215-220, 1980.

Takahashi, R.N., and Singer, G. Effects of body weight levels on

cannabis self-injection. Pharmacol Biochem Behav, 13:877-881,

1980.

Villarreal, J. Schedule-induced pica. Paper read at Eastern Psychological Association, Boston, April 1967.

Wallace, M., and Singer, G. Adjunctive behavior and smoking

induced by a maze-solving schedule in humans. Physiol Behav, 17:

849-852, 1976.

Wallace, M.; Singer, G.; Wayner, M.J.; and Cook, P. Adjunctive

behavior in humans during game playing. Physiol Behav, 14:651-

654, 1975.

AUTHOR

John J. Falk, Ph.D.

Department of Psychology--Busch

Rutgers University

New Brunswick, New Jersey 08903

278
Discussion

Complex Schedules and

Maintenance of Drug Dependence

James E. Barrett, Ph.D.

Behavioral pharmacology now has available a number of extremely

powerful techniques which can illuminate and intensify characteristic

aspects of drug seeking and other habitual behaviors. It is often

the case that certain problems remain intractable until the development of appropriate procedures renders them Subject to experimental

assault. Significant advances frequently stem from the widespread

application of findings that are fundamentally important (Morse

1975). Clearly, the studies described in this session by Goldberg

and Falk represent two major instances where the relatively recent

application of technical procedures has permitted the experimental

establishment and direct analysis of the persistent, excessive behavior typical of substance abuse. These areas are now ripe for fertile,

productive analyses and justify further the relevance of studies with

laboratory animals to problems of human drug dependence (Griffiths

et al. 1980; Schuster 1975).

These developments are interesting in several other respects. The

substantial levels of orderly and well-maintained behavior described

in the presentations of Falk and Goldberg arose from two rather different procedures. Falk focused on behaviors that have no specifically arranged consequences (schedule-induced behavior), whereas

Goldberg emphasized behaviors remotely maintained by an ultimate

consequent event (schedule-controlled behavior). The fact that these

different procedures can generate such tremendous amounts of behavior

is noteworthy. Whether or not the behaviors occurring under schedulecontrolled and schedule-induced conditions are similar in other

respects is another area of interest in behavioral pharmacology. Falk

(1964) asked several years ago whether the effects of various drugs

on schedule-induced behavior are similar to those found with schedulecontrolled behavior. A related question is whether drug effects

differ depending on whether drinking is induced by schedule variables

or by fluid deprivation. It has been shown recently that doses of

chlordiazepoxide that increased drinking produced by deprivation

decreased drinking induced by an intermittent schedule of reinforcement (Sanger and Corfield-Sumner 1979). Other questions likely to

attract increasing attention in the future will center on commonalities among schedule-induced behaviors. What other types of scheduleinduced behaviors show the same characteristics as schedule-induced

drinking? Are there general induction techniques? Are different

schedule-induced behaviors affected similarly by drugs? The answer to

these questions awaits further research. However, it is clearly

feasible to use pharmacological means to dissect these possible different behaviors.

279
A particular advantage of the use of second-order schedules described

by Goldberg is that behavior is maintained over extended periods by

environmental stimuli remotely paired with drug administration. This

feature illustrates the importance of environmental stimuli in supporting and sustaining persistent drug-seeking behavior. In addition,

techniques where drug injections occur only infrequently minimize the

direct effects of the drug and permit the maintenance of performances

by drugs from diverse pharmacological classes (Kelleher 1975).

In addition to offering up procedures which permit the resolution of

several interesting problems, behaviors maintained under or engendered by these techniques appear to have a great deal of durability,

intensity, and persistence. Indeed, the consequences ultimately maintaining or the factors responsible for engendering these behaviors

can often seem so remote or insignificant that the behavior itself

assumes the quality of having its own volition and appears to be

self-sustaining. We might even be inclined to invent or attribute

certain pathological or aberrant qualities to behaviors of this type;

they appear compulsive, compelling, addictive, and in Falk's words,

"counteradaptive." Yet, if we look at the factors responsible for

the genesis and maintenance of these behaviors they reside clearly

in the current environment and in the organism's past history.

This emphasis on the significance of environmental variables in drug

abuse is not meant to negate or deny the importance of pharmacological variables. An appropriate balance between dynamic forces must

always be struck. There are several instances where drugs have

remarkably uniform effects over a wide range of conditions (Balster,

this volume; Griffiths et al., this volume). This orderliness

allows for the screening of new drugs against known standards and

permits the prediction of potential abuse liability, analgesia, and

other relevant clinical phenomena. However, we have also seen

several instances where drugs and other events seem quite malleable

(Barrett, this volume; Young et al., this volume). The statement

that events are reinforcers under one condition but not others is

contradictory only on a superficial level. It does not imply that

screening techniques are invalid or that instances where drugs have

multiple effects reveal disturbing inconsistencies. Such results

highlight the importance of other variables which are nonpharmacological in nature, but nevertheless of obvious import in determining

the specific effects a drug will have on behavior. The analysis of

variables, both pharmacological and behavioral, that enter into the

production of these different effects promises to yield important

information for understanding the behavioral pharmacology of human

drug dependence.

REFERENCES

Falk, J.L. Studies on schedule-induced polydipsia. In: Wayner,

M.J., Ed. Thirst: First International Symposium on Thirst and

Regulation of Body Water. New York: Pergammon Press, 1964. pp.

Griffiths, R.R., Bigelow, G.E., and Henningfield, J.E. Similarities

280
in animal and human drug taking behavior. In: Mello, N.K., ed.

Advances in Substance Abuse. Vol. 1. Greenwich, Conn.: JAI Press,

Inc., 1980. pp. 1-90.

Kelleher, R.T. Characteristics of behavior controlled by scheduled

injections of drugs. Pharmacological Rev, 27:307-324, 1975.

Morse, W.H. Introduction: The control of behavior by consequent

drug injection. Pharmacological Rev, 27:301-305, 1975.

Sanger, D.J., and Corfield-Sumner, P.K. Schedule-induced drinking

and thirst: A pharmacological analysis. Pharmacol Biochem Behav,

10:471-474, 1979.

Schuster, C.R. Drugs as reinforcers in monkey and man. Pharmacological Rev, 27:511-521, 1975.

AUTHOR

James E. Barrett, Ph.D.

Department of Psychiatry

School of Medicine

Uniformed Services University

of the Health Sciences

4301 Jones Bridge Road

Bethesda, Maryland 20014

281
Discussion

Complex Schedules and

Maintenance of Drug Dependence

Nancy K. Mello, Ph.D.

The past decade has been punctuated by drug "epidemics" that often

assume crisis proportions. Oscillating waves of congressional

rhetoric and public fervor preceded Nixon's "war on drug abuse."

Each subsequent furor launched a variety of Federal initiatives

targeted to combat the abuse of marijuana, PCP, alcohol, etc.

The quasi-random aperiodicity of these intense spotlights on a

particular type of drug abuse tends to obscure the fact that drug

abuse is a continuing and perennial problem. Even enlightened

Federal recognition of the recurrent nature of drug abuse and its

complexity (Strategy Council 1973) has not been translated into

enduring, rational policies. Also unfortunate is the apparently

pervasive illusion that a brief targeted initiative can somehow

"solve the problem." Consequently, even the most modest progress

on any front may be followed by an abrupt shift of attention (and

resources) to another, suddenly visible, problem area.

Yet the most cursory examination of recent history reveals that

many contemporary drugs of abuse (e.g., alcohol, morphine, and

cannabis) have been used and abused in this country for over 200

years. Opium, alcohol, and cannabis have been available throughout the world for centuries. The fermentation of alcohol allegedly

occurred during the Paleozoic era, and the biblical depiction of

Noah's drunkenness is a familiar allegory. Opium was readily

available in America until about 1909, when emerging prejudice

against Chinese and black minorities became associated with fears

of opium addiction and eventually led to anti-narcotic legislation

in The Harrison Act of 1914 (Musto 1973). Some more recent entries

into the illicit and abused drug circle are PCP (Petersen and

Stillman 1978), khat (Halbach 1980), and coca paste smoking (Van

Dyke and Byck 1981). Tomorrow's new drug problems are as yet

unknown, but unquestionably there will be some.

Given the enduring nature of drug abuse in its myriad forms, it is

important to develop better and more stable strategies to try to

understand and eventually to modify excessive drug use patterns.

A consistent and predictable Federal commitment to research on the

problems of drug abuse may be more crucial than the types of

282
research strategies employed. It is the thesis of this essay that

a fragmented, intetmittent, crisis-oriented approach to drug abuse

is an untenable schedule which disrupts and retards research,

encourages divisive short-term (often short-sighted) policies, and

ultimately contributes more to the maintenance than to the deterrence of drug abuse. Why? Because the externally imposed schedule

of research funding is one critical determinant of the type, quality, and innovativeness of research programs and the ultimate scientific product.

There has been relatively little formal attention to the logistics

of research grant acquisition as a controlling schedule which

affects both the quality and frequency of occurrence of the research

end product. However, consider that 2 years of grant support allows

the investigator 1 year to work before he/she must reapply for

continuation of funds. The l-year contract is another compelling

case in point, which would seem to insure the routine application

of today's procedures to yesterday's questions. It may be that

short-term, 2- and 3-year funding patterns are potentially counterproductive, since these time constraints facilitate unambiguous

and perhaps unimaginative projects and do not encourage development

of exploratory programs. Moreover, short-term funding schedules

promote a variety of excessive adjunctive behaviors of which continual grant application preparation and the generation of unimaginative reports of safe studies are but two conspicuous symptoms.

In the language of behavioral science, a relatively short intergrant reinforcement interval may generate adjunctive research

behaviors which could be eliminated with longer inter-reinforcement

intervals, just as schedule-induced polydipsia, the prototypical

adjunctive behavior (Falk 197l, tends to decrease in frequency as

inter-reinforcement intervals 1engthen.1

Research scientists justifiably complain that by the time the staff

has been hired and apparatus set up to conduct a series of new

studies, actual experimental time is limited to a few months before

it is necessary to reapply for funds to continue. Prudence dictates

that the recipient of a 2-year grant award, funded on December lst,

should submit an application for continued support by February 1st

of the following year. Since many institutions have obligatory

internal reviews prior to submission of an application to the funding agency, the actual deadline could be as much as 2 months earlier. Any unforeseen event, e.g., delivery delays, subject dropouts, animal sickness, system down-time, cannot be easily accommodated on this production-line type of schedule. The now familiar

(facetious?) lament about trying to fit in some research between

grant application preparations approaches the status of a cliche!

Despite grumbling to colleagues, academic scientists seldom

1 . "The reinforcement intermittence and thwarting conditions which

yield adjunctive and displacement behaviors increase the organism's

probability of responding in strength to other possibilities in the

environmental context by increasing the gain on operant units

receiving relatively low, but appreciable facilitation from current

environmental stimuli." (Falk 1971, pp. 586-587)

283
militantly challenge the schedules that control their research

behavior. An ambivalent modesty about one's own research and its

importance, often qualified to the point of self-depreciation, is

a frequent accompaniment of scientific honesty and antithetical to

the "hard sell." Whatever the determinants of nonmilitancy in

scientists, the problem discussed here is one of the consequences.

There are serious questions as to whether or not the prevalent

short-term support schedule is most conducive to creativity and

productivity.

An alternative model of research support is provided by the intramural laboratories of the National Institutes of Health and of the

Alcohol, Drug Abuse, and Mental Health Administration. Assured of

stable salary and basic laboratory support, the Federal scientist

has more opportunity to begin research programs which involve longterm objectives and to engage in exploratory and developmental

projects. Although periodic internal and external reviews determine the budget for the next fiscal period, most Federal scientists

are not recurrently faced with the prospect of cataclysmic cessation of funding and unemployment for a trained research staff. The

outstanding research record of the National Institutes of Health

(NIH 1975) indicates that biennial anxiety infusions are not a

necessary prerequisite to research productivity. Perhaps an effort

to develop similar long-term support patterns for the extramural

scientists would further enhance the overall quality of science in

every area. Since "good" science in all of its guises is a common

goal for the supporters and supported alike, some extended dialogue

between all concerned about the optimal strategies for extramural

research support might be a valuable next step beyond sharing our

data and ideas as we have in this conference.

We are only beginning to appreciate the complexities involved in

the analysis of drugs as reinforcers. The research presented in

this volume illustrates the importance of this question. The

demonstration that second-order schedules which require extended

sequences of behavior leading to drug injection can effectively

control operant responding in primate models has profound implications for the clinical situation. The analogy between a monkey

responding for over an hour for a single drug injection and an

opiate addict procuring negotiable resources, then contacting the

supplier for a single "fix," is quite compelling. Use of this

available primate model should lead to considerable progress in

clarifying this type of symbolic control of behavior. Moreover,

research over the past few years has clearly indicated that the

reinforcing properties of drugs are not solely a function of the

inherent pharmacological properties of the drug. Drugs with many

diverse behavioral and physiological actions are abused. Polydrug abusers may use drugs with antithetical actions (e.g., stimulants and depressants) simultaneously or in rapid succession.

Such considerations have led me to postulate elsewhere that perhaps a critical aspect of drug reinforcement is subjective state

change and the direction of that than e in state, up or down, may

be less important than change itself (Mello 1978).

284
A conceptual framework and technology exist to address these issues

effectively. The groundwork has been laid for a comparative analysis

of drugs of abuse which may prove more productive than the tradition

of studying each drug in isolation. It is my contention that a

comparative approach will yield a behavioral analysis of similarities

and differences in the ways in which drugs control behavior (Mello

1980). These variables are amenable to systematic study. As we

begin to learn some basic principles which transcend the unique

pharmacology of particular drugs, we will be better prepared to deal

effectively with the drug abuse problems of tomorrow. A better

understanding of the way in which drug use behavior is maintained

may ultimately lead to improved treatment, prevention, and amelioration of the adverse medical, social, and economic consequences of

drug abuse.

The most dedicated commitment to these goals cannot insure realization of that promise. This requires stable support for research

which is dissociated from the unpredictable peaks of emotional public

response to each "new" drug menace and the effects of that outcry

on Congress. Without stable support to study the perennial problem

of drug abuse, research in this area becomes an adjunct to the thrice

yearly struggle for grant support. Only the obvious and safe

research will be done. Insofar as the schedules of reinforcement

control a variety of behaviors including research behavior, it is

not unreasonable to argue that under a predictable schedule with

extended funding periods, innovation and creativity will be encouraged and the great promise that behavioral pharmacology holds for

understanding drug abuse may be fulfilled.

REFERENCES

Falk, J.L. The nature and determinants of adjunctive behavior.

Physiol Behav, 6:577-588, 1971.

Halbach, H. Khat--The problem today. In: Harris, L.S., ed.

Problems of Drug Dependence 1979. National Institute on Drug Abuse

Research Monograph 27. DHEW Pub. No. (ADM)80-901. Washington, D.C.:

Supt. of Docs., U.S. Govt. Print. Off., 1980. pp. 318-319.

Mello, N.K. Control of drug self-administration: The role of

aversive consequences. In: Petersen, R.C., and Stillman, R.C., eds.

Phencyclidine PCP) Abuse: An Appraisal. National Institute on

Drug Abuse Research Monograph 21. DHEW Pub. No. (ADM)78-728.

Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1978.

pp. 289-308.

Mello, N.K., ed. Advances in Substance Abuse, Behavioral and

Biological Research, Vol. 1. Greenwich, Connecticut: JAI Press,

Inc., 1980. 376 pp.

Musto, D.F. The American Disease: Oriqins of Narcotic Control,

New Haven and London: Yale University Press, 1973.

National Institutes of Health. Research Advances 1975. DHEW Pub.

No. (NIH)75-3, 1975. 104 pp.

285
Petersen, R.C., and Stillman, R.C., eds. Phencyclidine (PCP)

Abuse: An Appraisal. National Institute on Drug Abuse Research

Monograph 21. DHEW Pub. No. (ADM)78-728. Washington, D.C.:

Supt. of Docs., U.S. Govt. Print. Off., 1978. 313 pp.

Strategy Council on Drug Prevention. Federal Strategy for Drug

Abuse and Drug Traffic Prevention, 1973. Washington, D.C.:

Supt. of DOCS., U.S. Govt. Print. Off. 150 pp.

Van Dyke, C., and Byck, R. Cocaine use in man. In: Mello, N.K.,

ed. Advances in Substance Abuse, Behavioral and Biological

Research, Vol. 3. Greenwich, Connecticut: JAI Press, Inc., 1981

(in press).

AUTHOR

Nancy K. Mello, Ph.D.

Associate Professor

Alcohol and Drug Abuse Research Center

Harvard Medical School--McLean Hospital

Belmont, Massachusetts 02178

286
Participants

CONFERENCE ON

BEHAVIORAL PHARMCOLOGY OF

HUMAN DRUG DEPENDENCE

Dr. Robert L. Balster

Department of Pharmacology

Medical College of Virginia

Va. Commonwealth University

Richmond, Virginia 23298

Dr. James E. Barrett

Department of Psychology

University of Maryland

College Park, Maryland 20742

Dr. George E. Bigelow

Department of Psychiatry

and Behavioral Sciences

Division of Behavioral Biology

Johns Hopkins University

School of Medicine

720 Rutland Avenue

Baltimore, Maryland 21205

Dr. Joseph V. Brady

Department of Psychiatry

and Behavioral Sciences

Division of Behavioral Biology

Johns Hopkins University

School of Medicine

720 Rutland Avenue

Baltimore, Maryland 21205

Or. Marilyn E. Carroll

Psychiatry Research Unit

Box 392 Mayo

Universitv of Minnesota

Minneapolis, Minnesota 55455

Dr. John L. Falk

Department of Psychology--

Busch

Rutgers University

New Brunswick,

New Jersey 08903

Dr. Marian W. Fischman

Department of Psychiatry

The University of Chicago

950 E. 59th Street

Chicago, Illinois 60637

Dr. Roland R. Griffiths

Department of Psychiatry

and Behavioral Sciences

Division of Behavioral Biology

Johns Hopkins University

School of Medicine

720 Rutland Avenue

Baltimore, Maryland 21205

Dr. Jack E. Henningfield

NIDA/Addiction Research Center

c/o Baltimore City Hospitals

4940 Eastern Avenue

Baltimore, Maryland 21224

Dr. Louis Lasagna

Professor of Pharmacology,

Toxicology, and of Medicine

University of Rochester

School of Medicine

601 Elmood Avenue

Rochester, New York 14642

Dr. Peter Levison

Committee on Substance Abuse

and Habitual Behavior

National Academy of Sciences

2101 Pennsylvania Avenue, N.W.

Washington, D.C. 20418

Dr. Ira Liebson

Psychiatry Research Unit

Baltimore City Hospital, D-5 W.

4940 Eastern Avenue

Baltimore, Maryland 21224

287
Dr. A. Thomas McLellan

Drug Dependence Treatment and

Research Center

VA Medical Center (158)

University and Woodland Aves.

Philadelphia, PA 19104

Dr. Richard A. Meisch

Psvchiatry Research Unit

Box 392 Mayo

University of Minnesota

Minneapolis, Minnesota 55455

Dr. Nancy K. Mello

McLean Hospital

115 Mill Street

Belmont, Massachusetts 02178

Dr. Jack H. Mendelson

McLean Hospital

115 Mill Street

Belmont, Massachusetts 02178

Dr. Charles P. O'Brien

Drug Dependence Treatment and

Research Center

VA Medical Center (158)

University and Woodland Aves.

Philadelphia, PA 19104

Dr. Roy W. Pickens

Psychiatry Research Unit

Box 392 Mayo

University of Minnesota

Minneapolis, Minnesota 55455

Dr. Charles R. Schuster

Department of Psychiatry

The University of Chicago

950 E. 59th Street

Chicago, Illinois 60637

Dr. Maxine Stitzer

Psychiatry Research Unit

Baltimore City Hospital, D-5 W.

4940 Eastern Avenue

Baltimore, Maryland 21224

Dr. Joseph W. Ternes

Drug Dependence Treatment and

Research Center

VA Medical Center (158)

University and Woodland Aves.

Philadelphia, PA 19104

Dr. Harold Weiner

Hoffman Division of Research

National Institute of Mental

Health

St. Elizabeths Hospital

Martin Luther King Boulevard

Washington, D.C. 20032

Dr. James H. Woods

Department of Pharmacology

University of Michigan

M-6322 Medical Science Building

Ann Arbor, Michigan 48109

Dr. George E. Woody

Drug Dependence Treatment and

Research Center

VA Medical Center (158)

University and Woodland Aves.

Philadelphia, PA 19104

Dr. Alice M. Young

Department of Pharmacology

University of Michigan

M-6322 Medical Science Building

Ann Arbor, Michigan 48109

NIDA STAFF

Dr. Steven R. Goldberg

Addiction Research Center

Box 2000

Lexington, Kentucky 40583

Dr. Donald R. Jasinski

Addiction Research Center

c/o Baltimore City Hospitals

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Dr. William Pollin

Director

National Institute on Drug Abuse

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Dr. Jack Blaine

Clinical-Behavioral Branch

Division of Research

Dr. Harold Ginzburg

Clinical-Behavioral Branch

Division of Research

288
Dr. Chris-Ellyn Johanson Dr. Heinz Sorer

Clinical-Behavioral Branch Biomedical Branch

Division of Research Division of Research

Dr. Marvin Snyder Dr. Travis Thompson

Director Clinical-Behavioral Branch

Division of Research Division of Research

Mrs. Eleanor Waldrop

NIDA Research Monographs

Division of Research

TECHNICAL REVIEW CONDUCT AND COORDINATION

Ms. Vennette Fuerth

Ms. Donna Prentes

Ms. Georgette J. Sobel

Koba Associates, Inc.

2000 Florida Avenue, N.W.

Washington, D.C. 20009

289
monograph series

While limited supplies last, single copies of the monographs may

be obtained free of charge from the National Clearinghouse for

Drug Abuse Information (NCDAI). Please contact NCDAI also for

information about availability of coming issues and other

publications of the National Institute on Drug Abuse relevant to

drug abuse research.

Additional copies may be purchased from the U.S. Government

Printing Office (GPO) and/or the National Technical Information

Service (NTIS) as indicated. NTIS prices are for paper copy.

Microfiche copies, at $3.50, are also available from NTIS.

Prices from either source are subject to change.

Addresses are:

NCDAI

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Room lOA-53

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1 FINDINGS OF DRUG ABUSE RESEARCH. Not available from NCDAI.

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2 OPERATIONAL DEFINITIONS IN SOCIO-BEHAVIORAL DRUG USE RESEARCH

1975. Jack Elinson, Ph.D., and David Nurco, Ph.D., eds. Not

available from NCDAI.

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3 AMINERGIC HYPOTHESES OF BEHAVIOR: REALITY OR CLICHE? Bruce J.

Bernard, Ph.D., ed.

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290
4 NARCOTIC ANTAGONISTS: THE SEARCH FOR LONG-ACTING PREPARATIONS.

Robert Willette, Ph.D., ed.

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5 YOUNG MEN AND DRUGS: A NATIONWIDE SURVEY. John A. O'Donnell,

Ph.D., et al. Not available from NCDAI.

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6 EFFECTS OF LABELING THE "DRUG ABUSER": AN INQUIRY. Jay R.

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7 CANNABINOID ASSAYS IN HUMANS. Robert Willette, Ph.D., ed.

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8 Rx: 3x/WEEK LAAM - ALTERNATIVE TO METHADONE. Jack Blaine, M.D.,

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Not available from GPO NTIS PB #253 763/AS $12.50

9 NARCOTIC ANTAGONISTS: NALTREXONE PROGRESS REPORT. Demetrios

Julius, M.D., and Pierre Renault, M.D., eds.

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10 EPIDEMIOLOGY OF DRUG ABUSE: CURRENT ISSUES. Louise G. Richards,

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in surveys and data collection. Not available from NCDAI.

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11 DRUGS AND DRIVING. Robert Willette, Ph.D., ed. Reviews

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on measures of impairment by different drugs at various levels.

Not available from NCDAI.

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12 PSYCHODYNAMICS OF DRUG DEPENDENCE. Jack D. Elaine, M.D., and

Demetrios A. Julius, M.D., eds. Theoretical and clinical papers

concerned with the intrapsychic determinants of drug addiction.

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13 COCAINE: 1977. Robert C. Petersen, Ph.D., and Richard C.

Stillman, M.D., eds. Reports the extent and limits of current

knowledge about cocaine, its use and misuse.

GPO Stock #017-024-00592-4 NTIS PB #269 175/AS $17

14 MARIHUANA RESEARCH FINDINGS: 1976. Robert C. Petersen, Ph.D.,

ed. Technical papers on which the 6th Marihuana and Health report

to Congress was based.

GPO Stock 1017-024-00622-O NTIS PB #271 279/AS $20

15 REVIEW OF INHALANTS: EUPHORIA TO DYSFUNCTION. Charles Wm.

Sharp, Ph.D., and Mary Lee Brehm, Ph.D., eds. Review of inhalant

abuse, including an extensive bibliography.

GPO Stock #017-024-00650-5 NTIS PB #275 798/AS $26

291
16 THE EPIDEMIOLOGY OF HEROIN AND OTHER NARCOTICS. Joan Dunne

Rittenhouse, Ph.D., ed. Task Force report on research

technologies and implications for studying heroin-narcotic use.

GPO Stack #017-024-00690-4 NTIS PB 8276 357/AS $18.50

17 RESEARCH ON SMOKING BEHAVIOR. Murray E. Jarvik, M.D., Ph.D.,

et al., eds. Includes epidemiology, etiology, consequences of

use, and approaches to behavioral change. From a NIDA-supported

UCLA conference.

GPO Stock #017-024-00694-7 NTIS PB #276 353/AS $27.50

18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS.

Norman A. Krasnegor, Ph.D., ed. Theoretical and empirical studies

of nonpharmacologic factors in development of drug tolerance.

GPO Stock #017-024-00699-8 NTIS PB #276 337/AS $14

19 THE INTERNATIONAL CHALLENGE OF DRUG ABUSE. Robert C. Petersen,

Ph.D., ed. Papers from the VI World Congress of Psychiatry which

deal with drug issues of particular interest worldwide.

GPO Stock 8017-024-00822-2 NTIS PB #293 807/AS $26

20 SELF-ADMINISTRATION OF ABUSED SUBSTANCES: METHODS FOR STUDY.

Norman A. Krasnegor, Ph.D., ed. Techniques used to study basic

processes underlying abuse of drugs, ethanol, food, and tobacco.

GPO Stock #017-024-00794-3 NTIS PB #288 47l/AS $20

21 PHENCYCLIOINE (PCP) ABUSE: AN APPRAISAL. Robert C. Petersen,

Ph.D., and Richard C. Stillman, M.D., eds. Pioneering volume for

clinicians and researchers assessing what is known about the

problem of PCP abuse.

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22 QUASAR: QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS OF

ANALGESICS, NARCOTIC ANTAGONISTS, AND HALLUCINOGENS. Gene

Barnett, Ph.D.; Milan Trsic, Ph.D.; and Robert Willette, Ph.D.;

eds. Reports from an interdisciplinary conference on the

molecular nature of drug-receptor interactions. Not available

from NCDAI.

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23 CIGARETTE SMOKING AS A DEPENDENCE PROCESS. Norman A.

Krasnegor, Ph.D., ed. Discusses factors involved in the onset,

maintenance, and cessation of the cigarette smoking habit.

Includes an agenda for future research.

GPO Stock 1017-024-00895-8 NTIS PB #297 72l/AS $17

24 SYNTHETIC ESTIMATES FOR SMALL AREAS: STATISTICAL WORKSHOP

PAPERS AND DISCUSSION. Joseph Steinberg, ed. Papers from a workshop cosponsored by NIDA and the National Center for Health Statistics on a class of statistical approaches that yield needed

estimates of data for States and local areas. Not available from

NCDAI.

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292
25 BEHAVIORAL ANALYSIS AND TREATMENT OF SUBSTANCE ABUSE. Norman

A. Krasnegor, Ph.D., ed. Papers present commonalities and

implications for treatment of dependency on drugs, ethanol, food,

and tobacco.

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26 THE BEHAVIORAL ASPECTS OF SMOKING. Norman A. Krasnegor, Ph.D.,

ed. Reprint of the behavioral section of the 1979 Report of the

Surgeon General on Smoking and Health; introduction by editor.

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27 PROBLEMS OF DRUG DEPENDENCE, 1979: PROCEEDINGS OF THE 41ST

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. Not available from

NCOAI.

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28 NARCOTIC ANTAGONISTS: NALTREXONE PHARMACOCHEMISTRY AND

SUSTAINED-RELEASE PREPARATIONS. Robert Willette, Ph.D., and

Gene Barnett, Ph.D., eds. Papers report research on sustainedrelease and long-acting devices for use with the narcotic antagonist naltrexone.

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29 DRUG ABUSE DEATHS IN NINE CITIES: A SURVEY REPORT. Louis A.

Gottschalk, M.D., et al. Epidemiologic study providing data on

drug-involved deaths and procedures for their investigations.

Not available from NCOAI.

GPO Stock 8017-024-00982-2 NTIS PB #80-178882 $15.50

30 THEORIES ON DRUG ABUSE: SELECTED CONTEMPORARY PERSPECTIVES.

Dan J. Lettieri, Ph.D.; Mollie Sayers; and Helen Wallenstein

Pearson, eds. Volume presents summaries of the major contemporary theories of drug abuse by each of 43 leading theorists.

GPO Stock #017-024-00997-l Not available from NTIS

31 MARIJUANA RESEARCH FINDINGS: 1980. Robert C. Petersen, Ph.D.,

ed. The text of the 8th Marijuana and Health report to Congress

and the background scientific papers on which this summary report

was based.

GPO Stock #017-024-01010-3 NTIS PB #80-215171 $18.50

32 GC/MS ASSAYS FOR ABUSED DRUGS IN BODY FLUIDS. Rodger L. Foltz,

Ph.D.; Allison F. Fentiman, Jr., Ph.D.; and Ruth B. Foltt. A

collection of methods for the quantitative analysis of several

important drugs of abuse by the technique of gas chromatographymass spectrometry.

GPO Stock #017-024-01015-4 NTIS PB #81-133746 $17

34 PROBLEMS OF DRUG DEPENDENCE, 1980: PROCEEDINGS OF THE 42ND

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D.. ed. Comprehensive

assemblage of ongoing research on drug abuse, addiction, and new

compounds.

GPO Stock #017-024-01061-8

293

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35 DEMOGRAPHIC TRENDS AND DRUG ABUSE, 1980-1995. Louise G.

Richards, Ph.D., ed. Estimates of probable extent and nature of

nonmedical drug use, 1980-1995, based on age structure and other

characteristics of U.S. population.

GPO Stock #017-024-01087-l

36 NEW APPROACHES TO TREATMENT OF CHRONIC PAIN: A REVIEW OF MULTIDISCIPLINARY PAIN CLINICS AND PAIN CENTERS. Lorenz K.Y. Ng, M.D.,

ed. A sharing of ideas among active practitioners in the treatment of pain.

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DHHS Publication No (ADM) 81-1137

Printed 1981