Neurobiology of

Behavioral Control

in Drug Abuse

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration
Neurobiology of Behavioral

Control in Drug Abuse

Editor:

Stephen I. Szara, M.D., D.Sc.

Division of Preclinical Research

National Institute on Drug Abuse

NIDA Research Monograph 74

1986

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

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Temple University School of Medicine

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Rensselaer Polytechnic Institute

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NB Associates, Health Sciences

Rockville, Maryland

KARST J. BESTEMAN

Alcohol and Drug Problems Association

of North America

Washington, D.C.

GILBERT J. BOTVIN, Ph.D.

Cornell University Medical College

New York, New York

JOSEPH V. BRADY, Ph.D.

The Johns Hopkins University School of

Medicine

Baltimore, Maryland

THEODORE J. CICERO, Ph.D.

Washington University School of

Medicine

St .Louis, Missouri

SIDNEY COHEN, M.D.

Los Angeles, California

MARY L. JACOBSON

National Federation of Parents for

Drug-Free Youth

Omaha, Nebraska

REESE T. JONES, M.D.

Langley Porter Neuropsychiatric Institute

San Francisco, California

DENISE KANDEL, Ph.D.

College of Physicians and Surgeons of

Columbia University

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Yale University School of Medicine

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New Jersey State Department of Health

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Neurobiology of Behavioral

Control in Drug Abuse
ACKNOWLEDGMENT

This monograph is based upon papers and discussion from a technical

review which took place on October 3 and 4, 1985, at the National

Institutes of Health, Bethesda, Maryland. The review meeting was

sponsored by the Division of Preclinical Research, National

Institute on Drug Abuse.

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Citation of the source is appreciated.

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DHHS Publication No. (ADM) 90-1606

Alcohol, Drug Abuse, and Mental Health Administration

Printed 1986, Reprinted 1900

NIDA Research Monographs are indexed In the Index Medicus. They

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iv
Preface

Advances in complex research fields are frequently driven by new

technologies developed within the field, or in a neighboring

field, to which the connections are not immediately obvious.

Drug abuse is a complex problem with significant social,

psychological, and biomedical components, and researchers are

constantly pressed to develop new and better methodologies for

prevention and treatment of drug abuse. The Idea for this review

evolved from a research retreat held 8 years ago, during which

hypotheses on the demand side of the etiology of drug abuse in

general were discussed and specific questions on drug action on

the brain, that might only be effectively studied through the

application of advanced technologies, were first explored. Now

that these advanced technologies are realities and it is possible

to visualize specific neurochemical entities, such as opiate,

dopamine, serotonin, and other receptors, in the living human

brain, the time is ripe for an examination of their potential for

advancing our understanding of the neurobiology of behavioral

control in the drug-abusing population.

This research monograph is a summary of discussions of invited

experts who participated in a 2-day Technical Review meeting held

at the National Institutes of Health campus in Bethesda,

Maryland, on October 3-4, 1985.

Stephen I. Szara, M.D., D.Sc.

Biomedical Branch

Division of Preclinical Research

National Institute on Drug Abuse

v

Contents

Page

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Introduction

Stephen Szara . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Basic Research Strategies for Imaging Neurotransmitter

Systems

Solomon H. Snyder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Measurement of Neurotransmitter Receptors by Positron

Emission Tomography:

J. James Frost

Focus on the Opiate Receptor

. . . . . . . . . . . . . . . . ............................. 15

The Personality Structure of Heroin Addicts

Robert J. Craig . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

Locus of Control and Need for Control Among Heroin Users

Don C. Des Jarlais . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Personality Characteristics and Self-Abusive Behavior

Donald G. Forgays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Sensation Seeking and the Endogenous Deficit Theory

of Drug Abuse

Marvin Zuckerman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Control vs. Lack of Control Over Aversive Stimuli:

Nonopioid-Opioid Analgesic Consequences

Robert C. Drugan and Steven F. Maier.......................71

Behavioral Contingencies Involved in Drug-Induced

Neurotransmitter Turnover Changes

Steven I. Dworkin and James E. Smith . . . . . . . . . . . . . . . . . . . . 90

vii
Page

Receptor Regulation as a Function of Experience

Frits A. Henn, Emmeline Edwards, and David Anderson...107

Clinical and Behavioral Considerations in Emission

Tomography Study Design

Reese T. Jones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

List of NIDA Research Monographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

viii
Introduction

Stephen Szara

At a meeting in 1977 of a Task Force on Research on Drug Abuse,

the concept of self-control was identified by many of our expert

consultants as a central issue in drug abuse:

The self-control concept in drug abuse research

should be of high priority, since it integrates a

number of concepts (Joseph Brady).

Looking for commonalities across various substances

of abuse may be an oversimplified notion. The selfcontrol concept may be the only commonality

(Charles R. Schuster).

Getting rid of drug-using behavior is dependent on

the successful establishment of a substitute

behavior. Drug abuse may be seen as a disorder of

effective self-control (Gene Smith).

Peptides and neurotransmitter amines may affect selfimage, feeling states, or even self-control; we just

have to find ways of measuring It (William Martin).

Some of the consultants actually suggested general guidelines for

research:

The endorphin story is very important and should be

followed up in human studies (Charles P. O'Brien).

To pin down disorders of self-control in drug abuse

patients, we should follow the natural history of

recovery and find out what accounts for their success

(Gene Smith).

Basic research is not necessarily biochemistry,

pharmacology, or anatomy; it is behavior that can

1
also be considered basic itself. We need good

objective measures of present status so that we can

measure change (Peter Dews).

Scanning the drug abuse literature for evidence of research

activities on this parameter, I was struck by the relative paucity

of papers in the drug abuse context. Digging into the

psychosocial literature, however, I was impressed with the

numerous studies that focused on the apparently narrow issue of

"locus of control," as measured by a single dimensional scale

devised by Julian Rotter, to assess the external/internal

attitudes for control of life events (Rotter 1966; Rotter 1975).

At least two books (Lefcourt 1976; Perlmutter and Monty 1979) and

hundreds of papers have been published on this topic in various

journals.

Some papers on alcoholism have dealt with subjective feelings of

losing control as a central feature of this disease (Rohsenow and

O'Leary 1978; Abbot 1984), and I found a few papers reporting on

some measure of control as playing a role in other drug abuse

situations (Langrod et al. 1983; Craig 1979).

There have been a number of questions raised in the psychological

literature as to the validity of the Rotter scale of locus of

control, and other psychological variables, such as sensation

seeking, have been suggested as crucial in getting involved with

drugs.

However, a major question can be raised, If self-control is such

an important issue in drug abuse, considering the fact that drugs,

including alcohol, are chemicals acting at the chemical level on

the brain, is there a relationship that can be identified and

explored so that we can gain a better understanding of what is

going on with drugs and the brain? Based on this, could we find

better ways of helping addicts to return to normal life or find

ways to prevent people from becoming addicted in the first place?

There is an enormous gap between the receptors, the points in the

brain where drugs presumably act, and issues at the conceptual

level, such as self-control, sensation seeking, etc. How do we

deal with this gap in a scientific manner? Paul Willner argues

(Willner 1984) that coming to grips with this question is the

central issue of psychopharmacology and proposes at least four

explanatory domains needed to bridge the conceptual gap between

the biochemical and subjective levels:' the biochemical, physiological, cognitive, and subjective. He suggested that we think in

terms of a computer analogy, according to which these four domains

roughly correspond to two levels of hardware and two levels of

software: components and wiring at the hardware level and

programming and editing at the software level. The four levels

may be generally described as follows:

2
1. Hardware level.This means the elementary active

operating components, such as transistors, gates, flip

flops, memory registers, etc. in computers. In the

brain these would correspond to neurons, cortical

columns, strfatal patches, islands, etc.

2. Connectivity between the components. In the computer,

connectivity between transistors defines their

interactions and forms the basis for higher level

action. In the brain, the connectivity pattern among

the functional units is extremely complex with multiple

feedback loops forming intricate patterns.

3. Program level. In computers the programs may reside in

a plugged-in module or have to be loaded in by the

user. In animals and humans the situation is much more

complex. Fixed action patterns (FAP) are recognized by

ethologists in animals as genetically determined

programs for action, and some of these are suspected to

have survived the evolutionary process although there

are some doubts as to whether they are operational in

man. In humans, much of the "programning" occurs at the

psychosocial and cultural levels as part of the lifetime

learning process.

4. Editing level. Here the analogy between brain and

computer breaks down. We don't have an equivalent

feature in computers of fntentfonality, consciousness,

and emotions, just to mention a few of the subjective

phenomena that are of obvious significance for human

behavior.

I would like to avoid getting bogged down in philosophical

discussion of these issues. Rather, I would like to focus on a

relatively narrow aspect of human functioning that would hopefully

be researchable. What I am proposing is to explore the possible

causal relationships between molecular events in the brain, as

revealed by Positron Emission Tomography (PET) scanning, and some

high-level symbolic action, for example holding a specific belief

of locus of control that appears to play a major role in the

decision processes involved in substance abuse.

Bridging the enormous gap that this represents has been attempted

before (Zuckerman 1984). This Technical Review asked the

participants to take a look at the newly emerging potentials of

high technology in visualizing functional states of specific

receptors in the living human brain and explore some concrete

hypotheses relevant to drug abuse that may be resolved using this

technology.

We know from preliminary research that PET-scanning techniques can

visualize receptors in the human brain in vivo (Wagner et al.

1983; Frost et al. 1985). and that locus of control measures are

available and have been useful in assessing some aspects of

3
substance abuse behavior (Langrod et al. 1983; Craig 1979).

Animal data suggest that some brain transmitters and/or receptors

are affected by awareness of the availability of "control" (Smith

et al. 1982; Drugan et al. 1981).

The following questions were addressed at the Technical Review:

What kind of specific hypotheses may be formulated that

would be of interest to drug abuse research and that could

be tested using the newly available methodologies?

Are these methodologies sufficiently sensitive and

specific to obtain reliable measures at the

biochemical/receptor level, the clinical/psychological

level, and the behavioral/instrumental level?

What kind of subject population may be most suitable: a

nondrug-using sample from the general population; current

drug users in treatment; some other diagnostic category of

patients; or all of the above?

What would be the most appropriate experimental design

to carry out these studies?

REFERENCES

Abbot, M.W. Locus of control and treatment outcome in alcoholics.

J Studies Alc 45:46-62, 1984.

Craig, R.J. Personality characteristics of heroin addicts: A

review of the empirical literature with critique--Part I & II.

Int J of Addict 14:513-532 and 607-626, 1979.

Drugan, R.C.; Grau, J.W.; Maier, S.F.; Madden IV, J.; and Barchas,

J.D. Cross tolerance between morphine and the long-term

analgesic reaction to unescapable shock. Pharmacol Biochem

Behav 14:677-682, 1981.

Frost, J.J.; Wagner, H.N.; Dannals, R.F.; Ravert, H.T.; Links,

J.M.; Wilson, A.A.; Burns, H.D.; Wong, D.F.; McPherson, R.W.;

Rosenbaum, A.E.; Kuhar, M.J.; and Snyder, S.H. Imaging opiate

receptors in the human brain by positron tomography. J of

Comput Assist Tomogr 9:231-236, 1985.

Langrod, J.; Des Jarlals, D.C.; Alksne, L.; and Lowinson, J.

Locus of control and initiation of detoxification among male

methadone maintainance patients. Int J of Addict 18(6):783-790,

1983.

Lefcourt, H.M. Locus of Control

Research. Hillsdale, NJ: Lawrence Erlbaum, 1976.

Current Trends in Theory and

Perlmutter, L.C., and Monty. R.A., eds. Choice and Perceived

Control. Hillsdale, NJ: Lawrence Erlbaum, 1979.

Rohsenow, D.J., and O'Leary, M.R. Locus of control research on

alcoholic populations: A review. I. Development, scales and

treatment. Int J of Addict 13:55-78, 1978.

Rotter, J.B. Generalized expectancies for internal versus

external control of reinforcement. Psychol Monogr 80:1-28,

1966.

4
Rotter, J.B. Some problems and misconceptions related to the

construct of internal versus external control of reinforcement. J Consult Clin Psychol 43:56-67, 1975.

Smith, J.E.; Co, C.;Freeman,M.E.; and Lane, J.D. Brain

neurotransmitters turnover correlated with morphine-seeking

behavior in rats. Pharmacol Biochem Behav 16:509-519, 1982.

Wagner, H.N.; Burns, H.D.; Dannals,R.F.; Wong, D.F.; Langstrom,

B.; Duelfer, T.; Frost, J.J.; Ravert, H.T.; Links, J.M.;

Rosenbloom, S.B.; Lukas, S.E.; Kramer, A.V.; and Kuhar, M.J.

Imaging dopamfne receptors in the human brain by positron

tomography. Science 221:1264-6, 1983.

Willner, P. Drugs, biochemistry and conscious experience: Toward

a theory of psychopharmacology. Perspectives in Biol and Med

28:49-64, 1984.

Zuckerman, M. Sensation seeking: A comparative approach to a

human trait. Behav Brain Sciences 7:413-471, 1984.

AUTHOR

Stephen Szara, M.D., D.Sc.

Biomedical Branch

Division of Preclinical Research

National Institute on Drug Abuse

5
Basic Research Strategies for

Imaging Neurotransmitter Systems

Solomon H. Snyder

INTRODUCTION

The advent of powerful new imaging techniques, such as positron

emission tomography (PET) scanning and magnetic resonance imaging,

has raised the possibility of evaluating metabolic functions in

the brains of intact humans. Substantial advances have already

been made in PET scanning, especially in studying 2-deoxyglucose

uptake. PET scanning has also been employed to image neurotransmftter receptors such as dopamine, opiate, and benzodiazepfne

receptors. Magnetic resonance imaging has thus far been restricted to studies of protons, permitting the visualization of anatomical structures but not studies of metabolism. In the not too

distant future, magnetic resonance imaging is likely to be employed for phosphorus, so that energy metabolism, such as the

disposition of ATP, will be imaged.

The major limitation of PET scanning is technological. Positronemitting isotopes have a very short half-life, so the synthesis of

appropriate ligands must be done at the site of the PET scanning

operation. Additionally, the cost of a cyclotron and the PET

scanning camera equipment is considerable. In some instances, one

might be able to accomplish similar objectives utilizing lfgands

such as iodine-123, which can be detected by single proton emission tomography, utilizing equipment that is already available in

most academic medical centers.

Thus, at the present time one can image almost any ligand provided

it can be synthesized with the appropriate isotope. For the

information to be useful, the ligand must interact only with the

desf red target site. Thus, if one wished to image opiate receptors, morphine would be unsuitable. While morphine does indeed

bind to opiate receptors, at pharmacologically effective doses

about 80 percent of the morphine in the brain is not bound to opiate receptors, but occurs at adventitious locations. Accordingly,

a sophisticated understanding of the relevant neurochemical system

is necessary to develop appropriate ligands. Sophistication is

also required in determining which systems may be of greatest

6
interest for imaging and can be approached with available

technology.

The types of neurochemfcal systems that have been explored or that

may be explored in the future can be placed in several categories.

The first has to do with comprehensive metabolic function as exemplified by studies with 2-deoxyglucose. As a neuron fires more

frequently, 2-deoxyglucose consumption increases. It appears that

neurons, rather than glia, account for the bulk of 2-deoxyglucose

uptake. There have been many demonstrations of 2-deoxyglucose

uptake varying with the functional state of neuronal groupings.

Investigators have begun to approach studies of protein synthesis

by PET scanning. As already mentioned, phosphorus disposition

might be evaluated by magnetic resonance.

In this essay, we will not deal with general metabolic markers

for imaging. Instead, we will limit our attention to studies of

neurotransmitter disposition at three levels. One involves labelling neurotransmftter receptors. A second involves labellfng

neurotransmitter-specific neurons. Yet a third has to do with

studies of second messenger systems for neurotransmftters.

NEUROTRANSMITTER RECEPTORS

Neurotransmitters come in different varieties, including amines,

amino acids, and peptides. At the present time, well over 50 distinct neurotransmftter candidates are known, and the total number

may be substantially higher. Generally, there are several subtypes of receptors for each neurotransmftter. Thus, the multiplicity of potential receptors to be imaged is considerable. Why

would one want to image any neurotransmftter receptor? One can

determine the detailed localization of the receptor in animal

studies far more efficiently than in humans. In humans, one presumably would be Interested prfmarfly in alterations associated

with specific disease states. The second possfbflfty has to do

with changes relating to drug treatment.

What might one be seeking in studies of neurotransmitter receptors

in disease states and following drug admfnfstratian? Presumably,

one would be looking for some sort of alteratlon. Two types of

changes can be potentially detected by fmaging. If the affinfty

of the receptor for its ligand changes, then the amount of a

tracer dose of the lfgand that binds would be altered. For instance, if a given disease state is associated with an alteration

in the protein structures of the receptor, so that its affinity

for ligands is decreased to one-tenth its original affinity, then,

with a tracer dose of radioactive drug, one would probably observe

much less binding. More straightforward would be changes in

actual numbers of receptors. These would be detected with tracer

doses of ligand, as well as with saturatfng doses. Distinguishing

between alterations in affinity or receptor number might be possible by utilizing different doses of the radioactive ligand in

imaging studies. Changes in receptor number would be apparent by

altered ligand binding of similar magnitude, regardless of the

7
dose of radioactive ligand. Altered receptor affinity would be

apparent in terms of changes in ligand binding only with low

ligand concentrations.

Conceivably, certain brain disorders are related to changes in

numbers of receptors. The limited investigations that have been

done thus far in postmortem brain have not been particularly

promising. Thus, though dopamine is thought to be involved in

schizophrenia, any changes in levels of dopamine receptors in

postmortem schizophrenic brain are thought to be related more to

drug treatment than to the disease process (MacKay et al. 1982).

Numbers of various receptors are changed in Huntington's disease

(Penney and Young 1982; Whitehouse et al. 1985), but this is not

surprising considering the vast deterioration of neurons, especially in the corpus strfatum. The same could be said for reports

of alterations in receptor number in Alzheimer's disease.

Might there be changes in receptor number with varying physiological state? In other words, would extreme and prolonged stress

alter number of receptors? If one anticipates such changes in

receptors to arise from an altered rate of receptor synthesis,

then the likelihood of detecting alterations would depend on the

rate of turnover of the receptors. Receptors are membrane proteins which do not turn over at a very rapid rate. However, rapid

changes in apparent numbers of receptors are associated with conformational alterations in the receptor protein; these alterations

change ligand binding. We know that GABA stimulates benzodiazepine receptor binding by allosteric effects that enhance the

affinity of the benzodiazepine receptor for drugs (Olsen 1981).

These types of changes may be the receptor-binding alterations

most likely to correlate with changes in total brain function.

For instance, if a drug-induced change in brain activity led to

increased firing of GABA neurons, the release of GABA might increase the affinity of benzodiazepine receptors, which would be

apparent in augmented levels of ligand binding.

There is yet another way in which transient changes in neuronal

firing might alter apparent numbers of receptors. This has to do

with receptor occupancy by transmitter. The conventional model of

neurotransmitter action assumes that interaction with receptors is

followed by a rapid dissociation of the neurotransmitter, leaving

the receptor vacant for occupancy by the transmitter associated

with the next nerve impulse. On the other hand, there is abundant

evidence that, under some circumstances, transmitters bind with

very high affinity to receptors, so that dissociation is slow.

This is usually the case in receptor desensitization. Many studies with different neurotransmftters suggest that a major mechanism of desensitization involves tight binding of the transmitter

to its receptor. Also, high-affinity binding of transmitter to

receptor occurs in the "active" state of certain receptors, as has

been best exemplified for catecholamines at beta adrenergic and

dopamine receptors (DeLean et al. 1980; Leff et al. 1985).

8
If a transmitter binds tightly to its receptor, then imaging with

a radioactive ligand may indicate an apparent decrease in receptor

number. On the other hand, if one administered a drug that displaced the tightly bound transmitter from its receptor, there

would be an apparent increase in receptor number. Examples of

this phenomenon derive from studies of opiate receptors. In our

earliest investigations of opiate receptor binding following opiate administration, we found apparent increases in receptor number

(Pert et al. 1973). The properties of these increases were quite

similar to increases observed if one merely incubated brain membranes in buffer solutions (Pasternak et al. 1975). In these latter studies, the increase in receptor binding was associated with

the release into the buffer solution of a small peptide molecule

with affinity for opiate receptors. Accordingly, we suspect that

a certain amount of enkephalin is normally tightly bound to opiate

receptors in a noncovalent fashion. Drug treatment of intact animals or incubating brain membranes at 37°C releases the bound

enkephalin, increasing the apparent number of opiate receptors.

One might speculate that altered physiological states associated

with increased firing of enkephalin neurons would lead to greater

receptor occupancy of tightly bound enkephalin, with an associated

decrease in apparent number of opiate receptors. Such changes

have been detected in studies wherein rats were forced to swim;

there was an associated apparent decrease in opiate receptor

number (Seeger et al. 1984).

NEURONS CONTAINING SPECIFIC TRANSMITTERS

No well-known disease state is "caused" by demonstrated changes in

receptor number, though we do know of conditions associated with

degeneration of neurotransmitter-specific neurons. In Alzheimer's

disease, there is a relatively selective deterioration of cholinergic- and somatostatin-containing neurons. Similarly, in

Parkinson's disease, degeneration of the nigrostriatal dopamine

pathway appears to be responsible for the major symptoms. Imaging

techniques have already been applied to dopamine neurons. 18FDOPA is administered to humans; decarboxylation to 18F-dopamine

takes place selectively in dopamine neurons, which can thus be

imaged. This technique has been employed to demonstrate a loss of

dopamine neurons in patients with idiopathic Parkinson's disease

and may detect early stages in the loss of dopamfne neurons, not

yet associated with clinical symptoms of Parkinson's disease. One

cannot predict by any conventional means who will be likely to

develop idiopathic Parkinson's disease, since this condition is

not genetically determined and has no known environmental cause.

MPTP (1-methyl-4-thenyl-1,2,3,6-tetrahydropyridine) is a

Parkinsonism-inducing neurotoxin occurring as a contaminant of

synthetic opiates sold illicitly as designer drugs. Some individuals who self-administered MPTP-containing preparations developed

an abrupt onset of Parkinsonism with demonstration of dopamine

neuronal degeneration at autopsy. However, the great bulk of 500

or more individuals who have received MPTP appear to be devoid of

neurological symptoms. Are any of these individuals at risk to

9
develop Parkinsonism? In normal subjects, dopamine neurons

deteriorate with age, so that by the age of 70 most normal people

have only about half of the dopamine neurons they had in young

adulthood. With a loss of 70 to 80 percent of dopamine neurons,

one obtains clinical symptoms of Parkinsonism. Conceivably,

asymptomatic MPTP users have a limited loss of dopamfne neurons,

but, as they grow older, the normal age-related loss of dopamine

neurons would bring them to the threshold where Parkinson's disease would become apparent. In four MPTP users with no neurological symptoms, Calne et al. (1985) have demonstrated a loss of

dopamfne neurons by PET scanning with 18F-DOPA. Presumably, this

or similar techniques could now be employed in patients with very

slight neurological abnormalities suggestive of Parkinson's disease to provide a differential diagnosis.

How else might one image neurotransmitter-containing neurons?

Conceivably, the precursor strategy might be applicable to other

neuronal populations. For instance, 5-hydroxytryptophan might be

converted to serotonin selectively by serotonin neurons. However,

the enzyme that carries out this transformation is enzymologically

identical to DOPA decarboxylase , so that most of the enzymatic

conversion may take place in dopamine neurons. Choline, the precursor of acetylcholfne, is involved in many other biochemical

pathways, so it may not be a suitable precursor for the imaging of

acetylcholfne neurons. The same is likely to hold true for glutamic acid, the precursor of GABA. Other amino acid transmitters,

such as glycine or glutamic and aspartic acids, are even more difficult to approach, because they are involved in so many metabolic

processes.

One approach to labelling transmitter-specific neurons takes

advantage of selective uptake mechanisms. Most amino acids and

amine neurotransmitters are inactivated by reuptake pumps. One

can regard the site where the transmitter is recognized on the

neuronal membrane prior to uptake as an "uptake receptor." Such

uptake receptors have been labelled in biochemical binding studies

for various transmitters. Serotonin uptake sites have been

labelled with antidepressant drugs such as 3H-imipramine, 3Hparoxetfne, and 3H-citalopram. Uptake receptors for norepinephrine neurons have been labelled with the antidepressant 3H-desfpramfne (Lee et al. 1982) and the appetite suppressant 3H-mazindol

(Javitch et al. 1984). In binding Studies, dopamine neuronal uptake sites have been labelled with 3H-matindol, which has similar

affinity for dopamfne and norepinephrine uptake sites. The highaffinity choline uptake system providing the precursor pool of

choline for acetylcholine synthesis has an uptake receptor that

can be labelled with 3H-hemicholinium, a potent inhibitor of the

high-affinity choline uptake process.

Might it be possible to image these neuronal systems in humans

with lfgands similar to the ones employed in biochemical binding

experiments? The considerations involved in assessing feasibility

are similar to those associated with labelling postsynaptic neurotransmitter receptors. Thus, at the tracer concentration of the

10
ligand employed, the great majority of the radioactive drug would

have to be associated with the uptake receptor being investigated.

Receptor occupancy is related to the affinity of the ligand for

the binding site. Dopamine and serotonin receptors have been

imaged by PET scanning utilizing derivatives of spiperone with a

dissociation constant of about 10-10M. The opiate that has been

employed for PET imaging 11C-carfentanil, has a similar affinity

for opiate receptors. In intact rats, 3H-diprenorphine, whose

dissociation constant for opiate receptors is approximately

10-10M, occupies 85 percent or more of opiate receptors in the

brain after intravenous-administration. By contrast, 3H-naloxone,

with a KD of about 2x10-9M, occupies only about 30 percent of

receptors under similar conditions. All the drugs that have been

employed as ligands to label uptake receptors have affinities for

uptake sites similar to that of naloxone, or even less affinity.

This would argue against their suitability for imaging purposes.

However, the number of uptake receptors in most cases is substantially greater than the number of postsynaptic neurotransmitter

receptors. Conceivably, a large number of binding sites may make

up for lesser affinity.

SECOND MESSENGERS

In our earlier discussion of neurotransmitter receptors, we were

dealing largely with the recognition site of the receptor. Equally important are the second messengers, which communicate to the

interior of the cell recognition information. Second messengers

are dynamic and may more likely show changes with varying physiological and pathological states than do the receptor recognition

sites. One might not anticipate major changes in biosynthesis of

second messenger proteins. However, most of the regulation of

second messenger proteins involves allosteric alterations, which

could cause marked and rapid alterations in apparent receptor

number. In vitro biochemical studies suggest this possibility.

What are some of the second messengers that might be explored?

The two major second messenger systems for neurotransmitters are

the cyclic AMP system and the phosphoinositide cycle. The

phosphoinositide cycle has only been recently elucidated but

appears to be involved in conveying messages for numerous neurotransmitters including acetylcholine, serotonin, norepinephrine,

and substance P, as well as a variety of hormones and general

mediators such as thrombin and even mitogenic growth factors.

The phosphoinositide cycle involves the triggering by receptor

recognition of the breakdown of phosphatidylinositol-bis-phosphate

into inositol triphosphate (IP-3) and diacylglycerol. IP-3 acts

upon receptor sites on the endoplasmic reticulum to release calcium within the cell. Diacylglycerol stimulates protein kinase C by

enhancing its sensitivity to the stimulatory effects of calcium.

The phorbol ester tumor promoters bind with nanomolar affinity to

protein kinase C. Indeed, what was thought first to be the phorbol ester receptor appears to be the enzyme kinase C. In this

way, protein kinase C may be regarded as the third messenger in

the phosphoinositide system.

11
Protein kinase C can be labelled in binding studies with radioactive phorbol esters. Autoradiographic maps reveal a discrete

localization of neuronal systems containing protein kinase C

(Worley et al., in press). This presumably provides a map of

those synaptic systems that make use of protein kinase C as a

messenger. Protein kinase C is extremely dynamic. It exists in

soluble and membrane-bound forms. Increases in intracellular calcium trigger a movement of the cytoplasmic enzyme to a membranebound state, which appears to be the active form of the enzyme.

We have found that stressful stimuli, such as needle injections

into the brain or stress associated with the agonal state, cause

ten- to fiftyfold increases in membrane-associated kinase C. The

development of appropriate ligands for imaging protein kinase C

might provide a dynamic reflection of synaptic activity in a number of neuronal systems. Phorbol esters have high affinity for

protein kinase C, though not as high as that of spiperone for

dopamine and serotonin receptors. On the other hand, the number

of protein kinase C molecules in the brain is more than 100 times

that of serotonin or dopamine receptors, a circumstance that might

facilitate imaging.

The cyclic AMP-forming system possesses a number of components.

Neurotransmitter recognition at receptors triggers an association

of the receptor recognition proteins with ATP-binding protein.

This "G" or "N" protein interacts with the catalytic unit of

adenylate cyclase to cause a conversion of ATP to cyclic AMP.

Some neurotransmitters stimulate cyclic AMP formation while others

inhibit. There appear to be distinct stimulatory and inhibitory G

proteins. Cholera toxin binds with fairly high affinity to the

stimulatory protein, and pertussis toxin binds to the inhibitory

protein. Conceivably, modified forms of cholera and pertussis

toxins might be used for imaging. Of course, these two toxins

would not pass the brain blood barrier without substantial

modification.

Another approach to the adenylate cyclase system might be to image

the catalytic unit of the enzyme, utilizing a derivative of forskolin. Forskolin is a plant derivative that potently stimulates

adenylate cyclase. 3H-forskolin binds to the enzyme with nanomolar affinity. As with protein kinase C, the number of forskolin

binding sites is substantially greater than the number of neurotransmitter postsynaptic receptors. Conceivably, some derivative

of forskolin would be useful for imaging the cyclic AMP system.

In summary, the possibility of imaging neurotransmitter-containing

neurons via their uptake sites, postsynaptic receptor recognition

proteins, or second messenger proteins is very real. The limitations at present are not conceptual but merely technological and

within the grasp of presently existing technology. The possibility of detecting alterations in brain function as a result of

changes in physiological status, drug treatment, or pathology

offers promise for application in the not too distant future.

12
REFERENCES

Calne, D.B.; Langston, J.W.; Martin, W.R.W.; Stoessl, A.J.; Ruth,

T.J.; Adam, M.J.; Pate, B.D.; and Schulzer, M. Positron emission tomography after MPTP: Observations relating to the cause

of Parkinson's disease. Nature 317:246-248, 1985.

DeLean, A.; Stadel, J.M.; and Lefkowitz, R.J. A ternary complex

model explains the agonist-specific binding properties of the

adenylate cyclase-coupled beta-adrenergic receptor. J Biol Chem

255:7108-7117, 1980.

Javitch, J.J.; Blaustein, R.O.; and Snyder, S.H. 3H-Mazindol

binding associated with neuronal dopamine and norepinephrine

uptake sites. Mol Pharmacol 26:35-44, 1984.

Leff, S.E.; Hamblin M.W.; and Creese, I. Interactions of dopamine agonists with brain D1 receptors labeled by 3H-antagonists.

Mol Pharmacol 27:171-183, 1985.

Lee, C.M.; Javitch, J.A.; and Snyder, S.H. Characterization of

[

3H]desipramine binding associated with neuronal norepinephrine

uptake sites in rat brain membranes. J Neurosci 2:1535-1525,

1982.

MacKay, A.V.P.; Iversen, L.L.; Rossor, M.S.E.; Bird, E.; Arregui,

A.; Creese, I.; and Snyder, S.H. Increased brain dopamine and

dopamine receptors in schizophrenia. Arch Gen Psychiatry

39:991-997, 1982.

Olsen, R.W. GABA benzodiazepine barbiturate interactions. J

Neurochem 37:1-13, 1981.

Pasternak, G.W.; Wilson, H.A.; and Snyder, S.H. Differential

effects of protein-modifying reagents on receptor binding of

opiate agonists and antagonists. Mol Pharmacol 11:340-351,

1975.

Penney, J.B., and Young, A.B.

neurotransmitter receptors i

32:1391-1395, 1982.

Quantitative autoradiography of

n Huntington's disease. Neurology

Pert, C.B.; Pasternak, G.; and Snyder, S.H. Opiate agonists and

antagonists discriminated by receptor binding in brain. Science

182:1359-1361, 1973.

Seeger, T.F.; Sforzo, G.A.; Pert, C.B.; and Pert, A. In vivo

autoradiography: Visualization of stress-induced changes in

opiate receptor occupancy in the rat brain. Brain Res 305:303-

311, 1984.

Whitehouse, P.J.; Trifiletti, R.R.; Jones, B.E.; Folstein, S.;

Price, D.L.; Snyder, S.H.; and Kuhar, M.J. Neurotransmitter

receptor alterations in Huntington's disease: Autoradiographic

and homogenate studies with special reference to benzodiazepine

receptor complexes. Ann Neurol 18:202-210, 1985.

Worley, P.F.; Baraban, J.M.;Snyder, S.H. Heterogeneous

localization of protein kinase C in rat brain: Autoradiographic

analysis of phorbol ester receptor binding. J Neurosci. in

press.

ACKNOWLEDGMENTS

Supported by USPHS grants MH-18501 and DA-00266, and by RSA

DA-0074.

13
AUTHOR

Solomon H. Snyder, M.D.

Department of Neuroscience

Johns Hopkins University

School of Medicine

725 North Wolfe Street

Baltimore, MD 21205

14
Measurement of Neurotransmitter

Receptors by Positron Emission

Tomography: Focus on the

Opiate Receptor

J. James Frost

APPLICATION OF POSITRON EMISSION TOMOGRAPHY TO NEURORECEPTORS

The impetus for developing noninvasive methods to image and quantify neuroreceptors by positron emission tomography (PET) was twofold: (1) the recognition that many widely used psychoactive

drugs exert their actions through binding to neuroreceptors, and

(2) the observation that neuroreceptors are altered (in number or

affinity) in some psychiatric and neurodegenerative disorders,

when measured by postmortem methods. For example, haloperidol, a

neuroleptic drug widely used in the treatment of schizophrenia,

exerts its action predominantly by binding to the dopamine receptor and inhibiting dopamfnergic neurotransmission (Creese et al.

1975; Seeman et al. 1975). Postmortem measurements of dopamine

receptors in the caudate nucleus of schizophrenics demonstrate an

increase in the number of dopamine receptors, giving rise to the

hypothesis that schizophrenia is a disorder resulting from an excess of dopamine receptors (Seeman et al. 1984; Owen et al. 1978).

Development of a method to measure dopamine receptors in vivo

would clearly be useful in confirming or refuting this hypothesis,

as well as providing a basis for rational drug therapy and possible subclassification of schizophrenia based on dopamine receptor

concentration. Such a method would also have obvious application

to other neuropsychiatric disorders in which receptor number or

affinity is altered.

POSITRON-EMITTING ISOTOPES

Positron emission tomography is a sophisticated method of measuring the distribution of positron-emitting isotopes in the brain or

other body regions (Phelps and Mazziotta 1985; Ter-Pogossian et

al. 1982). The principle of radioactivity detection is based on

the simultaneous detection of two 511-keV gamma rays emitted 180°

apart by a circular ray of opposed detectors. The registration of

only coincident gamma rays by detectors 180° opposed results in

(1) an approved spatial localization of the decaying isotope, and

(2) a simpler correction for gamma ray attenuation when compared

to methods utilizing the detection of single gamma rays. The

15
existence of positron-emitting isotopes of several elements of

biological interest makes PET even more suitable for imaging biological systems. These isotopes include carbon-11 (half-life=20

minutes), oxygen-15 (half-life=2 minutes), nitrogen-13 (halflife=10 minutes), and fluorine-18 (half-life=110 minutes). When

these isotopes are incorporated into appropriate molecules, biochemical processes that correspond to the labelled molecule can be

measured. Using this principle, it is possible to noninvasively

measure regional cerebral oxygen utilization using 150-02. regional cerebral glucose utilization using 18F-fluorodeoxyglucose,

regional cerebral blood flow using 15O-H20, regional cerebral

blood volume using 15O-CO, etc. (Phelps et al. 1979; Reivich et

al. 1979; Phelps et al. 1982; Reivich et al. 1982; Frachowiak et

al. 1980; Mintun et al. 1984b; Grubb et al. 1978; Raichle et al.

1983). When using such methods, the importance of tracer kinetic

models for quantitative estimation of metabolic or other parameters cannot be overemphasized; without such mathematical models,

quantitative interpretation of the PET images would not be possible (Phelps et al. 1982).

RECEPTOR IMAGING

In the case of receptor imaging, the situation is much the same as

described above. One challenge of developing methods for imaging

and quantifying neuroreceptors by PET is in identifying appropriate drugs or ligands to be labelled. Studies carried out over

several years provided the first insights into some of the properties a compound must have if the distribution of radioactivity in

the brain was to correspond closely to the distribution of a

neuroreceptor following intravenous administration (Klemm et al.

1979; Kuhar et al. 1978; Kuhar et al. 1976; Laduron et al. 1978;

Laduron and Leyson 1977; Hollt et al. 1977; Pert et al. 1975;

Yamamura et al. 1974). For the method to be successful, a high

degree of receptor-specific binding and a low degree of nonspecific or background binding in the brain had to be achieved at some

time following injection. For the ratio of specific/nonspecific

binding (or total/nonspecific binding) to be high, it became

apparent that drugs with dissociation constants on the order of

1 nM or less were necessary. Under these conditions, ratios of

specific/nonspecific binding as high as 10 could be achieved within a few hours following injection, making the methods amenable to

PET, using positron emitting isotopes with relatively long halflives, such as 11C or 18F The higher the ratio of specific/nonspecific binding for a given labelled drug, the more accurately

changes can be distinguished in in vivo receptor binding (other

parameters being constant). This increased accuracy has obvious

implications for the detection and quantitation of neuroreceptor

alterations in disease. A high receptor affinity appears to be an

important property of a ligand if prolonged in vivo receptor binding is to be achieved, although other parameters may be of importance (Frost and Wagner 1984).

In some cases, a labelled drug with a high affinity may not be

suitable for in vivo receptor labelling because of the high degree

16
of nonspecific or background binding. The nonspecific binding is

difficult to predict prior to in vivo studies, since the relationship between the drug's physiochemical properties and drug distribution, metabolism, excretion, and permeability is complex (Frost

and Wagner 1984). The choice of labelled drugs for PET studies is

therefore currently based on the study of labelled compounds in

animal models by direct tissue dissection methods. To synthesize

labelled drugs is often expensive and laborious, and of questionable value when their usefulness is in doubt. An improved understanding of the relationship between structure and specific- and

nonspecific-binding kinetics could improve the identification of

drugs for labelling neurotransmitter receptors in vivo. This

identification is important since the number of potentially useful

unlabelled drugs far exceeds the number of labelled drugs. Table

1 shows a series of labelled drugs identified for use in PET

studies of neuroreceptors.

TABLE 1. Partial list of drugs labelled with positron-emitting

radionuclides for in vivo neuroreceptor studies

Labelled Drug Neuroreceptor

11C-carfentanil

11C-diprenorphine

18F-acetylcyclofoxy

11C-methylspiperone

18F-methylspiperone

18F-spiperone

75Br, 76Br-bromospiperone

11C-raclopride

11C-SCH-23,390

11C-ketanserin

11C-methylketanserin

11C-methyl bromo LSD

11C-dexetimide

11C-quinuclidyn benzilate

11C-scopolamine

11C-Ro 15-1788

11C-suriclone

opiate

dopamine-2 and serotonin

dopamine-2

dopamine-1

serotonin-2

muscarinic cholinergic

benzodiazepine

OPIATE RECEPTORS

We have utilized 11C-carfentanil, a potent opiate agonist, to

image opiate receptors in vivo in humans (Frost et al. 1985;

Dannals et al. 1985). Carfentanil has a potency approximately

17
8,000 times that of morphine in the rat, with a correspondingly

high receptor affinity (Van Daele et al. 1976). Additionally, the

effect of sodium on carfentanil binding is small compared to most

opiate agonists, making carfentanil attractive for in vivo binding

studies (Stahl et al. 1977; Frost and Wagner 1984). The dissociation constant of carfentanil for mu opiate receptors measured in

the rat brain at 37°C is 0.051 nM (Frost et al. 1985). Carfentanil binds to delta and kappa opiate receptors under similar conditions with a 90- and 250-fold higher dissociation constant.

Therefore, 11C-carfentanil is expected to be highly selective for

mu opiate receptors in vivo.

HUMAN STUDIES

Human studies using 11C-carfentanil were carried out using PET

following the injection of approximately 7 μg (20 mCi) 11Ccarfentanil alone, and following the administration of 1 mg/kg

 naloxone (figure 1). Images obtained immediately following injec11C-carfentanil showed homogeneous and approximately equal

binding throughout the grey matter structures of the brain, with

and without naloxone (Frost et al. 1985). When 11C-carfentanil

was administered alone, the radioactivity in structures known to

be rich in opiate receptors such as the thalamus and basal ganglia

increased with time, whereas the radioactivity decreased in the

occipital cortex, a structure with very few opiate receptors

(Kuhar et al. 1973). The ratio of radioactivity when carfentanil

was given alone to that in the presence of naloxone increased

until 30 minutes after injection, then remained relatively constant for up to 60 minutes in the caudate nucleus, thalamus, and

amygdala (data not shown). This value is equivalent to the ratio

of total/nonspecific binding discussed previously. In the amygdala. the ratio of total/nonspecific binding is approximately 7.

This measured ratio is an underestimate of the actual total/nonspecific binding ratio, due to the finite spatial resolution of

the Neuro ECAT PET scanner (Hoffman et al. 1983). When the

corrections in this effect are made, approximately 90 percent of

the radioactivity in the amygdala is estimated to be specifically

bound to receptors. In the caudate nucleus and thalamus, the

percent of specific binding is somewhat less.

Figure 1 shows images from the two 11C-carfentanil studies for the

period 30 to 60 minutes after injection. The three imaging planes

are 32 mm apart with a slice thickness of approximately 16 mm.

The highest radioactivity concentrations are seen in the amygdala,

thalamus, and basal ganglia. Intermediate radioactivity levels

are observed in the frontal, parietal, and temporal cortex, the

cerebellum, and the hippocampus. Low levels of radioactivity are

observed in the occipital cortex, white matter regions, and primary sensory cortex. This distribution closely corresponds to the

known distribution of human mu opiate receptors (Kuhar et al.

1973).

The images in the bottom row of figure 1 are obtained using 11Ccarfentanil, following pretreatment with 1 mg/kg naloxone. In

18
FIGURE 1. Localization of opiate receptors in man using 1 1Ccarfentanil

NOTE: The Images in the top row were obtained using the Neuro ECAT from 30 to 60

minutes after IV administration of 20 mCI 11C-carfentanil, 7 μg. The three

Images were localized using x-ray CT at approximately 7.2, 4, and 0.8 cm

above the canthomeatal Iine. lmages in the bottom row were acquired at the

same time, following IV administration of the opiate antagonist naloxone,

1 mg/kg. and the same dose of 11C-carfentanil used in the first study. The

brightness of each image is normalized for the injected activity, the

acquisition time, and radioactive decay. A preferential accumulation of

activity is seen in areas known to contain high concentrations of opiate

receptors, such as the thalamus, basal gangIia, amygdala. and cerebral Cortex (particularly the cingulate cortex). Conversely, low activity is seen

where opiate receptors exist in low concentrations, such as the occipital

cortex, the postcentral gyrus, and the cerebellum. The Images in the

bottom row demonstrate the low level of nonreceptor binding in the brain.

Binding is not inhibited In the skull or venous sinuses.

19
these images, a low and homogeneous concentration of radioactivity

is seen throughout the brain, due to competitive binding of naloxone and 11C-carfentanil at opiate receptors. The radioactivity

was not significantly affected in the skin and skull or the venous

sinuses, consistent with the absence of opiate receptors in these

regions.

The ability to measure opiate receptor binding by PET in humans

will permit exploration of questions that cannot be addressed in

animals. Opiate receptors and endogenous opiate peptides have

been implicated in a variety of conditions such as Parkinson's

disease, schizophrenia, depression, pain disorders, and senile

dementia, as well as in individuals predisposed to drug addiction.

BINDING VS. CONCENTRATION

In studying these conditions by PET, opiate receptor binding must

be distinguished from opiate receptor concentration, since opiate

receptor binding can be altered without changing the receptor concentration. For example, changes in regional cerebral blood flow,

may alter the quantity of 11C-carfentanil or any other receptorblood-brain permeability,tissue composition, or other parameters

binding ligand that is available to bind to opiate receptors, and

thus alter the final image without a change in the number of opiate receptors. Additionally, changes in the rate (e.g., a KD

change) may also alter opiate receptor binding. Therefore, until

nonreceptor parameters are taken into account, changes in radioactivity levels from any receptor-binding ligand must be viewed

cautiously when studying neurological and psychiatric disorders.

TRACER KINETIC MODELING

Tracer kinetic modelling can permit the unravelling of a complex

process in vivo, so that the number of binding sites or rate

constants can be estimated if parameters such as the arterial

concentration of the tracer, regional cerebral blood flow, regional cerebral blood volume, and other parameters are known (Phelps

et al. 1982; Mintun et al. 1984b). Using such approaches, it has

been possible to determine quantitative estimates of important

biological processes such as regional cerebral blood flow, regional cerebral glucose utilization, and regional cerebral oxygen

utilization. Similar methods can also, in principle, be applied

to receptor binding in vivo as measured by PET.

A primary piece of independent information, which is necessary to

apply such techniques, is the tracer concentration as a function

of time in the arterial plasma. Most, if not all, of the labelled

drugs that have been used for receptor imaging are metabolized in

vivo. For example, we have measured the metabolism of 11C-carfentanil in human plasma during PET scan studies. At 10, 30, and 60

minutes after injection, the fraction of the total plasma radioactivity represented by 11C-carfentanil is approximately 85, 45,

and 25 percent, respectively. In addition, greater metabolism of

11C-carfentanil was observed following pretreatment with 1 mg/kg

20
naloxone. Using this information, the true kinetics of 11Ccarfentanil in the plasma can be computed and used with tracer

kinetic models. Additional issues to be addressed are the ability

of metabolites to enter the brain and the receptor-binding potential of metabolites. Although metabolites can be measured directly using chromatographic methods, the process is laborious and not

easily translatable to routine clinical studies. Following a

rigorous approach to tracer kinetic modelling, with the accurate

estimation of all involved rate processes, it should become

possible to simplify the methods where appropriate.

AREAS OF INVESTIGATION

In studying opiate receptor binding or binding to other receptor

types in vivo by PET, three fundamental areas of investigation can

be identified. First, it is of great interest to identify and

characterize changes in receptors as a function of disease and

aging. In this respect, it is of interest to obtain quantitative

estimates of receptor concentration and the rate constants for

receptor binding, which then can be compared to values obtained in

normal populations. This approach may lead to an improved biochemical characterization of neurological and psychiatric disorders, an ability to identify disease subtypes, and a rational

approach to drug therapy.

Second, in some receptor systems, it may be possible to detect

changes in receptor binding following alterations in receptor

occupancy by endogenous neurotransmitters. For example, it has

been recently demonstrated that the stress of swimming reduces

apparent opiate receptor binding in vivo, presumably by releasing

enkephalin, which then occupies receptors (Seeger et al. 1984).

Using this approach, the physiologic role of the opiate system

could be elucidated by PET scanning, usfng control-test paradigms

following stressful or painful stimuli. This approach could also

be used to study opiate addiction and withdrawal.

Third, changes in opiate receptor occupancy following the administration of exogenous drugs can also be detected, as was demonstrated for naloxone in the case of opiate receptor binding. Drug

therapy is currently monitored when possible by following the

plasma drug level, although, in many cases, the plasma level does

not closely mirror the therapeutic response. Ideally, the effective concentration of the drug at the receptor site with which it

interacts would be monitored. For example, it has been demonstrated by PET that approximately 85 to 90 percent of dopamine-2

receptors in the putamen of schizophrenic patients are occupied by

conventionally used antipsychotic doses of neuroleptic drugs

(Farde et al. 1986). Similar studies are in progress using 11Ccarfentanil to assess changes in opiate receptor occupancy and the

correlation of those changes with behavioral and subjective

changes in chronic-pain patients receiving morphine and related

drugs, narcotic addicts, and former addicts receiving methadone or

naltrexone.

21
SUMMARY

In summary, it is now possible to image the distribution of several neurotransmitter receptors by PET. When quantitative estimates of receptor number and affinity can be made, it will be

important to study (1) changes in receptor number or affinity as a

function of disease, (2) changes in receptor occupancy by endogenous neurotransmitters, and (3) changes in receptor occupancy and

correlation with behavior during drug treatment.

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H2(15)0. II. Implementation and validation. J Nucl Med

24:790-798, 1983.

Reivich, M.; Kuhl, D.; Wolf, A.; Greenberg, J; Phelps, M.; Ido, J;

Casella, V.; Fowler, J.; Hoffman, E.; Alavi, A.; Som, P.; and

Sokoloff, L. Study of cerebral function with positron computed

tomography. Circ Res 44:127-137, 1979.

Reivich. M.; Alavi, A.; Wolf, A.; Greenberg, J.M.; Fowler, J.;

Christman, D.; MacGregor, R.; Jones, S.C.; London, J.; Shiue C.;

and Yonekura, Y. Use of 2-deoxy-d [1-11C]glucose for the

determination of local cerebral glucose metabolism in humans:

Variation within and between subjects. J Cereb Blood Flow Metab

2:307-319, 1982.

Seeger, T.F.; Sforzo, G.A.; Pert, C.B.; Pert, A. In vivo autoradiography: Visualization of stress-induced changes in opiate

receptor occupancy in the rat brain. Brain Res 305:303-311,

1984.

Seeman, P.; Chau-Wong, M.; Tedesco, J.; and Wong. K. Brain receptors for antipsychotic drugs and dopamine: Direct binding

assays. Proc Natl Acad Sci USA 72:4376-4380, 1975.

23
Seeman, P.; Ulpfon, C.; Bergeron, C.; Riederer, P.; Jellinger, K.;

Gabriel, E.; Reynolds, G.P.; and Tourtellotte, W.W. Bimodal

distribution of dopamine receptor densities in brains of schizophrenics. Science 225:728-731, 1984.

Stahl, K.D.; Van Bever. W.; Janssen, P.; and Simon, E.J. Receptor

affinity and pharmacological potency of a series of narcotic

analgesic, anti-diarrheal and neuroleptic drugs. Eur J

Pharmacol 46:199, 1977.

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Mullani, N. PETT vs. positron emission tomography utilizing

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133, 1982.

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Aften, J.T.M.; and Janssen, P.A.J. Synthetic analgesics: N-(1-

[2-arylethyl]-4 substituted 4-piperidinyl) N-aryl-alkanamides.

Arzneim-Forsch (Drug Research) 26:1526, 1976.

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ACKNOWLEDGMENTS

This work was supported by USPHS grant NS150 80.

AUTHOR

J. James Frost, M.D., Ph.D.

Division of Nuclear Medicine

The Johns Hopkins Medical Institutions

615 North Wolfe Street

Baltimore, MD 21205

24
The Personality Structure of

Heroin Addicts

Robert J. Craig

INTRODUCTION

When a search of the literature for data that other clinicians and

researchers found in the area of personality characteristics of

drug abusers failed to uncover such a body of material, I decided

to produce it myself. My investigation culminated in several

research reviews (Craig 1979a; Craig 1979b; Craig 1982a; Craig

1982b).

My first review uncovered 98 articles from 1925 to 1975, and my

second review found an additional 47 articles from 1976 to 1979.

Clearly, research in this area was burgeoning with interest. This

is even more noteworthy when you understand that I included in

these reviews only articles that were empirical and that administered some type of assessment instrument. Clinical articles and

those based on opinion were not included in my review.

Given the steady volume of papers published on the personality

characteristics of drug addicts since then, another review was

warranted. (Within the last 5 years, another 50 papers have

appeared in scientific journals.) I wanted to produce more of an

integration and knowledge summary than my earlier work; when my

task was finished, I had produced a 75-page paper (Craig 1985b).

When Dr. Szara from NIDA said he wanted someone to discuss what is

known about the personality characteristics of drug addicts, in my

hand was the very paper I needed.

What follows is a distillation of this 75-page effort, adjusted

for the needs of this technical review.

METHODOLOGY

The methodology for this paper was simple but tedious. A literature search was conducted for any empirical study that used a

psychological test or scale with heroin addicts (HAS). Among

heroin addicts we include clients who abused any opiates, such as

heroin, methadone, codeine, Talwin, etc., but the overwhelming

25
emphasis in the literature has been on street addicts who abuse

heroin. The reasons for limiting this search to HAS are:

Opiates constitute the primary drugs of abuse in most drug

treatment programs, so these findings would have a significant

relevance to most of the drug abuse programs in the nation;

The literature overwhelmingly focuses on characteristics of

opiate addicts, perhaps because of their availability in drug

treatment programs and prisons.

Other than marijuana studies, there is a relative paucity of

research on personality characteristics of addicts who abuse

other drugs besides heroin, except when these abusers are

contrasted with a heroin-using group, so these studies are

likely to appear in this review as well.

While marijuana studies are plentiful, they often rely on

college students, and a primary marijuana-abusing client is a

rarity in most drug treatment programs.

ASSESSMENT INSTRUMENTS

By looking at the assessment instruments used in this research, we

can determine the areas of personality functioning that have

captivated the interest of researchers. The following is a rank

order of the most frequently used personality tests and scales

that appeared in this literature: the Minnesota Multiphasic

Personality Inventory (MMPI), the Eysenck Personality

Questionnaire/Maudsley Personality Inventory, Rotter's Locus of

Control Scale, Zuckerman's Sensation Seeking Scale, the Beck

Depression Inventory, the Adjective Check Lists, the Tennessee

Self Concept Scale, Rorschach, the Addiction Severity Index, the

16 Personality Factor Questionnaire, and Figure Drawings. We can

infer from these measures that investigators have focused largely

on such areas as general personality traits and symptoms, introversion/extraversion, locus of control, sensation seeking, depression, psychological need structure, self-concept, and something

akin to unconscious conflicts.

COMMENT ON METHODOLOGICAL ADEQUACY OF THE LITERATURE

Barnes (1979) has made a useful distinction between the preclinical personality (those traits and behaviors exhibited prior to the

onset of addiction) and the clinical personality (how the patient

presents following the onset of addiction) of the drug abuser.

All the research cited here pertains to the clinical personality

of the drug addict. We have no studies whatsoever that have

tested people prior to the development of their addiction. HOWever, we are not arguing that these traits did or did not predate

addiction. We merely suggest how a typical drug addict tends to

appear on psychological tests and what areas show improvement with

treatment. We find the concept of the "addictive personality" not

useful, clinically or otherwise, whereas a description of the

26
clinical state of the addict, including his personality, is central to the assessment process itself.

Most of the research is based on samples of males. Only recently

has literature appeared dealing with the personality traits of

female addicts.

The methodological adequacy of some of the studies varies, especially in determining an adequate control group with which to

compare addicts. For a more in-depth understanding of this issue,

the reader is referred to articles addressing this problem (Craig

1979b; Nathan and Lansky 1978).

PERSONALITY CHARACTERISTICS OF HEROIN ADDICTS

Locus of Control

Since locus of control is a major content item at this conference,

I want to make sure that I cover the studies that have used this

as a measure to study HAS.

Locus of control measures the extent to which a person perceives

gratification and rewards as emanating from personal actions and

responsibility (internal locus of control), or whether they are

perceived as emanating from luck, fate, chance, or the assistance

of others (external locus of control). An internal locus of control is more often associated with good psychological adjustment,

while an external locus of control is linked to maladjustment and

psychopathology.

Probably, after hearing this definition, one would predict that

HAS have an external locus of control orientation, but there are

conflicting findings in the literature.

Seven studies have found HAS to have an internal locus of control.

For example, Berger and Koocher (1972) found an internal locus of

control, plus a significant drop in externality, following an

announcement that a treatment facility would close. Here the

addicts were not depending on luck, fate, or help from others to

find alternatives. This suggests that locus of control can be

subject to environmental fluctuations as well as being a generalized trait. No evidence was reported to show that directionality

was maintained over time. These results may simply reflect the

addict's need and resourcefulness at locating another source of

supply.

Berzins and Ross (1973) found that black addicts were more external than white addicts, female addicts of both races were more

external than males of both races, and black female addicts were

more external than other comparison groups. However, 85 percent

of the total sample of 1,400 had an internal locus of control.

Callichia (1974) found HAS on methadone maintenance to be more

internal than abstinent addicts. It would have been interesting

27
to note whether or not any changes in control orientation occurred

after placement on methadone maintenance, but this study design

did not permit such a finding.

Studies using a trait approach to locus of control have demonstrated that addicts become more internal after 18 months in a

therapeutic community (De Leon et al. 1973) and after 9 weeks on

methadone maintenance (Henick and Domino 1974).

Two other studies (Smithyman et al. 1974; Platt and Scurra 1974)

also found HAS to have an internal orientation.

Now for the apparent conflict: Five studies have found addicts to

have an external locus of control (De Leon et al. 1973; Obitz et

al. 1973; Obitz et al. 1974; Manganello 1978; Pearlstein 1980).

The Pearlstein study compared locus of control in 38 HAS, 34 alcoholics, and 21 amphetamine users. The amphetamine group were more

externally directed than the HAS and the alcoholics.

Two studies found HAS to be undifferentiated in directionality

(Langrod et al. 1983; Platt 1975).

Methodology seems to account for these differences. In almost

every case where no control group was used and where addict scores

were compared to published norms of college students, HAS were

found to be externally directed. In studies which used relevant

control groups, results generally showed HAS to be internally

directed.

There are two issues that I want to address now. First, does it

make any difference whether addicts are internal or external in

orientation, and, second, how can drug addicts be internal anyway?

As to the first issue, locus of control as an orientation is

irrelevant unless it can be shown to be related to something else

more important. For example, in the Langrod et al. study (1983),

the hypothesis was tested that methadone maintenance patients with

an internal locus of control would be more likely to be willing to

begin detoxification. Results showed a "nonsignificant trend" in

support of that hypothesis. To a statistician, a nonsignificant

trend is no trend at all, and the null hypothesis is accepted.

Thus, having an internal locus of control was not much different

from having an external locus of control, when it came to beginning methadone detoxification. A more promising lead seems to be

in the area of "detoxification phobia" (Milby et al. 1980). I am

involved with a project now with Dr. Milby at the Veterans

Administration Medical Center in Birmingham. We believe that many

patients have developed a clinical phobia about methadone detox,

and plan to test this idea in a multicenter project. I suspect

that this will bear more fruit than considering their locus of

control.

Second, Strassberg and Robinson (1974) found that addicts with an

internal locus of control had higher levels of self-esteem, better

28
psychological adjustment, and higher motivation to achieve

success, and that locus of control orientation was not correlated

with length of drug use.

The idea of a HA having an internal locus of control, as indicated

by the literature, seems paradoxical. I suspect that they are

"pseudointernals." It is quite possible that the internal locus

of control seen in addict self-reports is largely a cognitive and

intellectual self-report that does not match day-to-day behavior.

It seems to serve a defensive function and to reinforce group

norms that assert that they are in charge of their lives. However, I suspect that HAS do not behave as if they were internal.

At the risk of getting "soft," let me cite some clinical material

that seems consistent with my view.

Wellisch et al. (1970) have reported on a relationship dyad among

HAS where the male member is supported and taken care of by the

female member, who typically adopts the role of pseudomother for

her male partner; hence the term "easy rider" syndrome. Outwardly, the male appears to be along for the joy ride and looks

independent. Inwardly, he is passive-aggressive in the fullest

sense, extremely dependent on someone to guide him through life.

When the relationship ends, he finds someone else to play this

role in his life.

Ganger and Shugart (1966) further report that the aggressive

behavior that some addicts exhibit toward their families when high

is actually "pseudoassertive" behavior that plays an important

role in family dynamics and that results in keeping the addict

addicted and dependent.

What is actually seen in these two examples is behavior that is

very externally oriented under the appearance of an internal

orientation.

Sensation Seeking

Sensation seeking as a trait, suggested as a possible factor in

the onset of heroin use, explores the tendency of addicts to

engage in thrill, adventure, and altered states of consciousness.

Most studies indicate that drug addicts have higher scores in

sensation seeking than normals (Galigio and Stein 1983; Platt

1975). This seems to hold true for drug use in college students

(Zuckerman et al. 1972) and for addicts on methadone maintenance.

Sensation seeking traits probably predated their involvement with

opiates (Kohn et al. 1979). Drug addicts seem to show a preference level of stimulation in sensation-seeking experiences that is

not seen among nonusers (Reith et al. 1975). Sensation-seeking

scores have been related to hallucinogen use in members of a labor

union (Khavari et al. 1977) and to the frequency of hallucinogen

use among Hispanic males in residential treatment (Kaestner et al.

1977). They also have been positively related to stimulant and

29
hallucinogen use and negatively related to the use of depressants

(Carol and Zuckerman 1977; Galigio and Stein 1983).

White addicts show higher levels of sensation seeking than black

addicts (Kaestner et al. 1977; Sutker et al. 1978). Addicts who

were higher in sensation seeking also used more categories of

drugs, had an earlier age of onset of first drug use, and cited

curiosity as their initial motive for using drugs.

Female addicts did not differ from male addicts in sensation

seeking (Sutker et al. 1978), and no differences occurred among

groups with high rates of parole success compared to recidivists

(Platt and Scurra 1974) on sensation-seeking traits. Successful

treatment in a therapeutic community decreased sensation-seeking

traits among addicts, but no comparable reduction was observed for

addicts in prison (Skolnick and Zuckerman 1979).

I would like to make one last point. Eyre et al. (1982) found

that 22 percent of a population of 157 HAS reported childhood histories of hyperactivity. Craig (1984a) reported that, based on

almost 500 MMPI profiles, HAS typically have high Scale 9

(hypomania) scores. All this seems to correlate with some central

nervous system "something." I would like to see a group of HAS

with high sensation-seeking scores and high Scale 9 scores in

studies designed to address the following questions: Do they have

histories of hyperactivity? Are their EEGs abnormal? What would

the results of CAT/PET scans show, when equated with HAS without

high sensation seeking and high hypomania scores?

SUMMARY OF PSYCHOLOGICAL TEST ASSESSMENTS

What follows is a summary of my 75-page review. You will have to

trust that what I am now reporting is true, since few references.

other than my own summary (Craig 1985b), will be presented:

Opiate addicts, as a group, score in the average range of IQ

level; this finding is true among a variety of addict subgroups

and is independent of the type of intelligence test used to

make the assessment.

Addicts show no group differences in development of moral

values and function largely around Kohlberg's Stage 3

(preconventional) level of moral reasoning. Any deficiencies

observed in this area by addicts are due to defective ego

controls rather than to deficits in moral reasoning.

Addicts tend to score in the mild to moderate range of

depression on most psychological tests and rating scales.

These depression scores subside with treatment.

Drug addicts are undifferentiated with respect to the traits of

introversion/extraversion.

30
Most addicts score in the direction of internality on locus of

control orientation, as opposed to alcoholics who score as

externally oriented. However, this is misleading and merely

reflects a cognitive belief which addicts hold as a defense--a

belief that is not matched by their behavior. Locus of control

is also subject to temporary fluctuations based on environmental threats. Addicts' locus of control moves toward greater

internality following appropriate treatment.

Psychiatric studies show that drug addicts have a paucity of

major psychiatric syndromes and neuroses and a plethora of

personality disorders and character disorders. Psychological

tests confirm this finding. This is not to say that major

psychiatric syndromes cannot coexist with drug addiction, but

merely that such a condition is the exception.

All studies found that addicts have a poor self-concept, which

improves with certain types of treatment.

Addicts have a higher need for sensation seeking than normal

controls.

Addicts are field dependent, relying on their environment to

give them structure and support.

Studies testing addicts' need hierarchies have often found them

to be high in self-reported dominance, aggression, succorance

(dependence), change, heterosexuality, and autonomy, and low in

endurance, affiliation, and nurturance. They report themselves

to be high in need for achievement, but their daily behavior

does not match this report. On most tests, addicts would be

described as hostile, demanding, aggressive, rebellious,

irresponsible, playful, impulsive, and independent, making the

establishment of a treatment alliance quite difficult.

Opiate abuse results in little or no impairment in cerebral

functioning (except for acute effects), as measured by neuropsychological tests given up to 9 weeks following abstinence.

When differences have been found, they have been described as

mild and detectable only with specialized tests, but not

suspected clinically.

A number of variables can influence test findings, particularly

time of testing, ethnicity, class of drugs, reasons for seeking

treatment, and the presence of coexisting clinical syndromes.

If the goal is to detect substance abuse with psychological

tests, then the MacAndrew Alcoholism Scale of the MMPI is

currently the best psychologically based scale to provide

information about substance-abusing tendencies.

31
PERSONALITY STRUCTURE OF HEROIN ADDICTS

Research using psychological tests and scales has found the personality of drug addicts to have the components of a weak ego,

character-disordered traits, field dependence, and stfmulus

augmentation. These findings parallel, but are somewhat different

from, similar reports on the alcoholic personality (Barnes 1979).

Weak Ego

Addicts, like alcoholics, have a weak ego, but it is manifested

somewhat differently from the personality of alcoholics. Like

alcoholics, they have a negative self-concept, show hostility,

immaturity, and impulsiveness , and have a low tolerance for

frustration. They are oriented toward the present rather than

showing goal-oriented behavior toward the future. Unlike alcoholics, they have a strong sexual identity, with high need for

heterosexuality but low need for endurance and affiliation. This

suggests that addict sexuality may be another area in life where

other people (females) are used to gratify and satisfy the

addict's need for intimacy without reciprocity or need for lasting

attachments.

Character-Disordered Traits

Addicts have traits typical of traditional antisocial psychopathy.

Relationships are superficial and instrumental only to the extent

that others gratify their narcissistic demands. Depression is

mild but chronic and low level. Anxiety is manifested through

impulsive behavior and somatic defenses. They aggress to achieve

their ends, try to dominate relationships, and are poor treatment

risks.

Field Dependence

Addicts are more field dependent than normals, suggesting that

they have a higher need for dependency than do normals. They rely

on their environment to provide them with structure and support.

Stimulus Augmentation

Addicts cannot tolerate boredom, are playful, want change, are

exhibitionistic, high in sensation seeking, and are stimulus

augmenters rather than stimulus reducers.

IMPLICATIONS FOR FUTURE RESEARCH

Now that the personality structure of heroin addicts is somewhat

in hand, the question remains, "So what?" Where do we go from

here?

I think we are at a point in our knowledge where it is no longer

sufficient merely to give drug addicts a personality test and then

report the results (the one exception might be cocaine abusers,

32
for whom little information other than demographics presently

exists). I believe that future directions should relate personality traits and styles to other variables of interest, particularly treatment response and treatment outcome (Craig 1982b).

This is the direction my own work has taken. For example, we have

learned that personality traits, as measured by the MMPI and the

Millon Clinical Multiaxial Inventory, are not related to treatment

dropout in our program (Craig 1984b; Craig 1984c), whereas interactional concepts have proved to be quite reliable indicators of

dropout upon cross-validation (Craig et al. 1982). Relating

personality traits to other variables of interest is the direction

in which we have to go.

Another important area has to do with effectiveness of treatment,

particularly personality change as a result of treatment. Most

drug addicts are treated in programs and not in private practice

(Craig 1985b). In our own program, we have data that demonstrate

the effectiveness of methadone maintenance (Craig 1980) but no

data on the effectiveness of our inpatient unit. We are currently

using the Adjective Check List, measuring needs, to see if need

patterns change after 3 weeks of intensive rehabilitation.

Retrospective studies are needed to determine the personality of

drug addicts prior to addiction. A few seminal reports of this

kind are available in the alcoholic literature and would be

extremely enlightening in the drug abuse literature as well. If

NIDA wants to have a real effect in this area, it should create a

grant for a researcher to go into a community, select random samples of community residents at risk for and with equal access to

drugs, and then follow them over time. The researcher should find

out which ones become addicts and which ones do not, then go over

their psychological test data to see if any traits or scores distinguish the users from the abstainers. This is what is really

needed.

We know quite a lot about how drug addicts appear on psychological

tests; now we have to determine what this means.

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Barnes, G. The alcoholic personality: A reanalysis of the

literature. J Stud Alcohol 40:571-634, 1979.

Berger, M.S., and Koocher, G.P. Locus of control in narcotic

addicts: State or trait phenomenon? J Clin Psychol 28:468-469,

1972.

Berzins, J.I., and Ross, W.F. Locus of control among opiate

addicts. J Consult Clin Psychol 40:84-89, 1973.

Callichia, J.P. Narcotic addiction and perceived locus of

control. J Clin Psychol 30:499-504, 1974.

Carol, E.N.,and Zuckerman, M. Psychopathology and sensation

seeking in "downers," "speeders," and "trippers": A study of

the relationship between personality and drug of choice. Int J

Addict 12:591-601, 1977.

33
Craig, R.J. Personality characteristics of heroin addicts: A

review of the empirical research with critique. Part I. Int J

Addict 14:513-532, 1979a.

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on multiple methods of classification. J Pers Assess 48:115-

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40:351-355, 1984c.

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hallucinogenic use. J Abnorm Psychol 86:172-178, 1977.

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Langrod, J.; Des Jarlais, D.C.; Alksne, L.; and Lowinson, J.

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Manganello, J. Opiate addiction: A study of identifying three

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15:737-747. 1980.

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9:757-760, 1974.

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locus of control in delinquent drug users. Int J Addict 8:723-

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Addict 15:277-282, 1980.

Platt, J.J. "Addiction proneness" and personality in heroin

addicts. J Abnorm Psychol 84:303-306, 1975.

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institutionalized heroin addicts: Personality correlates and

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Reith. G.; Crockett, D.; and Craig, K. Personality characteristics in heroin addicts and nonaddicted prisoners using the

Edwards Personality Preference Schedule. Int J Addict 10:97-

112, 1975.

Skolnick, N., and Zuckerman, M. Personality change in drug

abusers: A comparison of therapeutic community and prison

groups. J Consult Clin Psychol 47:768-770, 1979.

Smithyman, S.D.;Plant, W.T.; and Southern, M.L. Locus of control

in two samples of chronic drug users. Psychol Rep 34:1293-1294,

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of control and other personality measures in drug users. J

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Sutker, P.B.;Archer, R.; and Allain, A. Drug abuse patterns,

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syndrome: A pattern of hetero- and homosexual relationships in

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Consult Clin Psychol 39:308-321, 1972.

35
AUTHOR

Robert J. Craig, Ph.D.

Chief, Drug Abuse Program (123)

West Side Veterans Administration

Medical Center

820 South Damen Avenue

Chicago, IL 60612

36
Locus of Control and Need for

Control Among Heroin Users

Don C. Des Jarlais

INTRODUCTION

“LOSS of control" over substance use has long been considered to

be one of the primary characteristics that distinguish the true

"alcoholic" or "addict" from the "heavy user." The standard

conceptualization of full loss of control involves both use to the

point at which there are severe negative consequences of substance

use for the individual and an inability ever to return to "moderate" levels of use. The purpose of this monograph is to examine

possible new research techniques for interdisciplinary study of

this central problem in substance abuse. As part of this purpose,

we will first review some of our previous research on locus of

control among heroin users and then report on our current studies

of control over drug use among heroin users.

The concept of locus of control was first developed by Rotter

(1966) and was defined in terms of the individual's perception of

control over his or her reinforcements. A person with an

"internal" locus of control believed that control over reinforcements resided primarily within the individual; thus, rewards were

mainly the result of efforts and deliberate choices. Persons with

an "external" locus of control believed that control over reinforcements was located outside the individual. and that rewards

were primarily determined by factors such as fate, chance, or

powerful others.

There is a great volume of research on locus of control in the

psychological literature, with the great majority of findings

linking internality with positive mental health (Lefcourt 1976).

Since drugs are readily identifiable and powerful reinforcers,

there was an expectation that strong relationships between locus

of control and drug use might be found. Unfortunately, there are

contradictory findings as to whether drug users are internal

(Berzins and Ross 1973; Carroll, unpublished dissertation; Gross

and Morosko 1970) or external (Palmer 1971; Obitz et al. 1973),

and, if they are internal, whether they are "true" internals

(Berzins and Ross 1973; Carroll, unpublished dissertation) or

37
"pseudo" internals (Lefcourt 1976). Craig (this volume) recently

reviewed studies of locus of control among substance abusers and

found approximately equal numbers of studies showing drug abusers

to be internal, external, and neither internal nor external.

PRIOR STUDY

Several years ago, we conducted a study of locus of control among

methadone maintenance patients in an attempt to clarify relationships between locus of control and drug use. We believed that

clarification might be achieved by studying a specific behavior--

voluntary detoxification from methadone maintenance--that had

clear implications for control (Langrod et al. 1983).

Voluntary detoxification was selected as a specific behavior

because of its many links to control in patients' lives. Successful voluntary detoxification would objectively increase patients'

control over their lives. Patients would no longer have to report

to a clinic one or more times per week, receive mandatory counseling, submit urine specimens for analysis, or obtain prior approval

for personal or business travel. Voluntary detoxification is also

seen by patients as a desired treatment goal that depends upon

willpower and effort rather than chance factors.

From the great number of studies that showed relationships

between internality and positive mental health, we generated two

hypotheses:

Internality would be positively associated with stated willingness to begin a voluntary detoxification.

Internality would be positively associated with actually beginning a voluntary detoxification within the 90-day followup

period. (A reduction in methadone dosage was required as

evidence of actually beginning detoxification.)

These hypotheses were tested in a sample of 115 male methadone

maintenance patients, who were given the Rotter Locus of Control

Scale, interviewed regarding their perceptions of and willingness

to begin a voluntary detoxification, and then followed to see

which subjects had actually begun such a detoxification.

The findings from this study did not resolve ambiguities in the

relationships between locus of control and drug use. First, the

mean score on the Locus of Control Scale was 8.9, which was

neither "internal" nor "external" when compared to the means from

a large number of other samples. Second, there was only weak

support for the first hypothesis , a correlation of 0.15, p<.11,

between internality and stated willingness to begin detoxification. Finally, there was a reversal of the second hypothesis.

Among those subjects who indicated a willingness to begin detoxification, there was a statistically significant negative correlation between actually beginning detoxification (r=-0.30 with

Locus of Control Scale, p<.012) and internality,

38
REFORMULATION: NEED FOR CONTROL AS A MOTIVE FOR BEHAVIOR

These findings led us to question the value of the concept of

locus of control in studying drug use and abuse. Locus of control

is conceptualized as a relatively stable personality trait, a belief about how the world works and the person's relationship to

the working of the world. Our findings were best interpreted in

terms of a varying need for control. Need for control would vary

with both the general life situation of the individual and the

specific immediate situation. In general (outside of pathologic

conditions), control over reinforcers would be valued. Individuals who experience a sense of control over their reinforcers will

defend against losing their sense of control, and individuals who

experience a lack of control over reinforcers will actively seek

means of reestablishing such control.

By definition, drugs are an important set of reinforcers for “drug

abusers," and "control" over drug use thus will be an important

part of their lives. The methadone patients who felt a lack of

control over reinforcers (the "externals") would thus begin detoxification to gain a sense of control. Those methadone patients

who experienced a sense of control over reinforcers (the "internals") would avoid actually beginning detoxification, since failure at this important task would be a clear threat to their sense

of control. (The likelihood of successful detoxification and

abstinence afterward is relatively low, approximately one in six

(Des Jarlais et al. 1981)).

Within this reformulation, the Locus of Control Scale can be used

as an imperfect measure of need for control. "Externals" would be

considered to have an unmet need for control and would be likely

to take action that would lead to an increased degree of control

over reinforcers. "Internals" would be considered to have their

need for control met and would avoid action that would threaten

their current sense of control. The scale is thus being used to

measure differences in situationally produced motives for

behavior, not differences in the personalities of individuals.

This reformulation is consistent with the one area in which there

are theoretically plausible and empirically consistent data regarding locus of control and drug abuse. Studies from therapeutic

community treatment (De Leon et al. 1973) and methadone maintenance treatment (Henik and Domino 1974) show change from externality to internality during time spent in drug abuse treatment. An

unmet need for control over reinforcers would lead individuals to

enter treatment, and successful adaptation to treatment would be

associated with developing a sense of control over reinforcers in

one's life.

PILOT STUDY OF INTRANASAL HEROIN USERS

We have since conducted another study of methadone patients, relevant to relationships between perceived need for control and

important drug use behavior.

39
Acquired immunodeficiency syndrome (AIDS) has become the major

health threat to intravenous (IV) drug users in New York City.

Over 1,500 IV drug users in the city have contracted AIDS as of

September 1985; the total number of cases continues to double

approximately every year (New York City Department of Health

1985). HTLV-III/LAV, the virus that causes AIDS, appears to be

spread through the sharing of "works" (needles and syringes) among

IV drug users (Cohen et al. 1985; Weiss et al. 1985). As part of

our ongoing research on AIDS among IV drug users, we conducted a

pilot study of persons who had used heroin intranasally (sniffed)

to the point where they required methadone maintenance treatment,

but who had not become regular drug injectors.

Injecting heroin is a much more physiologically efficient route of

administration. (Our subjects estimated that they had to purchase

approximately three times the amount of heroin for sniffing to

achieve the same effects as by injecting.) Persons who sniff

large amounts of heroin are important to study, both in relation

to the practical aspects of limiting the spread of HTLV-III/LAV

among drug users and in relation to the theoretical issues of

control over amount of drug use and route of administration.

We interviewed 16 subjects with histories of intranasal use of

heroin who had entered a New York City methadone maintenance program during the previous year. These represented the majority of

20 such persons who had been treated at this particular program

over the previous 18 months.

The subjects were relatively young (mean age of 21 years, range of

17 to 24), primarily Hispanic (87.5 percent Hispanic, 12.5 percent

non-Hispanic white) and female (62.5 percent). They reported a

range of 2 to 9 years of sniffing heroin prior to entry into

treatment (mean of 4 years). They had used a variety of other

drugs, primarily marijuana and cocaine (not injected), in addition

to heroin. Of the 16, 4 had injected heroin but had not continued

this route of administration. They reported using an average of

$40 per day of heroin (four $10 bags) prior to entry into treatment (range from 1 to 10 bags).

The two questions in the interview that were most relevant to the

sense of and need for control were the reasons for not injecting

heroin and the reasons for entering treatment. (These questions

were open-ended and were asked prior to any questions on AIDS, to

reduce any interview demand characteristics. The respondents

could give multiple reasons but were not prompted with respect to

any particular reason.)

For the question concerning why the subject did not inject drugs,

14 of the 16 respondents mentioned a fear of needles. This fear

was often described as originating in childhood experiences with

physicians and involved both fear of pain and anxiety/nausea at

the thought of bleeding.

40
The second most frequently given response to the question on not

injecting heroin, mentioned by 11 subjects, was the belief that

injecting would lead to becoming a "street junkie." A street

junkie was described as a person for whom heroin use completely

dominated all other activities. For the junkie, all other values,

commitments, and relationships were sacrificed to obtaining and

using heroin. This sacrificing of all other interests was seen as

the final stage in loss of control over heroin use.

Significantly, this stage of loss of control also was seen to

involve loss of self-esteem and social respect. In talking about

street junkies, subjects made statements such as, "I didn't want

to get that low,"and "I couldn't see myself doing that." Respect

from others would be lost because being a junkie could not be

concealed from others.

("tracks,"

Both the physical evidence of needle use

the scars from frequent injection) and the willingness

to "do anything to obtain drugs" (including stealing from friends

and relatives, committing serious crimes on a frequent basis)

would lead others to learn of one's condition.

Interestingly, none of the subjects specifically mentioned a fear

of AIDS as a reason for not injecting drugs, though later in the

interview the majority did express great concern about AIDS.

Relationships among knowledge of AIDS, personal experience with

AIDS victims, and the decision not to inject drugs will be

presented in a separate paper.

The majority of reasons given for entering treatment were phrased

in terms of control over heroin use. Nine of the respondents

stated that they could no longer manage their use of heroin.

Physical dependence had developed, efforts to limit use had

failed, and they were now devoting large resources to heroin consumption (an average of $40 per day). This situation was often

described in terms of "being tired" of the "hassles" involved in

obtaining large quantities of heroin.

The second most frequently cited reason for entering treatment was

to avoid consequences of heroin use that were foreseen but had not

yet occurred. Seven respondents stated that they had entered

treatment to avoid impending negative consequences; of these,

three wanted to avoid becoming "street junkies," and two wished to

avoid becoming bad mothers to their children.

DISCUSSION

The results of the pilot study readily fit with the need-forcontrol formulation derived from the methadone maintenance detoxification study. Results indicate that individuals will defend

against loss of control over their reinforcers, and if loss of

control should occur, will actively seek to reestablish control.

Avoiding injection was often described as avoiding a fundamental

loss of control. Seeking treatment was typically described as an

attempt to regain control.

41
The pilot study results have conflicting implications for the idea

that drug abusers are characterized by either an internal or an

external locus of control. The pretreatment loss of control over

heroin use would be an experience that should induce an external

locus of control, while the ability to avoid regular injection of

heroin would be an experience consistent with an internal locus of

control. Thus, one can generate plausible predictions for either

"internality" or "externality" among these intranasal heroin

users. Locus of control scores taken at the time of the interviews (after treatment had begun) would not help in resolving

these contradictory implications, given the previously cited

studies showing movement towards internality with time in

treatment.

CONCLUSIONS AND IMPLICATIONS FOR FUTURE RESEARCH

From present data, there seems to be little evidence of a consistent relationship between perceived locus of control over reinforcers (as a stable personality characteristic) and substance

abuse. This is not to imply that control over drugs as reinforcers is not relevant to substance abuse. Relationships

between locus of control and specific behavior, e.g., time in

treatment, initiation of voluntary detoxification, have been

found. Drug users report loss of control and maintaining control

to be important reasons for behavior such as entering treatment

and avoiding injection of heroin.

A formulation of need for control over drug use as a central

concern for drug users avoids the problems associated with the

conceptualization of locus of control as a stable personality

characteristic. Perceived control over reinforcers might not be

stable over time; rather, need for control might vary according to

a variety of factors including intensity of present drug use,

psychophysiological adaptations to repeated drug use, availability

of drugs, approval or sanctions from significant others, treatment

status, and the user's self-concept.

Instruments and techniques for measuring need for control are

clearly needed if this concept is to be studied scientifically.

Because need for control is conceptualized as varying across both

persons and situations, instruments similar to the state/trait

measures of anxiety may be required.

After suitable instruments are developed, longitudinal studies of

need for control over drug use will be required. If this need

does vary over time, and if it is an important determinant in drug

use/abuse behavior, then meaningful results are likely only in

studies with time as a variable. Studies that do not include time

as a variable will probably replicate the theoretical confusion

and empirically conflicting data that characterize the present

research on locus of control in drug abuse.

42
REFERENCES

Berzins, J.I., and Ross, W.F. Locus of control among opiate

addicts. J Consult Clin Psychol 40:84-91, 1973.

Carroll. L.T. An Investiaation of the internal and external

control constructs in a-population of patients addicted to

narcotic drugs. University of Kentucky, 1968. Unpublished

doctoral dissertation.

Cohen, H.; Marmot-, M.; Des Jarlais, D.C.; Friedman, S.R.; Mildan,

D.; Yancovitz, S.R.; Mather, U.; El-Sadr, W.; Holtzman, R.; and

Spira, J.J. Behavioral risk factors for HTLV-III/LAV seropositivity among intravenous drug users. Paper presented at the

International Conference on Acquired Immunodeficiency Syndrome

(AIDS). Atlanta. GA. Aoril 1985.

De Leon; G.; Skodol, A.; and Rosenthal, M.S. Changes in psychological signs for resident drug addicts. Arch Gen Psychiatry

28:131-135, 1973.

Des Jarlais, D.C.; Joseph, H.; and Dole, V.P. Long term outcomes

after termination from methadone maintenance treatment. Ann NY

Acad Sci 362:231-238, 1981.

Gross, A., and Morosko, T.E. Relation between a dimension of

internal-external control and the MMPI with an alcoholic

population.

Henik, W.,

J Consult Clin Psychol 34:189-192, 1970.

and Domino, G. Selected psychological changes in

heroin addicts undergoing a methadone maintenance treatment

program. J Bronx State Hosp 2:45-50, 1974.

Langrod, J.; Des Jarlais, D.C.; Alksne, L.; and Lowinson. J.

Locus of control and initiation of detoxification among male

methadone maintenance patients. Int J Addict 18:783-790, 1983.

Lefcourt, H.M. Locus of Control: Current Trends in Theory and

Research. Hillsdale, NJ: Lawrence Erlbaum Associates, 1976

New York City Department of Health. AIDS Surveillance Update.

September 25, 1985.

Obitz, F.W.; Oziel, L.; and Unmacht, J. General and specific

perceived locus of control in delinquent drug users.. Int J

Addict 8:723-727, 1973.

Palmer,R.D. Parental perception and perceived locus of control

in psychopathology. J Pers 3:420-431, 1971.

Rotter, J.B. Generalized expectancies for internal versus external control of reinforcement. Psychol Monographs 80:1-28, 1966 

Weiss, S.H.; Ginzburg, H.M.; and Goeddart, J.J.

exposure among parenteral drug abusers in New Jersey. Paper

presented at the International Conference on Acquired Immunodeficiency Syndrome (AIDS). Atlanta, GA, April 1985.

ACKNOWLEDGMENTS

Support for data collection on the pilot study of intranasal

heroin users was provided by the New York State Division of

Substance Abuse Services, and by the National Institute on Drug

Abuse through grant R01 DA 03574.

43
AUTHOR

Don C. Des Jarlais, Ph.D.

Assistant Deputy Director of Research and Evaluation

New York State Division of Substance Abuse Services

Office of Alcoholism and Substance Abuse

Two World Trade Center

New York, NY 10047

44
Personality Characteristics and

Self-Abusive Behavior

Donald G. Forgays

INTRODUCTION

Five themes are relevant to self-abusive behaviors, notably tobacco, alcohol, and drug abuse and, to some extent, overeating.

The themes are:

Self-cure of many of these behaviors occurs much more frequently than interventional studies indicate.

Self-abusers of various kinds may have distinctive personality

characteristics, and there may be commonality of certain

characteristics across abuse types.

Subjects' differences may be related to ability to change the

abusive behavior, either by themselves or through intervention.

Personality characteristics may be related in somewhat different ways to each of the various stages of substance use, abuse,

and cure or fail potential.

Intervention and prevention programs and further research are

clearly indicated by an analysis which emphasizes individual

differences.

While this paper discusses each of these points, primarily the

first three are addressed.

SELF-CURE

Studies of therapeutic attempts to intervene in self-abusive behaviors report little success. For example, Leventhal and Cleary

(1980) reviewed smoking intervention studies in which the success

rate was, at best, 20 percent of the smokers. Success was defined

as high reduction or stoppage of smoking 1 year after intervention. Extensive literature reviews are also available for weight

reduction interventions for the obese (Stunkard and McLaren-Hume

1959; Wing and Jeffrey 1979). Only about 20 percent of the obese

45
can expect to lose as much as 20 pounds as a result of intervention. The interventional success rate for alcoholism and drug

abuse is expected to be at least as poor as that for smoking and

obesity. In many studies, there is considerable postintervention

improvement in the behavior of concern, but the rate of recidivism

is also great, leaving a small proportion of cures. The dismal

results usually reported for therapeutic interventions in these

behaviors do not support the notion that we know how to manage

these behaviors.

All the more startling, then, are the results of several provocative studies indicating a much higher level of cure. For example,

Schachter (1982) reports that as many as 60 percent of heavy smokers are able to quit or greatly reduce smoking. He reports a

similar statistic for obese persons who are able to reduce their

weight to nonobese standards. In most of these persons, interventional help was not needed for the change to occur. We recently

attempted to replicate the Schachter study (Rzewnicki and Forgays,

submitted for publication) and found that about 60 percent of our

subjects who were smokers were able to self-cure. The percentage

of our obese subjects who were able to self-manage their weight

was less than that reported by Schachter but higher than that

reported in most of the interventional studies.

In a fascinating recent study, Jeffrey et al. (1982) compared

three formats of a correspondence course with a standard behavioral group program for smoking reduction and for weight management. Subjects were randomly assigned to one of the four study

conditions. These authors report that even the basic home correspondence course was as effective as any of the other conditions

and produced significant changes in health behavior. While the

home course is an intervention, of course, the process is close to

self-management.

Other self-abusive behaviors may also be subject to selfmanagement. For example, Robins et al. (1980) studied a large

number of Vietnam veterans 3 years after they had left Vietnam.

Many had been frequent users of heroin during the war. The

authors reported that users managed to quit using heroin much more

often than general interventional data would predict and, again,

frequently without any special help. They also reported that some

of these former users returned to the use of heroin in this country and were able to give it up once more without help. Other

important findings in this study were that heroin users tended to

be polydrug users, using all drugs during the same period, and

that they were highly likely to have had serious social problems

before they began to use drugs. Robins and her colleagues concluded that our society has overemphasized the importance of

treatment for heroin and has tended to ignore the severe social

adjustment difficulties that such drug users have.

In an interesting book on de-addiction, Brill (1972) reports

several case histories of heroin addicts who were able to selfcure. While these individuals indicated that self-management was

46
difficult to achieve, they also made it clear that certain personality characteristics may have helped them to control these

important behaviors.

Several reports have provided data attesting to the voluntary

reduction and cessation of marijuana usage (Brown et al. 1974;

Raffoul and Cummins 1980; Sadava and Forsyth 1977). Most of the

subjects of these studies were college students whose drug reductions were associated with social psychological changes in their

status, principally life cycle changes and the acquisition of

nonstudent roles. According to the National Commission on

Marijuana and Drug Abuse, 1972, about half of those over the age

of 18 who had used marijuana stopped using it; presumably many of

these were self-cures. Data available from Information Canada

(1972) agrees with this finding very closely.

It has been difficult to find evidence of the self-management of

alcohol abuse. However, Statistics Canada (1981) provides data on

a national sample in which between 5 and 12 percent of drinkers

ceased drinking; presumably this was done on a voluntary basis.

Percentages varied with age and sex of respondent and were higher

for male and older subjects. Even though some of the notions that

Pattison et al. (1977) discuss are controversial, they list 74

studies reporting data indicating that former alcoholics not only

can be "cured' but can even return to controlled drinking without

becoming alcoholics again.

Thus, there appears to be substantial evidence that persons are

able to self-manage important self-abusive behaviors much more

frequently than the interventional literature would predict. One

clear possibility for such large differences in success rates

between self-management reports and the interventional studies is

that subjects in most of the interventional studies are selfselected and do not represent the self-abuse population. This

point is made emphatically by Schachter (1982) and by Rzewnicki

and Forgays (1985), for smoking and obesity, and by Taylor et al.

(1982) for alcoholism. Indeed, the studies of Schachter and

Rzewnicki and Forgays made use of at least 90 percent of the total

population of their subjects and thus can be seen to represent

well those limited populations. More studies with entire populations should be undertaken to assess better the distortion factor

involved in self-selected samples.

A second possibility is that subjects in the interview studies of

Schachter (1982) and Rzewnicki and Forgays (submitted for publication) may have made several attempts at self-management before

attaining success, while intervention seekers are making only a

single attempt, at least in the study proper. Multiple attempts,

especially of motivated self-managers, may be more successful than

a single attempt, especially one that is other-directed.

A third possibility is that the interventional programs that have

been employed to date have been ineffective and may even have

47
suppressed change which might have taken place otherwise. This

point will be elaborated shortly.

Thus, if a great number of persons are able to manage many of

these addictive behaviors, largely on their own, we have probably

erred in our research by focusing on the hardcore, intransigent,

and largely self-selected subjects in our interventional studies

and ignoring those who have “cured” themselves. To focus on the

successful may throw light on important subject characteristics,

intervention designs that may be promising, and prevention possibilities. In my laboratory, we have adopted this approach in

ongoing studies of smoking and obesity and are just beginning

similar pilot studies on alcohol and drug abuse.

PERSONALITY CHARACTERISTICS OF SELF-ABUSERS

It is an intriguing notion that self-abusive behaviors occur in

persons who have specific personality characteristics. If this is

so, then information on personality characteristics may point the

way to better design of intervention and prevention programs. Is

there evidence for such relationships? The answer to this question seems to be a resounding "yes" with respect to smoking, a

less vigorous "yes' with respect to alcohol and drug abuse, and an

“I don't know" with respect to obesity.

Lilienfeld (1959) has reported that cigarette smokers married more

often, moved more frequently, and changed jobs more often than

nonsmokers. Veldman and Brown (1969) found that smokers were less

well adjusted academically, socially, and physically than nonsmokers, but they state that their smokers did not appear to be

"neurotic." Using his own Personality Inventory on a large number

of middle-aged male subjects, Eysenck (1963) found that his Extraversion (E) scale was related to cigarette smoking, while pipe

smokers tended to be high on introversion (I). The Neuroticism

(N) scale was not related to smoking level, but those high on the

Neuroticism scale inhaled more deeply. The extraversion finding

was replicated by Smith (1970). In a most unusual study of the

use of maternity services in Britain, all infants born during a

particular week of the year were followed up every 2 years (Cherry

and Kiernan 1976). The Eysenck Personality Inventory was administered at the age of 16 years and smoking information obtained at

20 and 25 years of age. These authors confirmed the earlier finding of high extraversion scores for smokers, but also found that

smokers were reliably higher on the Neuroticism scale. The

neuroticism score was also related positively to the degree of

inhalation of smoke. All findings were true for both sexes. In

recent work following up his earlier studies, Eysenck (1980) again

found that smokers were higher than nonsmokers on the Extraversion

scale but that only his female subjects were higher on the Neuroticism scale. Smokers were also higher than nonsmokers on his new

Psychoticism (P) scale. While there are small differences in the

findings of several studies employing the Eysenck scales, the

principal findings appear to be robust.

48
Zuckerman (1979) reported mixed results with respect to the relationship between smoking and scores on his Sensation Seeking

Scales, with some studies finding higher sensation-seeking scores

but only for male smokers, not females; other studies found the

reverse. Zuckerman suggested that these mixed results might

reflect different motives for smoking--smoking for arousal might

occur in high sensation-seeking persons, while smoking to relieve

social tension might occur in low sensation-seeking persons.

Friedman et al. (1975) attempted to relate cigarette smoking to

myocardial infarction. They were not able to confirm a direct

relationship but concluded that smoking as a coronary risk factor

may vary with psychological status of the person.

The general picture of the relationship between smoking and personality characteristics has been summarized recently by Ashton

and Stepney (1982). Smokers tended to be high on Eysenck's scales

of Extraversion and Neuroticism. They tended to be high risk

takers, and have higher impulsivity and internal sensation

seeking. They also tended to be high on Eysenck's Psychoticism

scale, which may measure a dimension related to sensation seeking.

In general, heavy smokers are poorly integrated persons.

Only a small amount of information is available on the personality

characteristics of alcohol abusers. Schwarz et al. (1978) found

that sensation-seeking score in college-aged subjects was strongly

and positively related to alcohol use, while a measure of anxiety

was not. In these subjects, alcohol appeared to serve as a

"releaser" for normally restrained social behavior. Zuckerman

(1979) reported that persons with high sensation-seeking scores

were more likely to try any drug, including alcohol. He reported,

however, that alcoholics were not high scorers on his scale but,

rather, scored at their normal age levels. The differences

between these two reports may simply be the difference between

alcohol users and alcohol abusers, but they also suggest developmental differences which should be investigated in a longitudinal

design.

Are there unique personality characteristics of the drug abuser?

Sutker et al. (1978) reported that drug addicts as a group were

high on the Adjective Check List scales of Aggression and

Succorance. Zuckerman (1979) found that persons with high

sensation-seeking scores were more likely to try any drug than

persons with low scores. He reported that high sensation seekers

in both student and nonstudent groups were more likely to experiment with a variety of drugs, starting with marijuana. Sensation

seeking was found also to be related to drug use in college students by Galizio and Rosenthal (1983). A similar finding has been

reported by Khavari et al. (1977), who studied several hundred

male and female members of labor unions. They found that while

results depended upon the specific type of drug used, the use of

psychedelics was strongly associated with the need of their subjects to seek out new and often unconventional experiences. Other

findings were that marijuana users were different from users of

49
other drugs in that they seek social approval and display uninhibited modes of self-expression, while the use of other psychedelics was associated with higher manifest anxiety, tendencies to

seek out social stimulation, and extraversion, but not with

approval seeking or uninhibitedness.

Recent research on prediction of addiction behavior, including

alcohol abuse, has made use of the MacAndrew Scale (MacAndrew

1965; MacAndrew 1979; Rathus et al. 1980). This is an empirically

derived scale based on the Minnesota Multiphasic Personality

Inventory (MMPI). It appears to be a measure of impulsivity, risk

taking, high energy and activity, interest in excitement and

stimulation, and so on. The MacAndrew Scale reminds one of the

Sensation Seeking Scales and of Eysenck's Psychoticism scale.

Wisniewski et al. (1985) have found this measure to be the best

single predictor, as compared with a variety of sociodemographic

variables, of alcohol and drug use for both male and female

subjects.

The picture emerging in these studies appears to be that of a

personality profile in which important characteristics are shared

by self-abusers of tobacco, alcohol, or illegal drugs. The profile is one of high extraversion, probably some neuroticism, high

impulsivity, high risk taking, and a strong need to seek out new

and unconventional experiences. There are likely to be sex,

developmental, and social-class differences within this generic

profile.

The familiar chicken-egg issue permeates these relationships. Do

persons having this profile gravitate to abusing situations or

does abuse lead to the expression of the profile characteristics?

The literature has too little data on this issue. However, the

Cherry and Kiernan (1976) research is quite clear on the matter

with respect to smoking. Personality measures at age 16 and smoking measures at ages 20 and 25 showed that potential smokers had

high extraversion and neuroticism scores before they took up

smoking. Thus, it appears that we may be able to predict later

self-abusive behavior from earlier personality measures.

PERSONALITY CHARACTERISTICS AND CHANCE POTENTIAL AMONG

SELF-ABUSERS

If self-abusers share some personality characteristics which exist

before the self-abuse, it would be interesting to know whether

personality characteristics can also be related to the ability of

an abuser to reduce or stop the abuse. While most such evidence

exists for smoking, some does relate to alcohol and drug use.

Some of the smokers in the Cherry and Kiernan (1976) study had

given up smoking by the time they were 25 years of age. What were

they like? In general, they were extraverts who did not smoke at

a high daily level. Specifically, male extraverts who were stable

on the Neuroticism scale and who smoked at a low level were most

likely to give up smoking; 47 percent of this group were able to

50
do so by age 25. This proportion drops to 2 percent for the neurotic introverts who smoke at a high level.

Friedman et al. (1979) compared ex-smokers, continuing smokers,

and nonsmokers in a large number of white and black male and

female members of a health maintenance program. As compared with

continuing smokers, smokers who quit had fewer cardiovascular

symptoms, smoked fewer cigarettes for a shorter time, inhaled

less, were better educated, consumed less alcohol, and differed on

several other physiological indices. On a measure derived from

the MMPI (not described well in the article), quitters and never

smokers scored lower than the persistent smokers. The answers of

quitters in the 155 items on this scale were not like those who

later developed myocardial infarction. The authors conclude that

quitters are more analogous to never smokers than to persistent

smokers on several of their indices, including their personality

measure.

In his recent book, Eysenck (1980) reports his own data on never

smokers, persistent smokers, cured smokers, and failed smokers,

using his Eysenck Personality Questionnaire (EPQ) measure. He

found significant differences among these four groups on the

Psychoticism, Extraversion, and Neuroticism scales, but not on the

Lie scale. There were no reliable sex by group interactions. If

his data are combined across the sexes, the personality measures

for the four groups are as follows:

Those who never smoked have middle values on the Psychoticism

scale, middle values on the Extraversion scale, and low values

on the Neuroticism scale.

Those who persist in smoking have high values on the P scale,

quite high on E, and quite high on N.

Those who try but fail to quit smoking have the highest P

scores, the highest E scores, and the highest N scores of the

four groups.

Those who quit smoking have the lowest P scores, lowest E

scores, and somewhat elevated N scores.

Two relationships stand out in these data. The first is that

persistent smokers and failed smokers are similar in their profiles on this measure and score highly on all three scales, with

the failed smoker scoring somewhat higher than the continuing

smoker who does not try to stop. The second is that the cured

smoker is similar in profile to the never smoker, with the never

smoker being somewhat higher on the P and E scores and the cured

smoker being somewhat higher on N.

A recently completed smoking intervention study provided heavysmoking subjects with flotation relaxation in various time distributions, with or without messages that were attempts to modify

their attitudes about smoking (Forgays, in press). There were two

51
waiting-list control groups; one received the messages over the

telephone and the other did not. All subjects took a battery of

personality tests before active intervention, and each was followed for over a year to see whether or not any changes in smoking

behavior had taken place. We found, at l-year followup, that our

relaxation groups had reduced their smoking behavior to an extent

considerably greater than that most frequently found in the smoking intervention literature. To our surprise, however, we found

that our control subjects had reduced their smoking even more,

especially the group that had the least contact with us. Since we

found that there were quitters in each of the study groups, persons who had reduced smoking appreciably, and subjects whose smoking patterns were unchanged, we decided to compare these three

groups on the various personality measures. Remember that each of

these new groups represents all six groups of the original study.

The personality measures we employed included the Eysenck Personality Inventory (EPI), the Sensation Seeking Scales (SSS), the

Spielberger Trait Anxiety Scale, the Manifest Anxiety Scale, the

Rotter Locus of Control measure, the Jenkins Activity Scale,

Oerogatis' Symptom Check List-90, and Morris' Ways-to-Live

measure.

In comparing the cures with the reducers with the persistent

smokers, the following profile emerged:

On the EPI, the cures were somewhat higher, though not reliably

so, on the Extraversion scale, but were reliably higher on the

Neuroticism scale than were the reducers and the continuing

smokers.

On Zuckerman's SSS, the cures and the reducers were reliably

higher than the persistent smokers.

On the Spielberger Trait Anxiety Scale, the cures scored higher

anxiety than the continuing smokers.

No reliable differences were found on the Manifest Anxiety

Scale, but the cures showed more anxiety than the reducers, who

in turn showed more anxiety than the continuing smokers.

Average scores for the three groups of subjects were about the

same on the Locus of Control measure.

On the Jenkins Activity Scale, reliable differences placed the

cure subjects in the direction of Type A (63 percent score),

reducers about average (44 percent), and persistent smokers in

the direction of Type B (34 percent). Let me emphasize that

cures are not Type A and continuing smokers Type B. The scores

are not that extreme, but they are significantly different in

these directions.

On the Symptom Check List-90, the cure group is reliably less

stable, more somatic, more obsessive-compulsive, and more

52
anxious than the other two groups, and the reducers tend to

have more of all these characteristics than the continuing

smokers. Again, I wish to emphasize that these scores are not

that extreme; that is, the cures are not emotionally disordered, but they are notably different from the other

subjects.

On the Morris Ways-to-Live measure, the cure group displays a

low self-sufficiency pattern but also a high attraction to many

different ways to live their lives, compared with the other two

groups.

Based on this study, then, the general personality profile of

cured smokers is that they tend to be somewhat emotionally unstable, score in the direction of Type A, and are somewhat more

anxious than the persistent smokers. They are more obsessivecompulsive, have more somatic complaints, are less secure, are

more independent of others in making decisions, and like to do new

and different things more than do the continuing smokers. The

reduced smokers tend to be in between the cures and the persistent

smokers on most of these dimensions.

For alcohol abusers, the data are more sparse. McGovern and

Caputo (1983) report that the most significant predictor of treatment outcome for inpatient alcohol detoxification is the locus of

control score. Internalizers on this scale tend to be more

successful than externalizers in treatment outcomes. This finding

would appear to be in accord with the review findings of Craig

(1979).

In an interesting study, Hurlburt et al. (1984) compared Alcoholics Anonymous members with nonmembers who were alcoholics, on

Eysenck's EPQ scale. They found that members were higher on the

Extraversion scale, but lower on the Neuroticism and Psychoticism

scales.

Billings and Moos (1983) studied psychosocial processes of recovery among alcoholics and their families. They found that

patients who controlled their drinking showed improvements in

nondrinking aspects of their functioning, and members of their

families showed improved adjustment as well. These recovered

families were comparable to matched nonalcoholic families in

posttreatment functioning. The relapsed alcoholics and their

families suffered from multidimensional impairments. While they

did not report on personality measurement as such, it seems clear

from their data that the coping behaviors and social resources of

these controlled alcoholics and their families, as well ,as the

environmental stressors impinging on them, had as much influence

on the recovery process as the treatment experiences.

There is little information on sensation-seeking scores of recovered vs. relapsed alcoholics. Zuckerman's (Zuckerman 1979) finding of average SSS scores for alcoholics would not predict such

differences, perhaps, but study of the various alcohol groups,

53
nonuser and abuser, failed and cured, should be undertaken with

this instrument.

Data on the personality characteristics of drug users and nonusers, ex-users and failed users, are sorely lacking. Designs of

the sort described above in the smoking change studies should be

undertaken as soon as possible.

While many gaps exist in the data on change of abusive behavior,

the studies described at least suggest strongly that personality

characteristics are involved in the process.

PERSONALITY CHARACTERISTICS AND THE STAGES OF SELF-ABUSE

AND CHANGE

One of the difficulties encountered in the past in attempting to

relate personality measures to self-abusive behavior may be the

tendency to ignore the possibility that different personality

dimensions relate to different stages of abuse. In other words,

the kinds of factors that lead to abuse may be somewhat different

from those conducive to maintenance behavior, which again may be

different from those associated with later change. The picture

may be a delicate one, bludgeoned with simplistic research designs

and a quest for a magic bullet; i.e., uniform treatment plans for

substance abuse problems.

For example, Cherry and Kiernan (1976) found that neurotic extraverts would be more likely to start smoking cigarettes, while stable extraverts would be more likely to stop smoking. Ashton and

Stepney (1982) suggested that peer influence was very important in

starting to smoke but that other factors, largely personality

ones, were related to stopping. Keup (1982) reported that sociological reasons (friends, relatives, and media influence) and

psychological reasons (curiosity, enjoyment, novelty, escape)

accounted for virtually all the initiation of drug abuse in the

subjects he studied. Sadava and Forsyth (1977) found that

initiation to cannabis use was largely due to social variables,

including social support, sibling models, and the like, while

personality variables were largely responsible for the user's

stopping the abuse. They found that subjects who were able to

stop were less conforming and more independent and that social

variables were not important. Social factors regain their importance in relapses to drug use which may occur.

Admittedly, the information above is only suggestive. However,

it suggests the possibility of differential dynamics related to

initiation of abuse, perhaps to maintenance of the abuse, and to

later change. Research designs in the future should take these

distinctions into account, especially in investigations of

personality characteristics related to abuse pattern.

54
INTERVENTION, PREVENTION, AND FURTHER RESEARCH

Does the analysis provided suggest intervention, prevention, and

further research programs which might be applied to self-abusive

behavior? I believe it does.

In planning therapeutic interventions for such behaviors, we

should take the personality characteristics of the clients into

account. Zuckerman (1979) suggested that we take sensationseeking score into such account. Cherry and Kiernan (1976) stated

that the practical use of their data would include the possibility

of allocating clients to different types of smoking clinics. Our

own research and that of Eysenck (1980) suggests that matching of

client to interventional program will likely be a more successful

procedure than attempts to provide a uniform program for all

comers; The possible mismatching provided in past interventional

programs may be responsible, in part, for the mixed results

obtained. It is possible that, under these circumstances, therapeutic intervention may be actually inhibitory for some clients,

or perverse, as Schachter (1982) has called it.

For prevention programs, again the key word is matching of campaign to type of subject, following the logic that a uniform

program may not be meaningful for subjects with different personalities. Cherry and Kiernan (1976) have proposed that their kinds

of results should be incorporated in the design of antismoking

propaganda. Zuckerman (1979) has suggested that sensation-seeking

score might lead us to provide choices for high sensation seekers

other than drugs or crime; such choices might provide unusual

experiences in occupations or entertainment avenues. Indeed, it

might be less expensive to send kids to Disneyland than to provide

high-level therapy programs, especially if they do not work.

To take such a view of prevention is to bend the disease model

followed lately. Rather than await the display of self-abusive

behaviors and then jump in with therapeutic attempts to "cure the

disease," we should, perhaps, consider a prevention paradigm,

whether the inoculation is socially or physiologically based.

For research, I propose an epidemiological approach to these

issues. For each abusive behavior, we should study those who have

the behavior, and those who do not have it; those who have changed

the behavior, with and without intervention; and those who have

failed to change it. We should certainly pay as much attention to

the cases of success as to the failures. And we should emphasize

and measure carefully individual differences among subjects, as

Eysenck (1981) has recently pointed out. We should attend to the

time course of self-abusive behavior and should break down our

analyses into the initiation, continuance, and change stages. All

of this should be done in carefully controlled studies.

Nothing said here precludes the inclusion of a variety of physiological measures. There must be physiological substrata to these

behaviors, whether correlative or causal, and these substrata

55
should be investigated. Neither has anything been said that precludes the possibility of important genetic contribution to the

development of such behaviors, likely through the influence of

physiological processes that may underlie specific personality

characteristics.

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AUTHOR

Donald G. Forgays, Ph.D.

Department of Psychology

University of Vermont

Burlington, VT 05405

58
Sensation Seeking and the

Endogenous Deficit Theory of

Drug Abuse

Marvin Zuckerman

INTRODUCTION

Sensation seeking is a personality trait that is central to an

understanding of the biological disposition toward drug abuse.

The general definition of the trait is:

the need for varied, novel, and complex sensations and

experiences and the willingness to take physical and

social risks for the sake of such experience.

(Zuckerman 1979, p. 10)

The most frequent reasons given by users of many drugs, including

marijuana, narcotics, and hallucinogens, were "to experience something new" or "curiosity" (Segal et al. 1980). Thus, the primary

motive given by the drug users themselves sounds like the trait we

have called "sensation seeking." More important, sensation seeking has been shown to be the personality trait that is most

consistently and highly related to most types of drug use and is

most highly discriminating in comparisons of drug abusers with

control populations (Kilpatrick et al. 1976; Segal et al. 1980;

Zuckerman 1972; Zuckerman 1979; Zuckerman 1983a). Furthermore,

sensation seeking is based on a psychobiological theory that

offers a psychopharmacological model for the biological basis of

the trait (Zuckerman 1979; Zuckerman 1983a; Zuckerman 1984a;

Zuckerman et al. 1983b). Together with traits like extraversion

and impulsivity, sensation seeking has been related to the enzyme

monoamine oxidase (MAO), which points to the role of central monoamine systems in the trait. MAO, in turn, has been related to

drug use and other risk-taking activities. All these topics will

be addressed in more detail in this paper.

THE SENSATION SEEKING SCALES (SSS)

The first published form (II) of the SSS contained only a General

scale, based on a factor analysis of a broad variety of items

written to fit the hypothesized trait (Zuckerman et al. 1964).

59
The second versfon, form IV (Zuckerman 1971), based on more extensive factor analyses, contained four subscales:

(1) Thrill and Adventure Seeking (TAS): The desire to try risky

sports or activities involving elements of speed, movement,

and defiance of gravity.

(2) Experience Seeking (ES): The desire to seek experience

through the mind and the senses; through music, art, travel,

and an unconventional style of life with unconventional

friends.

(3) Disinhibition (Dis): The desire for or actual enjoyment of

uninhibited and socially extraverted activities, e.g.,

parties, social drinking, and a variety of sexual partners.

(4) Boredom Susceptibility (BS): A strong aversion to monotony

or a lack of change, and a preference for the unpredictable;

restlessness in confining, dull conditions.

Forms IV and V contain scales based on these factors. Form IV

also contains the General scale carried over from form II. Form V

(Zuckerman et al. 1978) contains a balanced scale of 10 items

representing each of the factors and a Total score based on all 40

items. Form VI (Zuckerman 1984b) contains only TAS and Dis scales

arranged in two sections: one dealing with past experience in

sensation-seeking activities, and the other with intentions for

future activities.

The many studies establishing the reliability and validity of the

SSS have been summarized elsewhere (Zuckerman 1978; Zuckerman

1979; Zuckerman 1983a; Zuckerman 1984a). The SSS have been related to a wide variety of risk-taking activities and a preference

for novelty, complexity, and intensity in cognitive styles, art,

music, reading, and media presentations. Biological correlates

have been found in psychophysiological and biochemical phenomena

(Zuckerman et al. 1980), and a large twin study (Fulker et al.

1980) has shown a relatively strong genetic determination for the

trait.

Sensation seeking has been correlated with many other personality

traits (Zuckerman 1979) including locus of control. Few significant relationships have been found between the SSS and locus of

control in college student populations. In patient and prisoner

groups the ES, Dis, and BS scales have shown positive relationships with the Locus of Control scale, indicating that high sensation seekers of these types tend to believe in an external locus

of control. Of course, in prisoners and hospitalized patients

this belief would be quite realistic in terms of their current

situations.

60
SENSATION SEEKING AND DRUG ABUSE

Previous articles have reviewed the area of sensation seeking and

drug and alcohol use (Zuckerman 1972; Zuckerman 1983b). Since two

of the SS scales contain some reference to drug use (ES and Dis),

correlations with these scales alone would be suspect. But in an

early study (Zuckerman et al. 1972), drug use correlated with the

General and all the subscales in college females, and with all but

the Dis scale in males. The Dis scale correlated with the extent

of alcohol use in both sexes. Segal et al. (1980). using large

samples of 1,095 college students and 350 naval personnel, found

the ES and Dis scales to be the most highly predictive of drug use

compared to other personality scales, including the Locus of

Control scale. The ES scale was consistently the best predictor

in all analyses in the college groups; the Dis scale was the best

one in two of the three Navy groups. The drug-relevant items had

been removed from the SSS before analysis so that the results

could not be attributed to content confounding. Findings with the

Locus of Control scale were inconsistent from sample to sample,

and differences between groups were small.

Kilpatrick et al. (1976) compared nonusers, occasional, and regular users of alcohol and/or drugs in hospitalized veterans. A

variety of personality trait measures were used, including the

Locus of Control scale. As in the Segal et al. study, the SS

scales, particularly ES, Dis, and BS, were by far the best concurrent predictors of regular drug use. The Locus of Control

scale did not differentiate among the groups.

Specific Drug Use

According to the earlier optimal level theory (Zuckerman 1969),

sensation seekers should be more prone to use drugs of all types;

among drug users, the higher sensation seekers should prefer drugs

that stimulate high cortical arousal levels rather than drugs that

depress arousal. In the Zuckerman et al. (1972) study, high sensation seekers were distinguished from mediums and lows on use of

marijuana, hashish, amphetamines, cocaine, and LSD, but not on

barbiturates, opium, heroin, demerol, morphine, or tranquilizers.

Khavari et al. (1977) found that the SSS correlated with use of

marijuana. hashish, and LSD in members of a labor union. However,

there were not many users of heroin in these groups. Kaestner et

al. (1977) discovered that sensation seeking was related to variety of drugs used by former drug abusers but not to the specific

drugs used. Carrol and Zuckerman (1977) found low but significant

positive correlations between use of stimulants and hallucinogens

and the Dis scale in a former drug abusing group, in contrast to a

lack of correlation with use of depressant drugs. Skolnick and

Zuckerman (1979) compared hard drug (mostly heroin) and soft drug

(polydrug including stimulants) users and found that the soft drug

users scored higher on SS scales. Despite these findings showing

some relationship between sensation seeking and a preference for

stimulant drugs, other findings suggest that young heroin users

are high sensation seekers relative to their peers (Platt and

61
Labate 1976) and that high and low sensation seekers do not react

differently to stimulant and depressant drugs (Carrol et al.

1982). However, results on the biological bases of sensation

seeking (Zuckerman et al. 1980) have led to a new model for the

trait that goes "beyond the optimal level of arousal" of the

cortex and suggests that drugs are used because of their effects

on neurotransmitters whose activity at moderate levels is

rewarding (Zuckerman 1979; Zuckerman 1983b; Zuckerman 1984a).

BIOCHEMICAL CORRELATES OF SENSATION SEEKING

Gonadal Hormones

Sensation seeking, particularly on the TAS and Dis scales, shows

consistent age and sex differences: males are higher than females, and scores on these scales decline with age (Zuckerman et

al. 1978; Zuckerman and Neeb 1980). These data suggested that

high sensation seekers might have higher levels of testosterone

than lows, even within sexes. Daitzman et al. (1978) found positive correlations between the Dis scale and plasma androgen and

between the Dis scale and plasma estrogen as well, the latter an

unexpected finding. The findings were confirmed in a second study

(Daitzman and Zuckerman 1980), in which subjects were selected for

high or low Dis scores. The high Dis subjects were significantly

higher than low Dis subjects on plasma testosterone, 17-ß-estradiol. and estrone. Testosterone also correlated positively with

scales of sociability, impulsivity, and heterosexual experience,

and negatively with neuroticism scales. Estradiol loaded positively on a factor defined by social deviancy on the positive end

and social conformity at the negative end. Although measures of

drug use were not included in this study, one would predict that

among males drug use, like sensation seeking, would be related to

both testosterone and estradiol. The testosterone is related to

the normal impulsive extraversion, while the estradiol adds a factor of social deviance that may lead to antisocial activities.

Schalling et al. (in press) reported that plasma testosterone

correlated with scales of Monotony Avoidance (sensation seeking),

aggression, sociability, and preference for physical sports in a

group of delinquent boys.

Monoamine Oxidase (MAO)

MAO is an enzyme that regulates the three monoamine systems in the

brain. A low level of MAO, measured in blood platelets, has provided an interesting biological marker for various psychiatric

disorders, as well as showing significant relationships with personality and antisocial, risk-taking behaviors in humans, activity

levels in human neonates. and sociable and dominant behaviors in

humans and monkeys (Zuckerman et al. 1980). Low levels of MAO

have been found among chronic alcoholics and marijuana users, and

low MAO males in normal populations report using more drugs and

smoking more cigarettes than high MAO types (Coursey et al. 1979;

62
von Knorring and Oreland 1985; von Knorring et al. 1984). Platelet MAO is a stable and reliable measure, and one that shows

strong genetic determination in twin studies.

Six studies involving nine groups of subjects have reported correlations between MAO and the SSS. In all but one of these groups

the correlation was negative, and in six of the nine groups the

negative correlation was significant. There is a very large range

in the magnitude of the significant correlations, from -.06 to

-.66, and the median of the correlations is only -.25. However,

the unquestionable existence of the finding, despite the fact that

some of the studies were done in Sweden and Spain using translated

SS scales and different kinds of subject populations, is interesting. Four studies have been done involving six groups and

using the Swedish Monotony Avoidance (MAv) scale. All the correlations were negative, and three of the six were significant

despite the fact that the median correlation was only -.22. Four

of the samples involved depressed patients, and in three of the

four the negative correlation was significant.

It should not be surprising that the typical correlations between

biological and personality traits are low. Personality may be

affected by MAO in the brain, but we are measuring a marker in the

blood. The actual correlation between platelet and brain MAO is

not known, although MAO levels in different parts of the brain

correlate fairly highly. However, there must certainly be an

attenuation of the correlation between brain MAO and the sensation-seeking trait. Even though the platelet MAO measure is fairly reliable, there is some change, as there is for the personality

measure. Above all, it would be foolish to expect that a complex

personality trait would be determined solely by a single brain

enzyme. MAO is one element in at least three complex neurotransmitter systems. While it may have some influence on the

activities of these systems at any given time, there are other

enzymes, receptors, and interactions between the systems themselves that would also be affecting the activity in each of the

systems. The wonder is not that the correlation is low, but that

it exists at all. What low MAO may indicate is that one of the

factors that stabilize the neurotransmitter systems related to

behavioral arousal (dopaminergic and noradrenergic systems) is in

deficit; therefore, we might expect large fluctuations in behavior

and mood and a failure of negative feedback mechanisms to control

these. One example is the bipolar or manic-depressive disorder

for which sensation seekers are at risk (Zuckerman 1985). The MAO

findings point to the monoamine systems as being involved in sensation seeking and related traits such as impulsivity. Studies

have just begun which generally use metabolites of the brain

neurotransmitters: norepinephrine, dopamine, and serotonin.

These few studies will be discussed next.

63
Monoamines and Their Metabolites

One of the effects of stimulant drugs such as amphetamine and

cocaine is a potentiation of the catecholaminergic systems

(dopamine and norepinephrine) in the brain. The euphoria and

energy that is initially produced by these drugs may be a function

of the increased activity in these systems and their activating

effects on the cortex. The opiate drugs undoubtedly act on the

opiate receptors, which normally respond to the endogenous opiates

(endorphfns) in the brain. Could the attraction of these drugs

lie in the normal state of the systems that they act upon? I will

return to this question later. First, let us examine the evidence

relating sensation seeking and other traits to the monoamines.

A study by Ballenger et al. (1983) examined the relationships of a

wide range of biochemical variables to normal and abnormal personality traits, including sensation seeking, in a group of screened

normal subjects. Age and body size (height and weight) were controlled through the partial correlation method. Sensation seeking

was negatively correlated with plasma dopamine-beta-hydroxylase

(DBH) and norepinephrine (NE) in the cerebrospinal fluid (CSF) in

males and females and in the total group. The negative correlation with DBH was found in two other studies (Kulcsar et al. 1984;

Umberkoman-Wiita et al. 1981). Both the DBH and NE findings would

indicate underactivity in the noradrenergic system in high sensation seekers, since DBH is the enzyme involved in the conversion

of dopamine to NE in the NE neuron.

Schalling et al. (1984) concentrated on CSF metabolites of serotonin (5-HIAA), dopamine (HVA), and norepinephrine (MHPG) in their

study of the relationships between monoamines and personality

traits in normals and patients. The serotonin metabolite, 5-HIAA,

correlated negatively with Eysenck and Eysenck's (1975) P scale in

the normal and two of the three patient groups. Although the

Eysencks have used the term "Psychoticism' to describe what this

scale measures, some factor analyses that we have completed

recently suggest that the P factor reflects unsocialized and

impulsive, sensation-seeking tendencies. If one wants to use a

diagnostic label for the scale, "Psychopathy" might be a better

one than Psychoticism. Persons scoring at the extreme on this

scale are liable to engage in unconventional and sometimes antisocial activities and would be expected to be among those experimenting with illegal drugs. The fact that high P scorers in the

normal and patient populations tend to be low in serotonin is

interesting in view of the clinical and comparative data. Low 5-

HIAA levels have been found in the brains of those committing

suicide and in the CSF of those attempting suicide, particularly

when the attempts are violent in nature (Lidberg et al. 1985).

Low levels of the metabolite have also been found in impulsive

murderers. The animal literature on serotonin depletion suggests

that serotonin serves to inhibit behavior in conflict or frustration situations. A deficit in serotonin is associated with impulsivity and a failure to inhibit behavior even in the face of

anticipated punishment. Remembering the definition of sensation

64
seeking as the "willingness to take risks," one might expect the

Monotony Avoidance scale to be related to 5-HIAA. It was negatively related to 5-HIAA in all three patient groups, but the correlation was not significant in the normal group. The dopamine

and NE metabolites showed little relation to personality in this

study, although the dopamine metabolite, HVA, correlated negatively with P and showed some low negative correlations with Monotony

Avoidance, as did MHPG.

A third major study, done at the Autonomous University of

Catalonia (Arque et al. 1985), used only indices available from

blood, but one of these, plasma MHPG, is regarded as a fair indicator of central noradrenergic activity. This measure correlated

negatively with Total, ES, and Dis SS scales in a normal group,

but not in a somatoform patient group. Although these findings

are consistent with the negative CSF-NE vs. SSS correlation in the

Ballenger et al. (1983) study, that study also used plasma MHPG

but found no significant correlations between this measure and SS

scales.

Endorphins

In a prior section, I commented on the fact that young heroin

users were also high sensation seekers, relative to their delinquent peers. There are greater risks entailed in heroin use than

in most other types of drugs. The legal penalties are more.

severe, and the expense of supporting a strong habit usually

necessitates criminal activity. Most users are aware of friends

who have "OD'd" (overdosed) and died as a consequence. Perhaps

the high sensation seeking in heroin users simply reflects the

greater readiness to assume the risks entailed in the search for

the sensations of euphoria. As tolerance develops, the high

euphoria of the "rush" is harder to achieve, and the user may

settle for the modest but more prolonged euphoria of the "nodding." Since the opiates act on endogenous opiate receptors, it

is possible that a lack of endogenous opiates, or endorphins, may

make exogenous opiates particularly attractive to those with such

a biological disposition. This possibility makes the levels of

endorphins in sensation seekers a matter of interest in explaining

why sensation seekers might abuse drugs whose primary effects are

depressant rather than stimulant. Stein (1978) and others have

suggested that there are two types of reward mechanisms in the

brain: arousal reward associated with activity of the catecholamine systems, and arousal reduction reward related to the

endorphin systems.

A study by Johansson et al. (1979) reported significant negative

correlations between CSF endorphins and two of the SS scales, Dis

and BS, suggesting that those high on these more antisocial kinds

of sensation seeking might suffer from a lack of endogenous

opf ates . However, the finding was not in drug abusers but in a

sample of patients suffering from chronic pain of either a psychogenic or organic origin. The study by Ballenger et al. (1983) in

non-drug-abusing normals failed to find any relationships between

65
sensation seeking and either endogenous opiates or beta-endorphin.

Studies of levels of endorphfns in former heroin abusers, who are

currently drug free, would be illuminating.

Other Biochemical Findings

Two new findings have recently emerged from the study by Arque et

al. (1985). Thyroid-stimulating hormone (TSH) was negatively correlated with Total SSS in both normals and somatoform patients.

The implication of this finding might be a high level of thyroid

hormone in high sensation seekers or a low level of the hormone in

low sensation seekers. These investigators did find a significant

positive correlation between T4 and the TAS scale in normals, but

not in patients in whom the correlation was low and negative.

Reexamination of unreported data in the Ballenger et al. (1983)

study revealed significant negative correlations between T4 and

both the TAS SS scale and the Eysenck Extraversion scales.

The Spanish investigators (Arque et al. 1985) also found significant negative correlations between acetylcholinesterase (ACH) in

both normals and patients. Acetylcholine systems in the brain

have been associated with arousal mechanisms, aggression (muricidal) in rats, and depression in bipolar affective disorders.

Physostigmine, a potent cholinesterase inhibitor, is reported to

ameliorate manic symptoms (Janowsky et al. 1972). ACH terminates

activity in the cholinergic system at the postsynaptic membrane.

A deficit of ACH in high sensation seekers might have some role in

the relationship of the trait to bipolar disorder and manic

behavior.

These preliminary findings may be signs that we must look beyond

the monoamine systems for a full explanation of the sensationseeking trait.

ENDOGENOUS DEFICIT THEORY OF DRUG ABUSE AND SENSATION SEEKING

It is interesting that most of the correlations between sensationseeking and neurotransmitters and neuroregulators are negative in

sign. In my Behavioral and Brain Sciences article (Zuckerman

1984a), I suggested that sensation seekers might seek stimulant

drugs because they are low in tonic catecholamine system activity

and need such drugs to bring this activity up to an optimal level

where they feel and function best. The significance of the low

MAO levels in sensation seekers and bipolar disorders, as well as

in impulsive personalities (Schalling and Asberg 1985), may be a

lack of regulation in monoamine systems leading to a positive

feedback of sensation-seeking behavior. The low sensation seekers

may have a strong biochemical negative feedback which would dampen

sensation-seeking activity if it ever got started.

66
NEW METHODOLOGIES AND THEIR POSSIBILITIES

I have noted how limited the current methodologies are in answering the questions concerning neurotransmitter actions in the brain

from levels of peripheral transmitters and metabolites. The new

developments in Positron Emission Tomography (PET) offer the

possibility of observing the activity of these systems in vivo in

the brain. Haier (1985) has already reported some preliminary

findings using the PET scan on persons given the Sensation Seeking

and other personality scales. Future research using neurochemically selective emission tomography could answer many of the

questions that have been raised about the link between sensatfon

seeking and drug abuse. Such research is expensive, but the

payoff--a basic understanding of what motivates people to derange

their neurons with potentially damaging substances--may be well

worth the price.

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25. New York: Academic Press, 1984 pp. 391-436.

AUTHOR

Marvin Zuckerman, Ph.D.

Department of Psychology

University of Delaware

Newark, DE 19716

70
Control Vs. Lack of Control Over

Aversive Stimuli: Nonopioid-Opioid

Analgesic Consequences

Robert C. Drugan and Steven F. Maier

INTRODUCTION

It is now well established that the behavior, physiology, and

stress pathology resulting from experience with noxious stimulation is markedly dependent upon the organism's control vs. lack of

control over the aversive event. The initial finding of differential impact of controllable vs. uncontrollable electric shock

was demonstrated by Seligman and Maier (1967). Subjects that were

unable to control an environmental stressor such as electric shock

showed many deleterious effects of the stress experience. Conversely, if the subjects were able to control or "cope" with the

stressor, then none of these stress pathologies were observed,

The concept of control can be characterized as the ability, or

lack of ability, to alter the onset, termination, duration, intensity, or pattern of an aversive experience. In the experiments

reported here, control over shock was accomplished by allowing the

subject to turn a wheel in the behavioral chamber in order to

terminate shock.

BEHAVIOR AND STRESS CHANGES PRODUCED BY INESCAPABLE SHOCK

The many stress pathologies or deficits observed following exposure to inescapable but not escapable shock have been referred to

as "learned helplessness" effects (Seligman and Maier 1967; Maier

and Seligman 1976). These deficits include: failure to learn to

escape shock in a different situation where escape is indeed possible (Seligman and Maier 1967; Maier and Seligman 1976), subsequent inactivity in the presence of shock (Anisman et al. 1978;

Drugan and Maier 1982; Drugan and Maier 1983; Jackson et al.

1978), reduced aggressiveness and dominance in a variety of situations (Maier et al. 1972; Payne et al. 1970; Powell and Creer

1969; Rapaport and Maier 1978), enhanced susceptibility to growth

of implanted tumors (Sklar and Anisman 1979; Visintainer et al.

1982), development of gastric ulcers (Weiss 1971), and immunosuppression (Laudenslager et al. 1983).

71
On a neurochemical level, inescapable but not escapable shock has

been shown to produce significant alterations in norepinephrine

(Weiss et al. 1981; Anisman and Sklar 1979), dopamine (Anisman et

al. 1981), serotonin (Sherman and Petty 1982), acetylcholine

(Anisman and Sklar 1979; Anisman et al. 1981), and GABA (Sherman

and Petty 1981). Alterations in all of these neurotransmitters

have been proposed to be important in the production of inescapable shock-induced deficits.

CONTROLLABILITY OF SHOCK AND NONOPIOID/OPIOID STRESS-INDUCED

ANALGESIA

Recently, much interest has focused on the reduction in pain

responsiveness following exposure to noxious environmental stimuli

such as electric shock, cold water swim, and restraint. This

phenomenon has been termed stress-induced analgesia (SIA) and has

been reviewed previously (Amir et al. 1980; Bodnar et al. 1980;

Chance 1980; Watkins and Mayer 1982). SIA has been demonstrated

to be either nonopioid or opioid in nature. For example, under

certain circumstances, the analgesic reaction that followed stress

was reversed by opiate antagonists (Amir and Amit 1978; Chesher

and Chan 1977) and was cross-tolerant with morphine (Chesher and

Chan 1977), while in other situations reversal by opiate antagonists and cross-tolerance with morphine did not occur (Bodnar et

al. 1978; Hayes et al. 1978). These different reports of opioid

vs. nonopioid SIA suggested that both opioid and nonopioid systems

were involved in mediating SIA, with some aspect of the stressor

determining which form occurred (Grau et al. 1981; Lewis et al.

1980; Maier et al. 1982; Lewis et al. 1981).

Critical factors modulating the appearance of either opioid or

nonopioid SIA have included continuity vs. intermittency of stress

(Lewis et al. 1980), intensity of the stressor (Terman and

Liebeskind 1983), type of stressor (Bodnar et al. 1978), and part

of the body shocked (Watkins et al. 1984). Also, the controllability/uncontrollability of the stressor has been shown to be a

critical factor in determining the form of SIA observed following

a stressor. Both escapable and inescapable shock led to SIA

shortly following exposure to stress, but only the SIA resulting

from inescapable shock was sensitive to blockade by opiate antagonists (Hyson et al. 1982). Furthermore, a brief exposure to

shock, itself insufficient to produce SIA, resulted in an analgesic reaction in subjects given inescapable shock 24 hours earlier

(Jackson et al. 1979). It appears that the subjects remained in a

"sensitized state" for at least 24 hours following uncontrollable

stress. Equal amounts of controllable or escapable shock did not

lead to such a reinstatable analgesia (Jackson et al. 1979).

Significantly, this reinstated analgesic reaction produced by inescapable but not escapable shock was completely blocked by opiate

antagonists (Maier et al. 1980) and was cross-tolerant with morphine (Drugan et al. 1981).

Due to the differential effects of escapable vs. inescapable shock

on long-term SIA, an important question is whether any differences

72
in pain responsiveness occur during the initial exposure to the

stressor in the two groups. Drugan et al. (1985c) observed the

analgesic time course during either 80 escapable or inescapable

shocks of identical intensity and duration (figure 1).

FIGURE 1. Mean tail-flick latency for subjects receiving either

saline or naltrexone (14 mg/kg) 30 minutes prior to

80 escapable or inescapable shocks

Inescapably shocked subjects showed a "double peak" pattern of

analgesia, confirming the prior findings of Grau et al. (1981).

Escapably shocked subjects also exhibited this biphasic pattern of

antinociception after 20 and 80 shocks. However, pretreatment

with the opiate antagonist, naltrexone, completely blocked the

inescapably shock-induced analgesia at 80 shocks, while leaving

the escape analgesia completely intact. Thus, escapable and

inescapable shock exposure resulted in an early nonopioid analgesia following 20 shocks which dissipated rather quickly and was

subsequently observed as either a nonopioid or opioid analgesia at

80 shocks for escapably or inescapably shocked subjects respectively.

Until recently, the time course of the analgesia following escapable and inescapable shock had not been studied extensively.

Maier et al. (1982) demonstrated that at 30 minutes postshock the

escapable shock analgesia returned to control levels, while the

inescapable shock analgesia was still present. A more detailed

time course of analgesia has since been conducted by Drugan et al.

(1985c). Following 80 shocks, the subjects receiving escapable

shock showed a very transient analgesia which returned to preshock

baseline levels after 10 to 20 minutes, while subjects receiving

73
inescapable shock remained analgesic for at least 2 hours

(figure 2).

FIGURE 2. Mean tail-flick latency following 80 escapable or

yoked-inescapable shocks

Thus, the type (opioid vs. nonopioid) and longevity of the

analgesic response to shock was markedly different depending on

the animal's control over the stressor.

The fact that inescapable shock resulted in an opioid form of SIA

and enhanced analgesic responsiveness to systemic morphine (Grau

et al. 1981) suggested the possibility that this sort of stress

might affect other characteristics of opioid activity, especially

dependence. Of particular relevance is the fact that opiate

receptor stimulation resulted in dependence. This dependence

occurred if the opiates were endogenous or systemically administered (Miglecz et al. 1979). Withdrawal symptoms were evident

with time elapsed since administration of synthetic opiates or

upon challenge by an opiate antagonist. This phenomenon occurred

after acute or chronic opiate exposure (Wei 1981; Wei and Loh

1976). Therefore, inescapable but not escapable shock might be

expected to exacerbate withdrawal reactions in response to a

challenge of an opiate antagonist. Assessment of opiate withdrawal behavior required an injection of an opiate agonist (i.e.,

morphine) 30 minutes prior to a challenge by naloxone (Brase et

al. 1976). Naloxone by itself did not lead to behaviors indicative of withdrawal. Moreover, earlier exposure to morphine augmented the degree of withdrawal observed, an effect indicating

that a single morphine injection followed by naloxone challenge

was sensitive to earlier opiate stimulation.

74
The above procedure for precipitating withdrawal has proven to be

ideal for assessing whether prior inescapable shock facilitates

withdrawal behavior, possibly because the stress leads to endogenous opioid stimulation. We examined whether prior stress

influences precipitated morphine withdrawal and whether the controllability of shock is an important modulating factor (Williams,

Drugan, and Maier 1984). Subjects received 2 sessions of 80

escapable or inescapable shocks or restraint (no shock) separated

by a 24-hour period. Twenty-four hours following the second day

of pretreatment , all subjects received a subcutaneous injection of

morphine sulfate (5 mg/kg). After 30 minutes, subjects were

injected intraperitoneally with naloxone HCL (5 mg/kg); withdrawal

observations began 3 minutes later. The results of this

experiment are represented in figure 3.

FIGURE 3. Mean frequency counts of three withdrawal measures for

subjects given a SC injection of morphine (5 mg/kg)

followed by a naloxone challenge 30 minutes later

NOTE: Withdrawal testing was conducted 24 hours after two daily sessions of

escapable shock, yoked-inescapable shock, or restraint (no shock).

As can be seen, the inescapable shock group displayed a significant potentiatfon of morphine withdrawal. Conversely, subjects

receiving the identical amount of escapable shock did not exhibit

any increase in withdrawal behavior in comparison to nonshock controls. On this index of opiate withdrawal, the inescapably

shocked subjects demonstrated previous opioid stimulation, whereas

the escapably shocked subjects did not. Naltrexone administration

prior to shock was conducted in order to insure that this enhanced

withdrawal response of inescapably shocked subjects was due specifically to previous opioid stimulation. Figure 4 demonstrates

75
that the enhanced precipitated opiate withdrawal response can be

blocked by prior administration of the opiate antagonist,

naltrexone.

FIGURE 4. Mean frequency Counts of three withdrawal measures for

subjects given an injection of morphine followed by a

naloxone challenge 24 hours after two sessions of

escapable shock, yoked-inescapable shook, or

restraint

NOTE: Prior to both of the pretreatment sessions. subjects were injected with

either saline or naltrexone (14 mg/kg).

The dissociation of nonopioid/opioid activity in controllably vs.

uncontrollably shocked subjects is quite puzzling from a mechanistic point of view. Are the two analgesic systems aroused by

the different stress experiences separate and unrelated, or does

control over shock engage a system which opposes or suppresses the

activity of endogenous opioid processes? One way to answer such a

question would be to see if prior exposure to escapable or controllable shock would block the appearance of opioid SIA following

a session of inescapable shock. These behavioral "imnunization"

studies have been conducted, showing that prior experience with

controllable shock blocks both short- and long-term opioid analgesia observed following inescapable shock (Moye et al. 1981; Moye

et al. 1983). Moreover, a more recent study (Drugan et al.,

1985c) has shown that prior experience with a longer session of

either escapable or inescapable shocks (80 shocks) has very profound effects on a subject's analgesic responsiveness to a session

of 80 inescapable shocks 24 hours later (figure 5).

76
FIGURE 5. Mean tail-flick latency during 80 inescapable shocks 24

hours following a session of either escapable or

inescapable shock

NOTE: Thirty minutes prior to the inescapable shock on day 2, subjects received

an injection of either saline or naltrexone (14 mg/kg).

As can be seen in figure 5, prior experience with controllable or

escapable shock resulted in a brief, nonopioid analgesia after 5

and 20 shocks, which rapidly dissipated to control levels; the

typically observed opioid analgesia at 80 shocks is completely

abolished. However, prior exposure to uncontrollable or inescapable shock hastened the arrival of opioid SIA on the second day of

inescapable shock exposure. Instead of being observed at 80

shocks, the opioid SIA was now present at 40 shocks. Thus, prior

experience with controllable shock blocked, while prior uncontrollable shock hastened, the expression of opioid SIA. It appears

that control over shock engaged an active process that opposed the

activation of endogenous opioid processes in response to inescapable shock.

A POSSIBLE MECHANISM FOR THE PROTECTIVE EFFECTS OF CONTROL OVER

SHOCK

What mechanism might be responsible for the protective effects of

"coping" or control over shock? As previously mentioned, this

protective effect of control is observed on SIA as well as many

other stress pathologies. Interestingly, control over shock and

treatment with benzodiazepines prior to uncontrollable stress both

prevent many of the same stress-related effects. For example,

benzodiazepines selectively inhibited the increase in plasma

corticosterone resulting from inescapable stress (LeFur et al.

77
1979). Similarly, controllable or escapable shock induced a much

more transient rise in plasma corticosterone levels, in comparison

to inescapably shocked subjects (Swenson and Vogel 1983). Benzodiazepines reduced gastric ulcers induced in rats by stress (File

and Pearce 1981), whereas stress-induced ulceration was observed

following inescapable but not escapable shock (Weiss 1971).

Benzodiazepines produced a significant attenuation of morphineinduced analgesia when injected intracerebroventricularly (ICV) or

into the periacqueductal gray (PAG) simultaneously with a subcutaneous injection of morphine (Mantegazza et al. 1982), while

escapable shock given prior to inescapable shock blocked both

short- and long-term opioid SIA (Drugan et al. 1985c; Moye et al.

1981; Moye et al. 1983).

The similarities between control over shock and benzodiazepine

administration prior to inescapable stress suggested the possibility that anxiety or fear may be a critical factor in the production or prevention of stress-induced opioid analgesia and other

stress pathologies. In fact, behavioral studies investigating the

relationship between fear and antinociception supported this contention. Specifically, although unconditioned analgesia induced

by a stressor is sometimes opioid and sometimes not, conditioned

analgesia appears to be opioid in nature (Sherman et al. 1984;

Watkins and Mayer 1982). In support of this idea is the finding

that conditioned analgesia was reversible by opiate antagonists

(Watkins and Mayer 1982). Finally, the analgesia elicited by cues

that have been paired with a stressor has been opioid in nature

even if the stressor itself led to a nonopioid analgesia (Watkins

and Mayer 1982).

If the opioid SIA observed following inescapable shock is in some

fashion a result of anxiety or fear, then an antianxiety compound

should block or attenuate this effect. Chlordiazepoxide (Librium)

is a classic 1,4 benzodiazepine which is known to have potent

anxiolytic action in both animals and man. However, it is important to tolerate out the side effects of muscle relaxation and

sedation to ensure that the effects of the compound are due to its

anxiolytic action. Therefore, prior to experimentation, all subjects were given one injection of 10 mg/kg chlordiazepoxide (CDP)

per day for 4 days, to tolerate out the sedative effects. Then,

on day 5, half of the subjects received an IP injection of 5 mg/kg

CDP, while the remainder of the subjects received distilled water

30 minutes prior to a session of inescapable shock. Twenty-four

hours later and 30 minutes prior to reinstating shocks and subsequent analgesia testing, subjects received an IP injection of

either CDP or saline (Drugan et al. 1984). Figure 6 demonstrates

the impact of a benzodiazepine on the inescapable shock-induced

long-term opioid analgesia.

As can be seen in the figure, CDP given prior to inescapable shock

completely blocked the long-term opioid analgesia. It is important to note that benzodiazepine administration prior to test on

day 2 had no effect. It appears that the initiation of anxiety or

fear resulting from the session of inescapable shock set into

78
motion some sort of

responsible for the

other deficits.

process (transmitter depletion?) that is

expression of the opioid SIA, and possibly for

FIGURE 6. Mean tail-flick latency 24 hours following 80

inescapable shocks

NOTE: Thirty minutes prior to inescapable shock and tall-flick testing, subjects

were given an injection of either distiIled water or chlordiazepoxide

(Librium, 5 mg/kg).

Control over shock protects the subject from many of the deleterious effects of inescapable shock in a similar fashion to the

benzodiazepines. Does control over shock act in the same way as

the pharmacological pretreatment of benzodiazepines prior to

stress? The benzodiazepine receptor appears to be functionally

coupled to both a gamma-aminobutyric acid (GABA) receptor and an

associated chloride ionophore (Paul et al. 1981). It has been

demonstrated that benzodiazepines increase GABA binding and can

facilitate GABAergic transmission (Biggio et al. 1977; Costa et

al. 1978). It is believed that benzodiazepines do not mimic GABA

but instead facilitate GABAergic transmission by sensitizing GABA

receptors to the natural agonist (Costa et al. 1976). Finally, it

has been proposed that it is the GABAergic system that mediates

the anxiolytic action of the benzodiazepines (Costa et al. 1976).

In support of this notion, GABA-mimetic drugs (e.g., valproic

acid) have anxiolytic activity comparable to diazepam in two types

of animal tests known to predict the anxiolytic action of drugs

(Lal et al. 1980). Hence, if control over shock is working in a

similar fashion to the benzodiazepines, then it should result in a

facilitation of GABAergic transmission as well. This increase in

GABAergic transmission would be reflected in greater GABA effectiveness and/or greater inhibition in the central nervous system

(CNS). A technique that gave an index of central GABAergic

79
processes would be informative in evaluating whether or not

control over shock augments GABAergic transmission.

The classic benzodiazepines (i.e., diazepam and chlordiazepoxide)

have anticonvulsant properties as well as anxiolytic actions. It

is believed that the anticonvulsant action of these drugs is due

to their action on the GABAergic system (Schmutz 1983). Drugs

such as bicuculline or picrotoxin, which antagonize GABAergic

transmission, are known to act as convulsive agents. In fact,

GABA-antagonist induced seizures have been used as a behavioral

index of the activity level of central GABAergic processes

(Soubrie et al. 1980).

Drugan et al. (1985b) used bicuculllne-induced seizures in subjects that received escapable shock, inescapable shock, or no

shock to assess the impact of controllability of stress on

GABAergic tone. Two hours poststress was used as the time point

for the precipitation of seizures for several reasons. There is a

dissociation between escapably and inescapably shocked subjects on

behavioral (Glazer and Weiss 1976), plasma corticosteroid (Swenson

and Vogel 1983). and analgesic (Drugan et al., 1985c) indices at

this time. The latencies to myoclonus (neck jerk) and clonus

(loss of posture) were chosen as dependent variables as these have

been used by other researchers in the field (Adler 1969; Greer and

Alpern 1977). Figure 7 shows the latency to myoclonus and clonus

for all groups given an IP injection of either 4, 6, or 8 mg/kg

bicuculline 2 hours postshock.

Interestingly, both control and lack of control over shock dramatically altered the subjects' susceptibility to bicuculline-induced

seizure in comparison to nonshocked controls. Escapable shock

protected against seizures, while inescapable shock facilitated

seizures. In addition, at the effective dose (6 mg/kg), control

over shock protected against the lethal effects of these chemically-induced seizures, in comparison to all other groups. More

specifically, following the 6 mg/kg challenge of bicuculline, 31

percent of the escapably shocked subjects, 69 percent of the inescapably shocked subjects, 69 percent of the restrained subjects,

and 63 percent of the naive subjects died following seizures.

Thus, not only did control over shock delay the onset of bicuculline-induced seizures. it also protected against the lethal

effects.

CONTROLLABILITY AND GABAERGIC TRANSMISSION: A THEORETICAL MODEL

In sum, it appears that experience with controllable vs. uncontrollable aversive events such as electric shock markedly

influence the organism's reaction to the stressor. Exposure to

uncontrollable shock leads to a variety of pathologies including

opioid stress-induced analgesia. Conversely, exposure to controllable shock results in few if any stress effects and a transient

nonopioid stress-induced analgesia. The data presented in this

paper suggest that anxiety and fear may play a major role in precipitating many of the stress pathologies and opioid SIA reported.

80
Since GABA is such a ubiquitous neurotransmitter in the brain,

having interactions with many stress- and anxiety-related systems,

a theoretical model is proposed to account for the effects of

FIGURE 7. Mean latency to the onset of myoclonic and clonic

convulsion following an IP injection of either 4, 6,

or 8 mg/kg bicuculline 2 hours following escapable

shock, inescapabte shock, restraint, or no treatment

(naive)

NOTE: Vertical bars represent standard errors.

control/lack of control over shock with GABA as the critical link.

Figure 8 (Drugan 1984) shows that GABA tonically inhibits many

systems thought to be critical in the expression of opioid SIA

(hypothalamopituitary adrenal axis) and anxiety (e.g., GABA

itself, norepinephrine, and serotonin).

Thus, facilitation or interference with GABAergic transmission is

hypothesized to have a profound effect on other critical systems.

For example, if control over shock results in GABAergic facilitation, then this should result in an inhibition of the release of

corticotropin-releasing factor from the hypothalamus, which would

mobilize the hypothalamopituitary adrenal (HPA) axis (Buckingham

1980). Conversely, if lack of control results in an interference

81
with GABA, then a release of inhibition of the HPA axis would

ensue, with release of pituitaryß-endorphin and opioid SIA. In

support of this notion, both basal and stress-induced activity of

the HPA axis in the rat were found to be reduced when GABA was

implanted into the third ventricle and were enhanced by the injection of the GABA-receptor antagonists, picrotoxin and bicuculline

(Makara and Starr 1974). This relationship between GABA and the

HPA axis is important because the pituitary-adrenal axis has been

demonstrated to be involved in the long-term opfoid SIA following

inescapable shock. Specifically, either hypophysectomy, adrenalectomy. or dexamethasone will completely block the inescapable

shock-induced opioid SIA (MacLennan et al. 1982).

FIGURE 8. A theoretical model which suggests that the differential impact of escapable vs. inescapable shock is

due to their respective effects on the GABAergic

system. This differential impact is proposed to

alter many important stress-related systems.

Another relevant interaction of GABA processes is its relationship

with other neurotransmitter systems thought to be involved in

anxiety-related behaviors. For example, pharmacologically increasing serotonin levels increases anxiety-related behaviors in

rats (Iverson 1983). Thus, augmenting serotonergic activity has

anxiety-inducing effects. Interestingly, it has been shown that

GABAergic neurons terminate on , and exhibit an inhibitory influence on, the raphe nucleus (Gallager 1978), the originating

82
nucleus for the ascending serotonergic (5-HT) tract, which

innervates certain components of the limbfc system thought to be

critical in anxiety (i.e., amygdala and hippocampus). Thus,

GABAergic facilitation, as observed in subjects able to control

shock, might be expected to have anxiolytic effects due to

inhibition of the ascending 5-HT system. Conversely, subjects

unable to control shock, resulting in interference with GABAergic

processes, would be expected to have anxiogenic effects resulting

from disfnhibition of this system.

Redmond and Huang (1979) have proposed that the dorsal noradrenergic bundle is important in the production of anxiety. Drugs

that are known to reduce the activity of the locus coeruleus (the

originating nucleus of the dorsal noradrenergic bundle), such as

benzodiazepines, have anxiolytic actions. However, drugs that

increase locus coeruleus activity cause anxiety in animals and

man, as does electrical stimulation of this area (Redmond et al.

1977). Significantly, GABAergic neurons terminate on, and exert

an inhibitory influence on, the locus coeruleus neurons (Iverson

1983). Thus, control over shock, resulting in GABAergic facilitation, might be expected to have anxiolytic action in this system

as well, due to inhfbition of locus coeruleus neurons. Finally,

inescapably shocked subjects would have an active ascending

noradrenergic (NE) system due to disinhfbition of GABA on locus

coeruleus neurons, which would result in anxiety.

PURPOSE OF MODEL

This theoretical model was not conceptualized to answer all the

questions about controllability and stress effects. Rather, it

has been proposed in an effort to provide a certain perspective on

how "coping" or control over stress might have protective effects.

It is hoped that this model will guide subsequent research on

subjects able to control stress, rather than examining merely

those unable to control. Our feeling is that the mechanism or

process modulating the protective effects of control over stress,

once understood and characterized, will result in better finetuning of pharmacotherapy in many stress-related disorders in

humans.

RELEVANCE TO DRUG ABUSE

At first blush, the data presented in this paper may not seem

directly relevant to the study of drug addiction. However, careful reconsideration will reveal that the dimension of controllability over a stressful event, or anxiety/fear, modulates the

activity of endogenous opiofds as evidenced by opioid SIA and

potentfated morphine withdrawal. In addition, this activation of

opiofd systems renders the subject more sensitive to the analgesic

effects of systemically administered morphine (Grau et al. 1981).

Since the previously mentioned opioid SIA is blocked by pretreatment with a benzodiazepine, anxiety or fear appears to be an

important precipitating factor. Thus, learned helplessness has

been conceptualized as being an animal model for anxiety-mediated

83
depression (Drugan et al. 1985a). Since addicts tend to score in

the mild-moderate range of depression (Craig, this volume), this

model may shed some light on the etiology of addictive behavior in

humans.

In a clinical setting, people who have experienced uncontrollability of life events, have chronic anxiety, or possess an external

locus of control may be candidates for drug abuse for several

reasons. First, as mentioned above, either uncontrollable aversive events or anxiety/fear result in activation of endogenous

opioid systems. This "primed" opioid system may alter the individual's first reaction(s) to an opiate (e.g., greater euphoria)

in comparison to those of other people. This different action of

the opiate may precipitate or hasten the addiction process. In

addition, these individuals may be more likely to experiment with

drugs as a "coping" mechanism in order to combat their emotional

predicament. Thus, this "coping through drug use" and the differential reaction to opiates themselves could be the mechanism

responsible for the acquisition and maintenance of drug abuse.

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Brain Res Rev 3:167-205, 1981.

Williams, J.L.; Drugan, R.C.; and Maier, S.F. Exposure to

uncontrollable stress alters withdrawal from morphine. Behav

Neurosci 98:836-846, 1984.

ACKNOWLEDGMENTS

This research was supported by NSF Grant BNS 82-00944 and RSDA

MH 00314 to S.F. Maier.

88
AUTHORS

Robert C. Drugan, Ph.D.

NIMH Post-doctoral Fellow

Unit on Behavioral Neuropharmacology

Clinical Neuroscience Branch

National Institute of Mental Health

Building 10, Room 4N-214

Bethesda, MD 20892

Steven F. Maier, Ph.D.

Professor

Department of Psychology

University of Colorado

Boulder, CO 80309

89
Behavioral Contingencies Involved

in Drug-Induced Neurotransmitter

Turnover Changes

Steven I. Dworkin and James E. Smith

INTRODUCTION

Recent advances in techniques used to investigate the neuroanatomical, neurophysiological, and neurochemical mechanisms of action

of psychoactive drugs have been substantial. Neuroscientists have

not only determined the chemical and physiological effects of

these drugs, but also, in some cases, the anatomical locus where

these effects are exerted. Investigations of the parameters of

opiate action exemplify how these neurobiological techniques have

increased understanding of the mechanisms of action of substances

that affect behavior. Receptor-binding and autoradiographic distribution studies have shown the complex behavioral effects of

opiates to be produced by actions at specific recognition sites in

the central nervous system. These techniques have also assisted

in the detection and characterization of endogenous substances

that interact with these receptors to produce effects that opiates

appear to mimic. However, irrespective of how sophisticated

neurobiological techniques for investigating the direct actions of

drugs become, understanding the basic mechanisms responsible for

substance abuse will likely not be possible unless these phenomena

are studied in the context of behavioral and environmental variables that result in and from drug self-administration.

CHARACTERISTICS OF SUBSTANCE ABUSE

One necessary component of substance abuse is behavioral--the use

or self-administration of the particular substance. Acknowledging

this component places appropriate emphasis on the importance of an

experimental analysis of the behavioral components of selfadministration, while not suggesting that physiological or neurobiological aspects are unimportant. Investigations of the neurobiological consequences of the administration of substances to

biological preparations can provide information concerning the

necessary conditions for abuse potential. Aside from occasional

self-administration of an inappropriate drug or dose regimen

(e.g., taking an antibiotic for a cold), there may be some common

neurobiological mechanism of action of substances. This mechanism

90
has been proposed by some to be an action on the mesolimbicmesocortical dopamine system (Wise and Bozarth 1981) or on the

noradrenergic-endorphinergic system (Belluzzi and Stein 1977).

Many substances with abuse liability have several characteristic

behavioral effects in common. These agents have response-ratealtering properties that result in modifications of ongoing levels

of activity, and stimulus properties that permit humans and nonhumans to detect their administration. These substances also have

reinforcing properties that result in their ability to maintain

high rates and extended sequences of behavior. However, these

properties are not invariant and are subject to modification by

pharmacological, neurobiological, and behavioral variables

(Barrett and Katz 1981; Barrett and Witkin, in press). Psychoactive substances are not qualitatively different from other

environmental stimuli that exert control over behavior. Research

into the control of behavior by consequent events (operant conditioning) has been beneficial in understanding the behavioral

parameters of substance abuse.

The dynamic properties of reinforcers are often overlooked. The

same electric shock can serve as a punisher and suppress behavior,

a negative reinforcer increasing behavior that results in its

termination, and a positive reinforcer maintaining behavior that

results in its presentation, even with the same animal (figure 1).

Squirrel monkeys initially trained to postpone electric shocks

(negative reinforcement) continue to respond when the same intensity shock is made contingent on responding (positive reinforcement). This responding is directly related to shock intensity

with higher intensity maintaining higher response rates. Responding extinguishes when shock is eliminated and occurs again when

shock is reintroduced. Electric shock can suppress food-maintained responding (punishment) and maintain responding that

results in its presentation (positive reinforcement) in different

components of a multiple schedule (Morse et al. 1977; Barrett and

Katz 1981). The importance of the precise contingencies between

responding and shock presentation is indicated by the demonstration that shock can reinforce behavior when delivered under an

interval schedule but punish behavior when delivered under a ratio

schedule (Branch and Dworkin 1981).

Similar results have been seen with psychoactive substances.

Cocaine (figure 2) and nicotine (figure 3) can be both positive

and negative reinforcers in the same animal (Spealman 1985).

Moreover, nalorphine (a mixed opiate agonist-antagonist) produces

severe withdrawal when administered to an opiate-dependent animal,

but can also serve as a reinforcer to opiate-dependent monkeys

(Goldberg et al. 1971) (figure 4). These and similar findings

demonstrate that behavioral history, particularly the different

types of contingent relationships between behavior and the delivery of an environmental event , can alter the punishing or reinforcing efficacy of that event.

91
FIGURE 1. Development of the positive reinforcing effects of

response-produced electric shock presesentation to

squirrel monkeys

NOTE: Responding was initially maintained by a Sidman Avoidance schedule where

responding postponed shock presentations (upper panels). A conjoint fixedinterval 5-minute schedule of shock presentation was then added to the

postponemant schedule. Most responses continued to postpone shocks.

However, responses produced shocks on a fixed-interval 5-minute schedule.

When the postponement schedule was eliminated, responding was maintained by

the fixed-interval schedule of shock delivery (third panel). The addition

of a conjoint ratio schedule of response-produced shock eventually eliminated responding by monkey 525. A behavioral history of different contingencies between responding and the delivery of electric shock altered the

reinforcing nature of shock, changing It from a negative reinforcer to a

positive reinforcer to a punisher. (Branch and Dworkin 1981.)

Copyright 1981, Society for the Experimental Analysis of Behavior, Inc.

IMPORTANCE OF CONTINGENCIES

Substances that have profound pharmacological and behavioral

effects should not be considered reinforcing until contingent or

contiguous relationships between behavior and administration are

evaluated. When it has been demonstrated that the behavior that

precedes administration is increased in frequency and that the

drug has not directly elicited the behavior, then the substance

can be considered reinforcing. Reinforcement cannot be assumed in

the absence of contingent or contiguous relationships (Skinner

1938).

The effects of noxious stimuli have also demonstrated the importance of behavioral variables. Although the noncontingent presentation of noxious stimuli have been shown to produce many

behavioral and physiological changes, other factors have been

implicated in stress-related diseases (Weiss et al. 1981). A

stress-inducing environment contains at least three components:

92
FIGURE 2. Development of the positive reinforcing effects of

NOTE:

nicotine

Responding was engendered and subsequently maintained by a nicotine

postponemant procedure. In the absence of responding, nicotine injections

were delivered (first panel). A fixed-interval schedule of nicotine

injections was superimposed on the postponement schedule (second panel).

After the postponement contingency was eliminated, responding was maintained by the fixed-interval schedule alone (bottom two panels). The

behavioral history of the different response contingencies changed the

effects of nicotine from a negative reinforcer to a positive reinforcer.

(Spealman 1985.) Copyright 1985, Alan R. Liss Company.

(1) a noxious stimulus (usually electric shock); (2) stimuli that

are paired with the presence or absence of a pending noxious stimulus (predictability); and (3) a coping response that results in

the postponement or termination of the noxious stimulus (control).

Several studies have shown that the second two components, considered to be "psychological," can modulate the behavioral, physiological, and neurochemical effects of noxious stimulation (Badia

and Culbertson 1972; Seligman and Maier 1967). Procedures used on

rhesus monkeys to assess simultaneously the effects of noxious

stimulation that could or could not postpone electric shocks have

demonstrated the importance of response contingencies (Brady et

al. 1958). One monkey received a shock every 20 seconds unless a

bar-press response was emitted, which delayed the shock for 20

seconds. A second monkey was yoked to the shock schedule of the

responding monkey but had no opportunity to postpone presentations. Thus, the number of shocks delivered to both subjects

was the same, but only one monkey could delay them for himself and

his yoked partner. This avoiding animal (with control) developed

extensive gastrointestinal lesions. Opposite effects were observed when rats were used in a systematic replication and extension of this study (Weiss 1968; Weiss 1971). Yoked rats (without

control) developed more and larger gastrointestinal lesions

compared to subjects that could delay shocks. It was suggested

that the major factor responsible for the differences observed

93
FIGURE 3. Development of responding simultaneously maintained by

a variable-interval schedule of IV cocaine injection

and a fixed-interval schedule of termination (timeout from cocaine injections)

NOTE: First panel shows responding maintained by a variable-interval contingency.

Responding on a single lever produced an IV cocaine infusion at variable

Intervals averaging 3 minutes. Subsequent panels show responding maintained by two concurrently scheduled contingencies. Responding on one

lever continued to produce cocaine injections under the variable-interval

schedule. Responses on a second lever were maintained by a fired-interval

5-minute termination schedule. Responses on this lever after a 3-minute

fixed Interval of time elapsed terminated the schedule of cocaine injections for a 1-minute time-out period. Thus, responding was simultaneously

maintained bv cocaine injections (positive reinforcement) and a time-out

from the opportunity to receive additional cocaine infusions (negative

reinforcement). (Spealman 1985.) Copyright 1985, Alan R. Liss Company.

between the two studies was the difference in response rates of

the shock-postponing animals (Weiss 1971; Weiss 1972). In the

first study, monkeys with the highest rates of responding were

designated as the avoiding subjects, while a random assignment

procedure was used in the rat study. Additional research supported the suggestion that response rates were important in

stress-induced physiological changes (Weiss 1968). Animals with

the opportunity to postpone electric shock presentation have

increased levels of brain neurotransmitters compared to yokedshock animals. Increases in norepinephrine, dopamine, and

serotonin were seen in the hypothalamus, anterior cortex, and

brain stem, respectively (Weiss et al. 1981). The ability to

control or predict the occurrence of noxious stimuli has considerable behavioral, physiological, and neuropharmacological effects.

It is not surprising that similar control over, or predictability

of, other environmental stimuli also have profound neurobiological

influences.

94
FIGURE 4. Demonstration of the reinforcing effects of nalorphine

delivered to a morphine-dependent monkey

NOTE: Various doses of nalorphine substituted for contingent morphine injections

over a 7 1/2-hour period and maintained higher rates of responding than

either morphlne (points above "C" and broken horizontal Iine) or saline

(points above "s"). (Goldberg et al. 1971.) Copyright 1971,

American Society for Pharmacology and Experimental Therapeutics.

NEUROBIOLOGICAL CONSEQUENCES OF REINFORCER PRESENTATION

The behavioral consequences of reinforcer presentation are thought

to result from, and in, changes in neuronal transmission in the

central nervous system. Reinforcer presentatfon likely initiates

neuronal activity in pathways that mediate and may be "dedicated"

to these processes (demonstrated by intracranial electrical selfstimulation). Thus, the neuronal events resulting from reinforcement are the neurobiological substrates of these phenomena. The

elucidation of these substrates would include the identification

of the neuronal circuits that mediate these processes (figure 5).

The identification of each component neuron and the receptors involved in the neuronal circuit would be necessary to such elucidation as would knowledge of the influence of other inputs. Such

information is not yet available for even the most simple

behavior. However, recent methodological developments such as

multiple neurotransmi tter turnover rates, 2-deoxyglucose autoradiography, and neurotransmitter receptor imaging will likely

permit significant new advancements.

NEUROBIOLOGICAL SUBSTRATES OF CONTINGENT REINFORCER PRESENTATION

The contingent presentation of an event that increases the

probability of the response that preceded its presentation is a

reinforcer. The noncontingent presentation of the identical

potentially reinforcing stimulus does not appear to have the same

95
Neurobiological Mechanisms

FIGURE 5. Neurobiological mechanisms

NOTE: The neurobiological substrates of a behavior would include knowledge of:

(a) the neuronal circuits and pathways that mediate the behavior with

identification of each component neuron and the neurotransmitters released

by each; (b) characterization of end localization of the neurohumoral

receptors involved; and (c) the role of other Inputs to each participating

neuron.

properties. As previously discussed, response-contingent presentation is necessary for an event to establish reinforcing properties, while response-independent presentation to the same organism

cannot be considered a reinforcer and may even be an aversive

stimulus. Rats that have produced response-dependent presentation

of electrical stimulation to a brain region will respond to terminate the same stimulation-delivered response independently on an

identical schedule (Steiner et al. 1969). Drugs with reinforcing

properties seem to have similar effects. Monkeys intravenously

self-administering cocaine will respond to terminate the opportunity to receive additional periodic cocaine infusions (Spealman

1985). These data suggest that the response-independent presentation of a potentially reinforcing stimulus is not a reinforcer to

organisms that have previously exercised control over its presentation. Moreover, the reinforcing nature of a stimulus can be

changed by alterations in the contingencies under which it is

presently removed.

96
NEUROBIOLOGICAL SUBSTRATES OF CONTINGENT DRUG PRESENTATION

Neuropharmacologic and behavioral pharmacologic data suggest that

the contingent presentation of drugs is clearly different from

noncontingent presentation. These differences must result from,

and in, differences in neuronal activity between the two conditions. These differences may represent reinforcing neuronal

activity and the neuronal processes associated with contingent

presentation that are directly related to reinforcement. Investigation of the neurobiological differences between intravenous

opiate self-administration and yoked-passive morphine or yokedvehicle infusion have suggested the involvement of specific neuronal systems in these processes (Smith et al. 1982; Smith et al.

1984a; Smith et al. 1984b).

Neurotransmitter Turnover Rates

Triads of male littermate rats were surgically prepared with

chronic jugular catheters and two of the littermates made physically dependent on morphine sulfate with hourly infusions of

increasing dosages (3 days each of 1.25, 2.5. 5.0 mg/kg/infusion

and 2 days of 10.0 mg/kg/infusion), while the third littermate received hourly vehicle infusions. One of the physically dependent

rats was then allowed to self-administer morphine intravenously

(10 mg/kg/infusion) with 24-hour access on a fixed-ratio schedule

increased from 1 to 10 during the first week. The other physically dependent littermate received identical yoked infusions of

morphine, while the third littermate continued to receive yoked

infusions of vehicle. When self-administration stabilized (3 to 4

weeks), each littermate was pulse labelled with radioactive precursors to the biogenic amine (0.5 mCi 3Hitryptophan and 1.0 mCi

H-tyrosine) and the amino acid (0.2 mCi 14C-glucose) neurotransmitters. Groups of litters were sacrificed by immersion in

liquid nitrogen after either 60 (n=5) or 90 minutes (n=6), at a

time when each self-administering animal was most likely to take

another self-infusion (calculated from self-administration intervals for the previous 72 hours). The brains were removed at

-20 °C, cut into 1 mm coronal sections, and dissected into 11

brain regions at -20 °C. Each brain region was pulverized in

liquid nitrogen and a portion of tissue taken for the extraction

and assay of the content and specific radioactivity of the biogenic amine neurotransmitters; another portion was taken for the

same determinations of the amino acid neurotransmitters. The

half-life was determined for each from a semilogarithmic plot of

the specific radioactivities at the two time points, and rate

constants and turnover rates were calculated (Smith et al. 1982).

Biogenic Monoamine Turnover Rate Changes

Passive morphine infusion (yoked-morphine vs. yoked-vehicle) resulted in fewer and generally smaller significant changes in dopamine (DA), norepinephrine (NE), and serotonin (5-HT) turnover than

did the contingent administration (self-administering animals vs.

yoked-morphine infused) (figure 6). Four significant changes

97
FIGURE 6. The effects of noncontingent passive intravenous

morphine infusion determined by comparing yokedmorphine and yoked-vehicle infused littermates) and

contingent intravenous morphine self-administration

determined by comparing the self-administering

animals with the yoked-morphine infused littermates)

on the turnover rates of dopamine, norepinephrine,

and serotonin in 11 brain regions

NOTE: Values are the percent change of the significant differences.

in turnover occurred in the yoked-morphine infused littermates

compared to the yoked-vehicle infused animals, while seven significant differences were seen between the self-administering and the

yoked-morphine littermates. The decreases in turnover of NE in

the amygdala and 5-HT in the entorhinal-subicular cortex likely

represent a direct drug effect, since these changes were seen in

both drug groups irrespective of the contingency. The increase in

DA turnover rates in the caudate nucleus-putamen of the yokedmorphine group was even further increased in the self-administering group, while the increase in the nucleus accumbens was

reversed to almost no turnover at all in the self-administering

98
animals. In one situation, the self-administration contingency

exacerbated a change and in the other, it totally attenuated the

change and resulted in an even greater effect in the opposite

direction. It is interesting to speculate about the underlying

basis of these changes. The differences between the contingent

control of reinforcer presentation and the noncontingent presentation of a potential reinforcer may not represent simply reinforcing efficacy differences. The potential reinforcer presented

noncontingently may activate some pathways that participate in

reinforcement when the drug is administered response-dependently

(e.g., DA innervations of the caudate nucleus-putamen). Furthermore, noncontingent presentation may have aversive properties

resulting in a reversal and change in the opposite direction to

that of contingent presentation (e.g., DA turnover in the nucleus

accumbens).

Five changes in biogenic monoamine turnover rates appear to be

related to the reinforcing properties of contingent self-administration. These include increases in DA turnover in the frontal

cortex and septum, the increase in NE turnover in the septum, and

decreases in NE and 5-HT turnover in the nucleus accumbens of the

self-administering animals.

Amino Acid Turnover Rate Changes

The passive noncontingent administration of morphine resulted in

11 significant changes in aspartate (Asp), glutamate (Glu), and

gamma-aminobutyric acid (GABA) turnover, while the contingent

self-administration resulted in 22 changes (figure 7). Four turnover rate changes appeared to be direct pharmacological effects of

morphine since they were identical in both drug groups, regardless

of the contingency. These changes included increases in Asp turnover in the septum, Glu turnover in the nucleus accumbens and

septum, and in GABA turnover in the entorhinal-subicular cortex.

Five of the other changes in the yoked-morphine group may be

related to the differences between contingent self-administration

and noncontingent administration , since they were nullified and

often significantly changed in the opposite direction in the selfadministering animals. These changes included the decreases in

turnover rates of Asp and Glu in the caudate nucleus-putamen, Asp

in the amygdala, and GABA in the septum, and increases in GABA In

the caudate nucleus-putamen and nucleus accumbens. Two significant changes in the yoked-morphine group were even greater in the

self-administering littermates. These changes included the increased turnover rates of GABA in the caudate nucleus-putamen and

hypothalamus.

Of the 22 changes resulting from the contingent self-administration, 15 appear to be related to the reinforcing properties of

intravenous morphine. These include the increases in Asp turnover

rates in the frontal cortex, hippocampus, thalamus, motor-somatosensory cortex, and brain stem; increases in Glu turnover in the

frontal cortex, hippocampus, amygdala, and motor-somatosensory

cortex; and increases in GABA turnover in the frontal cortex,

99
hippocampus, amygdala, thalamus, motor-somatosensory cortex, and

brain stem. Six other changes were reversals of the changes seen

in the passive morphine-infused group, which included increases in

turnover rates of Asp in the caudate nucleus-putamen and amygdala,

in Glu in the caudate nucleus-putamen, in GABA turnover in the

septum, and decreases in the nucleus accumbens. The remaining two

changes were even greater increases in turnover of GABA in the

self-administering littermates in the caudate nucleus-putamen and

hypothalamus.

FIGURE 7. The effects of noncontingent passive intravenous morphine infusion and contingent intravenous morphine

self-administration on the turnover rates of aspartate, glutamate, and gamma-aminobutyric acid in 11

brain regions

NOTE: Values are the percent change of the significant differences.

100
Acetylcholine (ACh) Turnover Rate Changes

The turnover rates of ACh were determined in 14 brain regions of

14 additional triads of littermates to assess the role of cholinergic neuronal systems in contingent and noncontingent morphine

presentation. Three significant changes in turnover rates were

seen in the yoked-morphine infused group and four were seen in the

self-administering group (figure 8). Two of the three changes in

the yoked-morphine infused littermates appeared to be related to

the direct effects of morphine, since the changes were seen in

both drug groups, regardless of the contingency. These included

the increase in turnover in the diagonal band region and the medial septum. The increase in ACh turnover in the frontal cortex in

the yoked-morphine group was even greater in the self-administering littermates, while decreases in turnover were seen in the

pyriform cortex, nucleus accumbens, and amygdala of this latter

group.

FIGURE 8. The effects of noncontingent passive intravenous morphine infusion and contingent intravenous morphine

self-administration on the turnover rates of acetylcholine in 14 brain regions

NOTE: Values are the percent change of the significant differences.

101
Neurotransmitter Receptor Changes Correlated With Contingent and

Noncontingent Presentations of Intravenous Morphine

The tissue remaining from the litters in which ACh turnover rates

were measured was used to determine muscarinic cholinergic- and

benzodiazepine-binding characteristics. Scatchard analysis and

Hill plots demonstrated significant differences in muscarinic

cholinergic-binding between the noncontingent and contingent presentations of morphine (figure 9). Four changes in the yokedmorphine group appeared to be direct drug effects, since these

FIGURE 9. The effects of noncontingent passive intravenoue

morphine infusion and contingent intravenous morphine

self-administration on the density of binding sites

for 3H-quinuclidinyl bensilate and 3H-flunitrazepam

determined in eight brain regions

NOTE: Values are the percent change in BMax for the significant differences.

were also present in the self-administering animals. These

include the increase in muscarinic cholinergic-binding in the

pyriform cortex and decrease in the cingulate cortex, and the

decrease in benzodiazepine-binding in the hippocampus and entorhinal-subicular cortex. Three significant changes in muscarinic

cholinergic-binding were observed in the self-administering

102
animals that appeared to be related to the reinforcing effects of

contingent drug delivery. These included the increase in the

amygdala and the decrease in the frontal cortex and entorhinalsubicular cortex. The changes in the amygdala and frontal cortex

were the inverse of changes in ACh turnover seen in these areas,

while the changes in binding in the entorhinal-subicular cortex

suggested a net increase in total activity that was not observed

as a turnover rate change. The pulse-labelling intervals for ACh

turnover were 5 and 10 minutes. The turnover-rate measures may

not be representative of the total neuronal activity during the

11O-minute interinjection interval. Accordingly, the increases in

ACh turnover in the frontal cortex of the yoked-morphine group and

in the pyriform cortex and nucleus accumbens of the self-administering animals may not represent net changes in neuronal activity,

since no changes in muscarinic cholinergic-binding were observed

in these areas. However, the changes in the frontal cortex and

the amygdala of the self-administering littermates are consistent

with total net changes in activity since inverse changes in

binding were observed.

NEURONAL CIRCUITS MEDIATING THE REINFORCING EFFICACY OF CONTINGENT

MORPHINE PRESENTATION

Integrating these neurochemical data and data from studies of the

effects of pharmacological blockade or neurotoxin lesion on intravenous morphine self-administration with knowledge of neurotransmitter-specific neuronal pathways suggests two neuronal circuits

to be involved in the processes maintaining intravenous morphine

self-administration, which include its reinforcing efficacy (Smith

et al. 1984a). A nucleus accumbens-pre-optic nucleus-amygdalaentorhinal cortex-hippocampus-nucleus accumbens circuit and a

frontal cortex-striatum-frontal cortex circuit were identified

that included ACh, DA, NE, 5-HT, Asp, Glu, and GABA neurons.

Activity in these circuits appears to be modulated by feedforward

pathways from brain stem biogenic monoamine systems, while GABA

feedback pathways from these circuits appear to modulate activity

in these brain stem centers. These circuits may represent general

reinforcement systems and not just opiate reinforcement processes,

since 2-deoxyglucose autoradiography in the brains of animals

intracranially self-stimulating identified many of the same regions as in these intravenous morphine self-administering animals.

OTHER NEUROBIOLOGICAL EVIDENCE FOR DIFFERENCES BETWEEN CONTINGENT

AND NONCONTINGENT PRESENTATION OF REINFORCERS

Responding by rats can be maintained by the termination of electrical stimulation of brain regions where such stimulation was

previously self-administered (Steiner et al. 1968), suggesting the

development of potential aversive properties when control over

presentation is removed. The autoradiographic assessment of the

distribution of 3H-2-deoxyglucose in the brains of animals electrically self-stimulating intracranially, compared to noncontingent presentation to previous self-stimulators, showed increases

103
in glucose utilization bilaterally in the medial prefrontal cortex

and ventrolateral thalamus, and ipsilaterally to the stimulating

electrode in the nucleus accumbens (Porrino et al. 1984). These

data suggest that neuronal activity in these regions was increased

in the animals receiving contingent presentation of the electrical

stimulus. However, no significant differences in the noncontingent stimulated group (not seen in the contingent group) that

could be identified as resulting from changes in neuronal activity

potentially correlated with the aversive properties of this loss

of control over a previously contingent reinforcer were seen.

CONCLUSIONS

The noncontingent intravenous presentation of morphine results in

fewer and generally smaller changes in the turnover rates of seven

neurotransmitters and two neurohumor binding sites than does the

contingent presentation of the drug. Response-contingent drug delivery has greater effects upon these systems than those effects

observed to be related to the drug itself. These differences

likely result from the reinforcing properties resulting from control over drug presentation. Behavioral consequences appear to

determine some of the neurobiological consequences of drug action.

Investigations of the biological effects of abused substances

should likely include the behavioral context of excessive selfadministration, especially if biological treatment approaches are

the goal of such research.

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ACKNOWLEDGMENTS

This research was supported in part by USPHS grants DA-03631

(SID), DA-01999, DA-03628, and DA-03832 (JES).

105
AUTHORS

Steven I. Dworkin, Ph.D.

James E. Smith, Ph.D.

Psychiatry Research Unit

Departments of Psychiatry and Pharmacology

Louisiana State University

School of Medicine in Shreveport

P.O. Box 33932

Shreveport, LA 71130

106
Receptor Regulation as a

Function of Experience

Fritz A. Henn, Emmeline Edwards, and David Anderson

INTRODUCTION

Seligman and Beagley (1975) demonstrated that exposure to

uncontrollable shock produces a behavioral deficit described as

"learned helplessness." This phenomenon transfers across different aversive training and testing contexts; the apparent development of an escape deficit seems to depend on factors such as the

nature of the aversive stimulus (Goodkin 1976; Weiss and Glazer

1975), the parameters of the presentation of that stimulus

(Anderson et al. 1976; Rosellini and Seligman 1978), and the

nature of the escape response (Seligman and Beagley 1975; Wilson

and Butcher 1980).

The mechanism by which exposure to uncontrollable shock produces

this behavioral deficit remains undefined. However, we have

established a psychobiological concept of "learned helplessness,"

including a distinct behavioral and neurobiological mechanism

(Henn et al. 1985). Our laboratory has been studying a modified

version of Seligman's "learned helplessness" model in which our

experimental animals are exposed to mild uncontrollable shock

only. With this approach, we have compared two distinct groups of

rats that emerged when subjected to a mild course of uncontrollable shock. The selection was from two different groups of

animals: (1) those that showed no deficit in subsequent shockescape tests, and (2) those that showed a profound learning

deficit. This selection has provided a better medium for behavioral and pharmacological manipulations.

ESTABLISHMENT OF A MODEL

Sprague-Dawley rats were used in our experiments. These rats were

obtained from Charles River Breeding Laboratories and were delivered to the Division of Animal Resources, where they were kept

under standard conditions. Upon arrival, these rats, weighing 150

to 200 gm, were maintained on an ad libitum food and water schedule. Behavioral training and testing sessions were scheduled

during the light phase of a 12-hour light/dark cycle.

107
The critical element of our behavioral, biochemical studies is the

consistency and accuracy with which the behavior can be quantified. There have been numerous reports of a learning deficit that

occurs after exposure to uncontrollable shock; these reports show

only a degree of internal consistency within each investigator's

paradigm. Researchers from various laboratories have agreed that

there is a behavioral difference between response-deficient rats

and rats that have received identical shock but still respond at

control levels (Katz 1981). There is a high degree of variability

in obtaining the behavioral deficit after inescapable shock

training; therefore, in our studies, a revised "learned helplessness" model was used. In our experimental setup, the rats were

placed in an experimental chamber with an electrified grid floor.

Each chamber measured 12 x 18 x 12 cm. Sides and ceilings were

constructed of aluminum and Plexiglas. The floor was constructed

of stainless steel rods spaced 1.9 cm apart. During the shockescape test, a level was mounted 7 cm above the grid floor on one

wall. A yellow cue light was placed 5 cm above the lever. Shock

was delivered to each chamber by a Coulborn solid-state shock

source (model E13-16).

SHOCK TRAINING

Training consisted of placing the rats in the experimental chamber, where they received intermittent inescapable 0.8-mA footshock. Each training session lasted 40 minutes. The onset and

offset of the shock being established by a probability generator

resulted in an average schedule of 20 minutes of shock with a

minimum time of 1.5 seconds between on and off events.

SHOCK-ESCAPE TESTING

Twenty-four hours after training, each rat was individually tested

in an escape situation where footshock could be eliminated by a

single bar-press. Shock was delivered at the intensity of 0.8 mA

in a pulsating schedule of 35 msec on/35 msec off, with the yellow

cue light on during the shock period. Shock onset began one

trial; pressing the lever, or the end of 60 seconds, shut off the

shock. Intertrial intervals of 24 seconds began with the yellow

cue light out. Fifteen trials were given in each testing session.

Latencies up to 20 seconds before the lever was pressed and the

shock terminated were considered to be successful escape from

shock. Latencies of 20 to 60 seconds were recorded as failures.

Scores were recorded automatically, with nonspecific effects of

footshock eliminated by including internal controls in the testing

paradigm. Behavioral, pharmacological, and biochemical determinations were carried out for these internal controls. These rats

were subjected only to the shock-escape test, enabling us to

determine the effects of shock per se. Past experiments in our

laboratory demonstrate that these controls routinely do not show

significant changes either behaviorally or biochemically from

measures on nondeficient or naive rats.

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BEHAVIORAL DEFICIT

Behavioral deficits were measured as the number of failures using

the following criteria:

Rats scoring 1 to 5 failures in a 15-trial testing session were

not response deficient (ND) and learned the shock-escape test

as quickly as controls.

Rats scoring 11 to 15 failures in a 15-trial testing session

were considered response deficient (RD).

In a typical experiment, in which a total of 40 rats were used

(10 internal controls; 30 trained and tested in shock paradigm),

30 percent of the trained and tested rats were response deficient

(RD), while another 30 percent were nondeficient and responded at

a level similar to control rats in the shock-escape test. Rats

scoring in the range of 6 to 10 failures were not considered in

subsequent analysis. Behavioral and biochemical determinations

performed on rats falling into the 6-to-10-failures group revealed

a high degree of heterogeneity within the group. In addition, a

large percentage of the 6-to-10-failures group exhibited improved

shock-escape scores when subjected to additional shock treatment

FIGURE 1. Features of escape responding after exposure to

inescapable shock and control responding

NOTE: The figure shows failures to escape In rats trained 24 hours previously.

Dark shading indicates the subpopulation defined as having severe response

deficits (RD), while the lighter shadlng denotes animals having no deficit

(ND) after undergoing identical treatment. The total number of animals

involved was 592, with 27 percent falling in the range of 10 to 15 fallures, and 37 percent between 0 and 4 failures.

109
FIGURE 2. Testing of naive rate: Animals exposed to the escape

paradigm with no prior training

NOTE: Sixty percent of these animals scored 0 to 4.

(repeated training sessions). Biochemical determinations, mainly

beta-adrenergic receptor analysis, also revealed a high degree of

variability within the group.

The behavioral deficit exhibited after exposure to uncontrollable

shock was reversed with time. When deficient rats were again

tested in a shock-escape situation, 3 weeks later, their behavior

paralleled the behavior of controls.

We noted that the percentage of rats developing the shock-induced

behavioral deficit was dependent on the strain of rats used.

Routinely, 30 percent of the trained and tested Sprague-Dawley

(SD) rats from Charles River Breeding Laboratories (CRBL) developed a behavioral deficit in a shock-escape test, while the

Biolabs strain produced only 21 percent of response-deficient (RD)

rats. Rats obtained from Taconic Farms and Simonsen Laboratories

yielded only 11 percent, respectively, response-deficient rats in

the standard training and testing paradigm. This suggested that

the behavioral deficit emerging after exposure to mild, uncontrollable shock may involve a genetic component. Our laboratory has

undertaken the selective breeding of response-deficient (RD) rats,

nondeficient rats, and controls. With data from only three generations of each group, hereditary differences between our selected

lines are becoming evident. New litters from response-deficient

SD, CRBL rats have produced, under identical conditions of shock

training and testing, 44 percent of escape-response-deficient

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rats. Conversely, litters from nondeficient SD rats have produced

less than 2 percent of animals with a shock-escape deficit. However, the effect of hereditary differences on behavior must be

characterized thoroughly by biochemical analysis.

NEUROBIOLOGICAL CHANGES

We have identified some neurobiochemical differences between the

two groups emerging after a mild course of uncontrollable shock.

These differences may pinpoint the anatomical locus of the behavioral deficit.

NEUROTRANSMITTERS

Various brain regions were analyzed for their concentrations of

DA, NE, and 5-HT. These neurotransmitter levels were analyzed by

simultaneous assays performed by reverse phase high performance

liquid chromatography (HPLC) with electrochemical detection. HPLC

determinations of the biogenic amines in various brain regions did

not reveal any significant changes in norepinephrine, epinephrfne,

dopamine, or their metabolites in response-deficient rats when

compared to nondeficient rats. However, in the hippocampus, the

serotonin/norepinephrine ratios (5-HT/NE) disclosed some differences between response-deficient rats, nondeficient rats, and

controls. In general, small, consistent increases in 5-HT and

decreases in NE levels were observed.

RECEPTORS

Beta-adrenergic and serotonin receptors were studied in responsedeficient rats, nondeficient rats, and controls. The various

brain regions analyzed included the cerebellum, hippocampus,

hypothalamus, septum, and anterior neocortex. Major differences

in beta-adrenergic receptors were seen in the hippocampus of

response-deficient rats. The status of beta-adrenergic receptors

(

125I-CYP) as the probe. Briefly, hippocampal membrane prepara-

 was assessed by a filtration assay, using 125I-cyanopindolol

tions were incubated for 55 minutes at 37 °C, with increasing

absence of 10-6M propanolol used for nonspecific binding deterconcentraions of 125I-CYP (0 to 240 pm) in the presence or

mination (Engel 1981).

In response-deficient rats, the beta-adrenergic receptor was upregulated in the hippocampus, but not in the anterior neocortex

nor the septum. Changes in hippocampal beta receptors follow a

time course similar to the shock-escape deficit; a strong correlation between beta-adrenergic receptor status and shock-escape deficit scores has been established for the response-deficient rats.

Within 3 weeks following the shock-escape test, both failure

scores and beta-adrenergic receptor status of response-deficient

rats were comparable to controls. Adenylate cyclase responsiveness to norepinephrine was determined in response-deficient,

nondeficient, and control rats. Basal and stimulated cyclic AMP

111
FIGURE 3. Behavioral and beta-receptor changes with time after

exposure to inescapable shock

NOTE: (A) Rats were trained and tested as described In the text. Cohorts of animals were subsequently retested at 4, 8, 16, 23, and 42 days. Control

values throughout the experiment remained at approximately 4+2 failures.

(8) Hippocampal beta-receptor measurements were determined using 125I-CYP

as the Iigand and assayed In individual animals according to the method of

Engle (1981). Binding saturation curves were analyzed using an EadieHofstee transformstion, and BMax was obtained through extrapolation (Zivin

and Wand 1982). Data are expressed as percent of control values. Significance was determined using a two-tailed t-test for differences between

means.

112
levels were measured using the protein binding assay of Gilman

(1970), in kit form, as provided by Amersham, Inc. Responsedeficient rats exhibited a large increase in adenylate cyclase

activity in hippocampal slices, indicating that an amplification

of the noradrenergic receptor adenylate cyclase system may be

linked to the behavioral changes seen in our model of shockinduced deficit. Modifications at the receptor level in response

to environmental conditions attest to the plasticity of the

central nervous system and to the involvement of neurochemical

mechanisms in some behavioral responses. In our modified version

of "learned helplessness," there is a biochemical modulation of

the brain in response to a purely environmental manipulation.

This suggests that certain stimuli, obviously drugs among them,

can lead to altered behavioral patterns driven by altered CNS

structures.

PHARMACOLOGY

Pharmacological interventions produced a time-dependent reversal

of both the shock-induced behavioral deficit and the beta-adrenergic receptor up-regulation characteristic of response-deficient

rats. In our drug studies, we followed the schedule of training

and testing of our regular paradigm, but shock-escape testing was

followed by a 5-day drug treatment. Tested controls were divided

into two groups, drug treated and vehicle treated. Simultaneously

trained and tested rats were first divided into response-deficient

and nondeficient rats, then each of these two groups were further

divided into a drug-treated group and a vehicle-treated group.

To date, drug studies performed with our model of shock-induced

deficit have focused on compounds known to interact with either

noradrenergic or serotonergic systems. Imipramine (10 mg/kg x 5

days), a relatively nonspecific catecholamine uptake inhibitor,

reversed the behavioral deficit. The shock-escape score of

response-deficient rats improved in 80 percent of the rats retested after the imipramine treatment (11.6±1.8 --> 4.2±3.6

failure scores). A number of tricyclic antidepressants, monoamine

oxidase inhibitors, and second-generation antidepressants were

tested. All clinically effective drugs reversed the learning deficit; nonspecific drugs, such as neuroleptics, sedatives, or stimulants, do not appear to reverse the learning deficit. Among the

drugs tested were the relatively specific 5-HT uptake inhibitor

fluvoxamine and the novel compound mianserin, thought to act

mainly through the 5-HT system. Each of these compounds caused

behavior reversal of the deficit.

Interestingly, the reversal of the shock-induced learning deficit

was accompanied by a significant down-regulation of the beta-adrenergic receptor in the response-deficient rats. This was expected

for the TCAs such as imipramine , which have previously been shown

to down-regulate beta receptors. It was surprising that the

behavioral changes and down-regulation by betareceptors induced by

imipramine appeared to be similar to, but faster than, the downregulation caused by this compound in naive animals. Imipramine

113
reversed the behavioral deficit and significantly down-regulated

the hippocampal beta receptors (25 percent down-regulation as

compared to control). Even more unexpected, mianserin lowered the

up-regulation of the beta receptor in response-deficient animals,

while causing no change in the hippocampal beta receptor of nondeficient rats. Mianserin had previously been shown not to downregulate the beta-adrenergic receptors in behaviorally naive rats

(Mishra et al. 1980). Mianserin reversed the behavioral deficit

and significantly down-regulated the hippocampal beta receptors of

response-deficient animals (28 percent down-regulation as compared

to control). Hence the up-regulated receptor seen in our animal

model may be either more sensitive to presynaptic influences or

under the exquisite control of a postsynaptic regulatory process.

So, specific drugs may have an exclusive effect on a pathologic

transmitter system while exhibiting no control over receptors in a

normal or naive animal.

NEUROREGULATORY ROLE OF 5-HT

Studies with mianserin and fluvoxamine suggested that a serotonergic mechanism may also be involved in the mediation of the deficit

produced by mild, uncontrollable shock. The decrease of serotonin

levels prevented the development of the shock-induced behavioral

deficit seen in our model. Sprague-Dawley rats pretreated with

PCPA, a known 5-HT synthesis inhibitor, exhibited shock-escape

scores similar to nondeficient and control rats (3.O±.17 PCPA

treated, vs. 7.6±3.3 saline treated, t=5.96, P<.001).

Bilateral lesions of serotonergic tracts with 5,7-dihydroxytryptamine (5,7-DHT) also prevented the development of shockinduced behavioral deficit after the training and testing

paradigm. Receptor binding assays or S2 receptors (

3

H-spiroperidol binding) and S1 receptors (3H-serotonin binding) in the

anterior neocortex and the hippocampus did not reveal any significant differences in either the affinity or the maximum number of

sites in response-deficient, nondeficient, or control rats. However, a normal level of 5-HT activity was necessary to maintain

beta levels in the hippocampus. Recent experiments in our laboratories revealed a significant down-regulation of hippocampal beta

receptors after various treatments known to influence 5-HT levels

and 5-HT transmission (BMax in fm/mg protein was 116.5±9.2 in

response-deficient rats, vs. 62.8±5.7 in 5-HT depleted rats).

These studies suggest that a feedback mechanism between noradrenergic and serotonin systems could act as a mediator of the behavioral and biochemical characteristics of our response-deficient

rats. Such an hypothesis would support the work of Sulser (1983),

who has suggested that an intact serotonergic input is necessary

for the down-regulation of beta receptors by various therapeutic

drugs.

Our current data do not disclose a simple relationship linking

drug-induced alterations in the 5-HT system, uncontrollable shock,

and behavioral deficits. However, we are focusing our research

114
efforts on the following anatomical circuit for our "learned

helplessness" model:

Anterior Neocortex ---> Hippocampus ---> Fornix ---> Septum

GABA NE GABA 5-HT

5-HT

This partial limbic circuit including the hippocampus and the

septum is modulated by neurotransmitter and neurohormonal inputs.

This complex functional "lobe" receives serotonergic, adrenergic,

cholinergic, and peptidergic input in addition to the local

circuitry.

DRUG ABUSE RESEARCH

This work points to the interplay of environmental and genetic

factors in defining the behavioral response to a defined stimulus.

It also shows that the behavioral changes are correlated with the

long-term CNS changes, a correlation that points to the adaptive

plasticity of the CNS. Since addictive behavior appears to share

an interplay between nature and nurture, it may be possible to

utilize animals bred for different responses to drug and alcohol

exposure in isolating anatomic pathways responsive, by addictive

behavior, to these environmental and chemical stimuli. In our

model, successful reversal of the deficit is not produced by stimulants such as amphetamine and cocaine as was found by Sherman et

al. (1979). The role of stimulants merits further testing; the

idea that a particular genetic substrate is required for altered

behavior to occur may be a powerful one for research into drug

abuse. As a start, we would suggest tests of self-administration

under conditions in which there is a wide behavioral response by

animals. The fact that stimulants and hallucinogens have actions

on amine systems also suggests that the circuit activated in our

stress model should be examined under conditions of drug use.

REFERENCES

Anderson, D.C.; Koehn, C.; Crowell, C.; and Lupo, J.V. Different

intensities of unsignalled inescapable shock treatments as

determinants of nonshock motivation open field behavior: A

resolution of disparate results. Physiol Behav 17:391-394,

1976.

Engel, G.; Hoyer, D.; Berthold, R.; and Wagner, H. (±)125Iodocyanopindolol, a new ligand for beta-receptors: Identification

and quantitation of subclasses of beta-adrenoceptors in guinea

pig. Naunyn-Smeideberg's Arch Pharmacol 317:277-285, 1981.

Goodkin, F. Rats learn the relationship between responding and

environmental events: An expansion of the learned helplessness

hypothesis. Learn Motiv 7:382-393, 1976.

Gilman, A.G. A protein binding assay of adenosine 3',5'-monophosphate. Proc Natl Acad Sci USA 67:305-312, 1970.

115
Henn. F.A.; Johnson, J.O.; Edwards, E.; and Anderson, D. Melancholia in rodents: Neurobiology and pharmacology.

Psychopharmacol Bull 21(3):443-446, 1985.

Katz, R.J. Animal models and human depressive disorders.

Neurosci Biobehav Rev 5(2):231-246, 1981.

Mishra, R.; Janowsky, A.; and Sulser, F. Action of mianserin and

zimelidine on the-norepinephrine receptor coupled adenylate

cyclase system in brain: Subsensitivity without reduction in

beta-adrenergic receptor binding. Neuropharm 19:983-987, 1980.

Rosellini, R.A.; and Seligman, M.E.P. Role of shock intensity in

the learned helplessness paradigm. Anim Learn Behav 6(2):143-

146, 1978.

Seligman, M.E.P., and Beagley, G. Learned helplessness in the

rat. J Comp Physiol Psychol 88:534-541, 1975.

Sherman, A.D.; Allers, G.L.; Petty, F.; and Henn, F.A. A neuropharmacologically-relevant animal model of depression.

Neuropharm 18:891-894, 1979

Sulser, F.; Manier, D.H.; Janowsky, A.J.; and Okada, F. Regulation of the noradrenergic receptor systems in brain that are

coupled to adenylate cyclase. J Neural Trans Suppl 18:121-130,

1983.

Weiss, J.M., and Glaser, H.I. The effects of acute exposure to

stressors on subsequent avoidance behavior. Psychosom Med

37:499-521, 1975.

Wilson, W.J., and Butcher, L.L. A potential shock reducing contingency in the back shock technique: Implications for learned

helplessness. Anim Learn Behav 8:435-440, 1980.

Zivin, J.A., and Wand, D.R. Mini review - How to analyze binding,

enzyme and uptake data: The simplest case, a single phase.

Life Science 30:1407-1422, 1982.

AUTHORS

Fritz A. Henn, Ph.D., M.D.

Professor and Chairman

Emmeline Edwards, Ph.D.

Instructor

David Anderson, M.S.

Research Associate

Department of Psychiatry

and Behavioral Science

State University of New York

at Stony Brook

Stony Brook, NY 11794

116
Clinical and Behavioral

Considerations in Emission

Tomography Study Design

Reese T. Jones

INTRODUCTION

Quantitative imaging of neuroreceptors in the living brain has

only recently passed beyond the "show and tell" demonstration of

feasibility and rather fuzzy, low resolution, computer-generated

images. Much remains to be done, but there is reason for optimism. As chemists become more skilled in synthesizing high specific activity, high affinity, and positron emitting radioligands.

we can expect experiments with Alzheimer's patients (acetylcholine

receptors), schizophrenics (dopamine receptors), opiate addicts

(the families of opioid receptors), tobacco addicts (nicotine

receptors), etc. Many hitherto untestable models of diseases (at

least untestable in humans), assumed to involve receptor dysfunction, will be put to the test.

A RETURN TO THE STUDY OF HUMAN PHARMACOLOGY

Positron emission tomography studies of neuroreceptors, particularly quantitative imaging, present a number of challenges to

currently popular research strategies. One major challenge is

that humans are probably the best subject population. Because of

the physics of emission tomography, a large brain is an asset.

Given the resolution of existing and likely instruments in the

near future, rodent brains are too small. Researchers could use

baboons or other large, nonhuman primates; however, the number of

large-brain primates available is relatively small compared with

humans. Even if available, the recording time to accumulate

satisfactory images is so long that the use of unanesthetized or

lightly restrained baboons in the usual emission tomography

setting is not practical. Studies of anesthetized primates are

not the most efficient research strategy if understanding relationships between receptor function and behavior or cognition is

the goal. Thus, largely because of the technological constraints,

the best research subjects are humans.

The promise of learning about human brain function is the great

advantage and justification for support of expensive, innovative

117
technologies. However, most of what we know for sure about receptor function, binding of drugs to receptors, and neurochemistry

comes from rodent tissue cell cultures (often homogenized and

separated) using research strategies and approaches that have not

had to deal with the problems of clinical studies. This chapter

will consider some of the practical problems of dealing with human

research subjects in tomography studies.

Despite justified optimism, proper application of emission tomography requires careful thought when posing research questions. It

will be a challenge to design experiments that efficiently confirm

specific hypotheses rather than simply demonstrate that predictions are correct. A host of neurochemical, chemical, biophysical, and radiologic considerations must be attended to. Other

chapters in this volume (Frost, this volume; Snyder, this volume)

suggest that with time and adequate resources most of these problems can be managed. Even when procedural and technological

problems are solved, some major constraints will remain for the

design of experiments by those interested in human behavior or

psychology. Limitations on experimental sample size, the special

task demands for research subjects in emission tomography studies,

feasibility of repeated measures, and uncertainty about which subjects may be adequate controls will test the skills of investigators attempting the early definitive experiments. Although my

focus here is on drug dependence research, many considerations are

general ones relevant to any emission tomography studies of brain

receptor function.

LEVELS OF CHALLENCE DEPEND ON QUESTIONS ASKED

There is a gradation of experiment complexity and demand on the

technology, depending on specific questions. To be most useful,

the imaging of receptors must provide quantitative indices. At

the simplest level, anatomic localization of many types of receptors is obviously feasible; the degree of success will depend

mostly on clever chemists producing a ligand with suitably selective and specific high-affinity binding and high-activity labelling. Physicists and engineers must provide high-resolution

machines. The studies at Johns Hopkins University, described in

other chapters (Frost, this volume; Snyder, this volume), show how

a large group of adequately supported scientists can enable us to

visualize receptor fields in a living brain. However, it is a

long step from the relatively crude anatomic localization of receptor fields to precise quantitative measures of receptor concentration, distribution, and activity necessary to investigate

mechanisms of disease states.

One limitation in existing technology is the relatively poor

resolving power of currently available imagers, though, at some

installations, resolving power close to the theoretical will soon

be available. For most neurological diseases that are thought to

involve neurotransmitter dysfunction, the variation in neuroreceptor concentrations seems relatively small. The utility of

emission tomography to quantify small, and probably variable,

118
deviations in receptor-field density in small anatomic structures,

for example, the locus coeruleus, must await confirmation. The

precise counting, or otherwise indexing, of numbers of receptors

is a greater task than the semiquantified demonstration of

relatively imprecise anatomic localization evinced so far.

The technology must ultimately provide quantitative indices of

receptor activity, that is, measures of uptake or turnover of

neurotransmitters or other dynamic indices of receptor activity.

Measuring levels of neurotransmitters only, be it in the brain or

elsewhere, tells relatively little about function and can be misleading. The turnover--the dynamics of neurotransmitters--is what

must be determined, which puts a great burden on our still relatively simple kinetic models that relate input and output functions to receptor concentrations. As yet, a complete in vivo

validation of relationships between neurotransmitter uptake or

turnover measures and receptor concentrations is lacking.

Validation in vivo in intact humans may be a formidable task.

MEASURING AMOUNT OF DRUG DELIVERED TO DRAIN

Measuring, even estimating, the actual delivered dose of a

labelled ligand to the brain is not a trivial problem. Dose

deliverance to a specific region of the body or organ is rarely

considered in psychopharmacologic experiments. For example, after

IV administration, before the ligand is available to bind to

receptors in the brain and emit positrons, it first must traverse

the arm, right heart, lung, and left heart before reaching the

brain. All the complexities of peripheral binding, disposition,

and metabolism must be determined before true quantitative indices

of brain measures can be obtained. What is the actual delivered

dose of ligand to brain? The dose , unfortunately, is going to be

different from the dose injected into a forearm vein. For exampie, the dose, or ratio of injected ligand to brain dose, may vary

with different ligands used to selectively label the families of

opiate receptors.

There are, of course, research strategies for measuring organ

dose. Some strategies are purely matters of proper application of

mechanics and plumbing (e.g., carotid artery or lung injections

compared with injections by other routes). The knottier scientific problem stems from the vicissitudes of quantifying peripheral

drug kinetics, particularly in tissues other than blood. This

quantification can barely be done adequately for the clinical

pharmacology studies that now go on. The proper application of

high technology will force us to deal with the measurement of

far smaller quantitative differences in the face of greater

unaccounted-for variability in drug kinetics.

SLOW MEASURES OF FAST SYSTEMS

The time necessary to accumulate a quantiffable image (currently,

under optimal conditions, about 1 minute; more typically, 15

minutes) places constraints on experimental design and limits

119
researchable questions. To a great extent, decreasing image

collection time is a matter of improving the chemistry and physics

of emission tomography. More efficient detection systems and

higher-activity ligands will decrease this time, but there still

will be a relatively narrow time span to work in when trying to

measure dynamic, and probably rapidly changing, neurochemical

events relating to a particular mental state or relating receptor

function to specific behaviors. Most mental states or behaviors

do not hold still for a minute; therefore, the measured receptor

activity may only reflect averaged events.

When attempting to measure a steady state (i.e., more trait-like

mental conditions), the time required for emission tomogram

collection is less of a consideration, and collection can be more

leisurely. But when moving further away from trait-determined

measures into behaviorally or psychologically dynamic states, then

time to accumulate an image becomes a primary consideration for

design of experiments. A previously new and exciting high technology development from 25 years ago (brain wave-evoked potentials

using an electrical index of brain activity) still has unsolved

problems with this limitation in attempting to measure brain

function correlates of rapidly changing behavioral, psychological,

or subjective states.

HOW RELIABLE ARE THE INDICES?

One tradeoff in using high-activity ligands is the dosimetry

factor, particularly, a more rapid cumulative exposure to radiation. When beginning experiments with any new technology, the

optimal research strategy should include measures of reliability,

whatever the measure. Reliability data will not rapidly accumulate since, with current technology, repeated doses of labelled

ligands may, by increments, rapidly exceed recommended radiation

exposure, at least in the case of normal, nondiseased volunteer

research subjects. Of course, when performing a procedure on

someone with an illness and the procedure is to that patient's

benefit, higher radiation doses may be rationalized (assuming it

is a well-designed experiment). Nevertheless, cumulative radiation dose remains a constraint for the near future,

A related consideration that has relevance to the use of highaffinity ligands and also depends on metabolic considerations is

that adding any drug, maybe even at what are assumed to be,

pharmacologically speaking, "tracer" doses, may perturb the biological system, particularly as the ligand becomes more potent and

more specific. Traditionally, most perturbations of a biological

system are thought to have a finite time course. It is assumed a

repeated drug challenge will give a similar response some hours,

days, or perhaps weeks later. But what if this new technology

provides the ultimate in sensitivity to small changes in receptor

function? Does that mean that the neuroreceptor correlates of

differences in sensitivity to opiates, as shown by behavioral

indices months or perhaps even a year after a single dose, may now

be evident? This possibility makes repeated-measure experiments a

120
little more complicated to interpret, assuming that emission

tomography provides a very sensitive measure.

MERGING NEURORECEPTOR AND PSYCHOLOGICAL MODELS

Other chapters in this volume (Frost, this volume; Snyder, this

volume) discuss neurochemistry, radiologic physics, and a variety

of psychological models and constructs. Implicit in this unusual

mix of topics is a hope or a promise that there should be some

linkage of emission tomography measures of neuroreceptor function

and psychological measures of function, states, and traits (e.g.,

sensation seeking, locus of control, and dependence). Actually

demonstrating such quantitative relationships, no matter how high

the technology, certainly will be akin to finding the Holy Grail.

Optimism should be tempered slightly by noting that, in much

simpler biological models (e.g., rodents or their isolated organs

in Ringer's solution), relationships between receptor-binding

kinetics, receptor function, and psychological function or behavfor have been modest demonstrations at best and, for the most

part, have not been thoroughly investigated. The question of why

clearly demonstrated and consistent relationships between receptor

kinetics and an organism's function are relatively rare, becomes

relevant when considering the application of an extremely highcost, relatively high-risk technology to address questions such as

the relationship between receptor kinetics in one organ system (in

this case, the brain) and behavior or mood. Is it a consequence

of inadequate technology that thus far this has been only tenuously demonstrated when using simpler technologies, or is there a

problem with our models?

WHAT RESEARCH SUBJECTS TO STUDY?

The already complicated list of subject populations appropriate

for the study of drug-dependence-related phenomena becomes more

complicated if one considers the subtypes of drug users described

in Dr. Forgays' chapter (Forgays, this volume). A minimal list of

populations in which one might expect differences in receptor

and/or psychological profiles and functions now includes the

following groups:

Nondrug users ("normal people") who have never used;

Drug users who are not patients in treatment and who:

(1) have no history of treatment,

(2) have a history of failed treatment,

(3) want to stop, or

(4) do not want to stop using drugs;

Former drug users, posttreatment;

Former drug users who are self-determined quitters, who have

never sought treatment.

121
This additional level of complexity of user vs. nonuser, treatment

vs. nontreatment subclassifications results from the considerations discussed in Dr. Forgays' chapter. One must assume that

there should be neurochemical/neurotransmitter and psychological

state/trait correlate differences for these subgroups. If not,

why should one, a priori, assume no differences?

Patient selection considerations in studies of the neurochemistry

or neurophysiology of any drug are complex. Given the special

constraints of emission tomography, subject selection becomes even

more important. For example, if a researcher studies current and

regular users of a drug (either the drug of interest or other

drugs), then abstinence syndromes become a potential confounding

problem. When studying opiate receptors, is it best to withhold

tobacco or coffee from the typical tobacco-smoking, coffeedrinking research subject before the experiment (as is often the

case) for 4, 8, or 12 hours, or is it best to allow regular drug

use? Depending on the researcher's choice, the research subject

is studied in the midst of some ill-defined withdrawal state that

must have neurochemical correlates, or in the midst of an equally

ill-defined drug-induced state, or perhaps somewhere between these

extremes. If a research subject is a regular user of almost any

psychoactive drug, there will be no readily attained, steady, nondrug state. Given the kinetics of most commonly abused or used

psychoactive drugs, the subject is either entering or leaving a

drug-induced state. A steady (or nondrugged) state in pharmacokinetic/dynamic terms is illusionary in psychopharmacologic

experiments employing people who use psychoactive drugs.

WHO ARE THE CONTROL OR COMPARISON RESEARCH SUBJECTS?

Researchers typically recruit a control sample of some sort of

"nondrug" users. Questions arise such as, who are they? do we

consider caffeine a drug? if we include caffeine users, do they

get their usual caffeine before the experiment, and what are the

implications of caffeine use on adenosine receptors and related

neurochemical consequences? Because there are no clear guidelines, to a great extent, the research questions must be

constrained. Much of what we know of neurochemistry has been

generated by studies of inbred, relatively pure genetic strains of

rodents or their even simpler isolated ileum strips or vas

deferens; such experimental preparations do not exist in human

studies. Furthermore, is a completely nondrug-using (no alcohol,

coffee, tobacco, etc.) human control subject a proper control for

many things? I doubt it. If diet to some extent alters neurochemistry, should we control or manipulate that as well?

One solution to the problems deliberately or accidentally posed by

recruiting addicts of one type or another is to create models of

dependent individuals in relatively short-term experiments. This

solution is feasible and, I would argue, not unethical with proper

informed consent. Some preliminary research questions may be

tested with the emission tomography technique by giving opiates,

stimulant drugs, or depressant drugs to nondrug users (or almost

122
nondrug users) for a long enough period of time to produce a

sufficient state of dependence.

SAMPLE SIZE

Generally, emission tomography studies that will include large

numbers of subjects in single experiments are unlikely. Large

here refers to large in the statistical data sense. Even though

the cost of an emission tomography experiment will gradually

decrease as technological efficiency is improved, it will still

remain relatively expensive to conduct this procedure for each

test subject. Considering the cost of cyclotron time or other

means of isotope generation, chemical synthesis and cleanup,

personnel, and amortization of rapidly depreciating equipment

(obsolescence is a rapid process in high technology), the total

cost to a granting agency or an institution for each subject

tested in experiments such as those considered in this volume is

in the range of $2,000 per test session. A pilot experiment could

easily cost $10,000 or more to study six subjects.

WILL GOOD MODELS BE PREMATURELY REJECTED OR BAD ONES LINGER?

If a goal is to relate receptor level neurochemical phenomena and

psychological phenomena, particularly concepts such as locus of

control, sensation seeking, or personality variables, studies with

sample sizes of six, or even two or three times that size, are not

likely to be very informative. Good hypotheses and ideas may be

prematurely discarded simply because of tests without adequate

statistical power. Erroneous assumptions of the existence of

relationships resulting from small sample sizes are less of a

problem. False assumptions of the presence of a phenomenon tend

to be disproven with replication. However, possibly good ideas or

good hypotheses relevant to drug dependence, if not confirmed by

the first hundred-thousand-dollar tomography study, may not be

studied again for some years, if ever. The size of samples most

likely to be studied makes impractical the testing of neuropsychological relationships that usually appear as 0.3 correlations where only 10 percent of the shared variance is accounted

for.

High technology research studies are not frequently repeated,

since only a relatively limited number of research groups will

have resources to repeat such an experiment and often will not be

inclined to do so. Eventually, when isotope generators become

portable and readily available and when inexpensive emission

tomography transducer rings approach the price of a personal

computer, this situation will change. But even when the hardware

becomes more available, the nature of quantitative receptor imaging is such that the system complexity, the demands on the subjects, and the enormous array of attractive new experiments will

make replication less common than should be the case with a developing technology. Even poorly posed research questions in this

area of inquiry have such enormous intellectual appeal that it is

unlikely that an investigative group would take time to replicate

123
someone else's work rather than proceed with their own "new"

exploratory or, as they might rationalize, more definitive

demonstrations of answers to their own questions.

THE TEST SETTING AND SPECIAL CONSEQUENCES

Currently, and likely for the near future, emission tomography

recording procedures demand relative immobility from research

patients. This need will decrease as technology and chemistry

improve, but it will remain to some degree. Computer processing

of images will improve the situation and correct for some movement, but for ultimate high resolution, relative immobility will

remain a requirement. Thus, many behavioral tasks will be awkward

to run during data collection. Subjects with impaired ability to

cooperate present additional problems.

The mental task assigned to a patient undergoing tomography may be

important. We have learned from emission tomography metabolic

studies that the working areas of the brain have different characteristics, different metabolic patterns, and different blood flow

than relatively quiescent areas. As more sophisticated research

questions are posed, one might assume that this will be true of

receptor function, probably even more so. There probably is no

test condition whereby we can assume that a patient is not performing some mental task or operation. The typical instruction,

"Just relax and don't think about anything," merely gives an

enormous range of options to a patient. The instruction, "Take

the number 938 and successively subtract 7, add 1 to each remainder, then give the final value at the end of the experiment,"

assigns a more specific, limited, and operationally defined

task. The experience during quantitative EEG recordings (an earlier high technology development which some researchers thought

would elucidate brain functions) suggests that individual differences and uncontrolled variance can be reduced by assigning a

task. Almost any task is better than no task. Simply instructing

a person whose head is inside a transducer ring to "lie still and

don't do or think about anything" is a task most humans appear not

to be able to carry out.

A potential problem may arise when assigning tasks. At some

level there should be interactions between psychological constructs such as locus of control, sensation seeking, introversion/

extraversion, and neurochemical/receptor function. The demands of

the test situation certainly will alter state, both psychological

and physiological, during the test procedure. Thus, the interactions of trait differences and state effects will need to be kept

in mind when using a sensitive, high resolution procedure purportedly measuring correlates of mental function. When dealing with

linear, monotonic functions, the complexity may be unravelled.

However, when nonmonotonic, nonlinear, inverted U, and other complex mathematical functions describe relationships among receptor

function, psychology, and behavior, clever experiments are

necessary if we are to understand these complex relationships.

124
CONCLUSION

The application of high technology to the study of human brain

function does not make the design of proper experiments any

easier. As the sensitivity and specificity of brain function

measures improve, attention must be paid to experimental design

considerations that were previously less important because our

measurement techniques were cruder.

ACKNOWLEDMENTS

National Institute on Drug Abuse grants DA01696 and DA00053

provided partial support for the preparation of this paper.

AUTHOR

Reese T. Jones, M.D.

Drug Dependence Research Center

Langley Porter Psychiatric Institute

University of California, San Francisco

San Francisco, CA 94143

125
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1 FINDINGS OF DRUG ABUSE RESEARCH. NCDAI out of stock

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2 OPERATIONAL DEFINITIONS IN SOCIO-BEHAVIORAL DRUG USE RESEARCH

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NCDAI out of stock

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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,

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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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11 DRUGS AND DRIVING. Robert Willette, Ph.D., ed.

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16 THE EPIDEMIOLOGY OF HEROIN AND OTHER NARCOTICS. Joan Dunne

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17 RESEARCH ON SMOKING BEHAVIOR. Murray E. Jarvik, M.D., Ph.D., et

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18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS.

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19 THE INTERNATIONAL CHALLENGE OF DRUG ABUSE. Robert C. Petersen,

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20 SELF-ADMINISTRATION OF ABUSED SUBSTANCES: METHODS FOR STUDY.

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21 PHENCYCLIDINE (PCP) ABUSE: AN APPRAISAL. Robert C. Petersen,

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22 QUASAR: QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS OF

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32 GC/MS ASSAYS FOR ABUSED DRUGS IN BODY FLUIDS. Rodger L. Foltz,

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