National Institute on Drug Abuse

RESEARCH

MONOGRAPH SERIES

Neurobilolgical

Models for

Evaluating

Mechanisms

Underlying Cocaine

Addiction

U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health

145
Neurobiological Models for

Evaluating Mechanisms

Underlying Cocaine Addiction

Editors:

Lynda Erinoff, Ph.D.

Roger M. Brown. Ph.D.

NIDA Research Monograph 145

1994

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

National Institutes of Health

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, MD 20857
ACKNOWLEDGMENT

This monograph is based on the papers from a technical review on

“Neurobiological Models for Evaluating Mechanisms Underlying Cocaine

Addiction and Potential Pharmacotherapies for Treating Cocaine Abuse”

held on November 9, 1991. The review meeting was sponsored by the

National Institute on Drug Abuse.

COPYRIGHT STATUS

The National Institute on Drug Abuse has obtained permission from the

copyright holders to reproduce certain previously published material as

noted in the text. Further reproduction of this copyrighted material is

permitted only as part of a reprinting of the entire publication or chapter.

For any other use, the copyright holder’s permission is required. All other

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

Opinions expressed in this volume are those of the authors and do not

necessarily reflect the opinions or official policy of the National Institute on

Drug Abuse or any other part of the U.S. Department of Health and Human

Services.

The U.S. Government does not endorse or favor any specific commercial

product or company. Trade, proprietary, or company names appearing in

this publication are used only because they are considered essential in the

context of the studies reported herein.

National Institute on Drug-Abuse

NIH Publication No. 94-3600

Printed 1994

NIDA Research Monographs are indexed in the Index Medicus. They are

selectively included in the coverage of American Statistics Index,

BioSciences Information Service, Chemical Abstracts, Current Contents,

Psychological Abstracts, and Psychopharmacology Abstracts.

i i
Contents

Page

Role for the Mesocortical Dopamine System in the Motivating

Effects of Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

George F. Koob, Barak Caine, Athina Markou, Luigi Pulvirenti,

and Freidbert Weiss

Dopamine, a Common Substrate for the Rewarding Effects of Brain

Stimulation Reward, Cocaine, and Morphine . . . . . . . . . . . . . . . . . . 19

Conan Kornetsky and Christine Duvauchelle

Neurobehavioral Pharmacology of Cocaine: Role for Serotonin in

Its Locomotor and Discriminative Stimulus Effects . . . . . . . . . . . . . . 4 0

Kathryn A. Cunningham and Patrick M. Callahan

A Review of the Effects of Dopaminergic Agents in Humans:

Implications for Medication Development . . . . . . . . . . . . . . . . . . . . . 67

Richard B. Rothman

Use of Rodent Self-Administration Models to Develop

Pharmacotherapies for Cocaine Abuse . . . . . . . . . . . . . . . . . . . . . . . . 88

Steven I. Dworkin and Raymond C. Pitts

Pharmacological and Behavioral Treatment of Cocaine Addiction:

Animal Models ......................................... 113

Marilyn E. Carroll

Preclinical Assessment of Cocaine Antagonist Drugs in Squirrel

Monkeys .............................................. 131

Jack Bergman

Cocaine Self-Administration Research: Treatment

Implications ......................................... 139

Richard W. Foltin and Marian W. Fischman

iii
Neurobiological Mechanisms Underlying the Acquisition and

Expression of Incentive Motivation by Cocaine-Associated

Stimuli: Relationship to Craving . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Agu Pert

Cocaine Reward and Cocaine Craving: The Role of Dopamine in

Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Roy A. Wise

iv
Role for the Mesocortical

Dopamine System in the

Motivating Effects of Cocaine

George F. Koob, Barak Caine, Athina Markou, Luigi Pulvirenti,

and Freidbert Weiss

The search for a neurobiological substrate for the stimulant and

reinforcing properties of cocaine has focused for some time on a

particular part of the forebrain, the mesocorticolimbic dopamine (DA)

system. This mesocorticolimbic DA system innervates the region of the

nucleus accumbens (NACC) (ventral striatum) in the anterior part of the

basal forebrain and appears to play a critical role in mediating the acute

reinforcing effects of cocaine and amphetamine.

This chapter reviews the role of mesocorticolimbic DA in the reinforcing

properties of psychomotor stimulants as measured by intravenous (IV)

drug self-administration in rats. In addition, the primary neuropharmacological mechanism for cocaine reinforcement provides a rich substrate for

studying nondopaminergic modulation of the reinforcing actions of

cocaine.

NEUROPHARMACOLOGICAL MECHANISM OF ACTION OF

COCAINE AND OTHER PSYCHOMOTOR STIMULANTS

Psychomotor stimulant drugs such as cocaine have important effects

on monoamine metabolism. Cocaine blocks noradrenaline,

5-hydroxytryptamine (serotonin), and DA reuptake and increases

monoamine turnover (Groppetti et al. 1973). Amphetamine has similar

effects on monoamine reuptake but also increases monoamine release and

blocks monoamine oxidase activity (Groppetti et al. 1973). The local

anesthetic properties of cocaine (for which it is still used clinically) are

not thought to be critical for the production of its acute reinforcing effects

in humans, since similar subjective effects cannot be observed with other

local anesthetics such as procaine (Fischman et al. 1983). However,

procaine is self-administered IV ‘in animal studies (Johanson 1980).

1
Dopamine and the Activating Effects of Psychomotor

Stimulants

In animals, cocaine and amphetamine acutely increase motor activity

(Groppetti et al. 1973), decrease food intake (Groppetti et al. 1973), have

psychomotor stimulant actions on operant behavior (Spealman et al.

1977), enhance conditioned responding for a variety of reinforcers

(Spealman et al. 1977), decrease thresholds for reinforcing brain

stimulation (Kornetsky and Esposito 1981), and are readily selfadministered IV (Koob et al. 1987a). As a psychomotor stimulant,

cocaine is shorter acting and less potent than amphetamine (Simon 1973).

Nevertheless, higher doses of cocaine produce the intensely stereotyped

behavior associated with amphetamine or apomorphine, although cocaine

may be less effective in provoking a maximal response (Simon 1973).

A critical role for mesocorticolimbic DA in the psychomotor-activating

effects of amphetamine was identified by the observation that microinjections of the DA receptor antagonist haloperidol into the NACC

blocked amphetamine-induced locomotor activity (Pijnenburg et al.

1975). Also, the locomotor activation produced by amphetamine or

cocaine was blocked by 6-hydroxydopamine (6-OHDA) lesions of the

NACC (Kelly and Iversen 1976; Kelly et al. 1975). This lesion effect

was thought to be largely due to DA depletion since a norepinephrinesparing lesion (6-OHDA plus pretreatment with the norepinephrine

reuptake blocker desmethylimipramine) remained effective in blocking

the effects of amphetamine and cocaine (Kelly and Iversen 1976; Kelly et

al. 1975). Furthermore, similar 6-OHDA lesions of the NACC blocked

the locomotor stimulant effects of d-amphetamine but not of caffeine or

scopolamine (Joyce and Koob 1981), heroin, or corticotropin-releasing

factor (Swerdlow and Koob 1985).

A Role for Dopamine in the Acute Reinforcing Effects of

Psychomotor Stimulants-Intracranial Self-Stimulation

Experimental situations implicating a role for DA in reward processes

have included studies of the effects of DA-releasing drugs on reward

thresholds (Kornetsky et al., this volume), measures of preference for the

environment paired with drug administration (Van der Kooy 1987), and

IV or intracerebral self-administration of the drug. Reward thresholds

have been measured using the procedure of intracranial self-stimulation

(ICSS) (Olds and Milner 1954). In this procedure, an animal selfadministers electrical stimulation to certain brain regions, effectively

2
short-circuiting the reinforcement process (Kornetsky et al., this volume).

Amphetamine and cocaine reduce ICSS reward thresholds using a

rate-independent procedure (Kornetsky and Esposito 1979, 1981), and

systemic injections of DA receptor antagonists such as pimozide produce

both reward and performance effects on ICSS using rate-intensity

methods, rate-frequency methods, and discrete-trial threshold procedures

(Kornetsky et al., this volume; Stellar and Rice 1989). The

reward-decreasing effect of amphetamine and cocaine on brain

stimulation reward (BSR) has been shown to be counteracted by DA

receptor antagonist treatment (Gallistel and Karras 1984; Kometsky et

al., this volume).

A limited amount of work has explored site-specific effects for the

facilitation of brain stimulation by psychomotor stimulants (Stellar and

Rice 1989). A study on rats used a choice procedure where the same

animals had continuous access to brain stimulation from three separate

electrodes via three concurrently available levers (Koob et al. 1977).

Current levels for ICSS were adjusted to produce equal rates of

responding for self-stimulation at each electrode. The rats, when injected

with d-amphetamine, selected a single lever for responding for different

lengths of time depending on the dose. The lever selected when the

animals were given moderate or high doses of d-amphetamine

corresponded to an electrode location that paralleled the course of the

mesocorticolimbic DA system. Taken together, these results suggest that

DA in the mesocorticolimbic DA system has a role in ICSS reward and

may mediate the facilitation of ICSS produced by psychomotor

stimulants.

A Role for Dopamine in the Acute Reinforcing Effects of

Drugs

DA has been strongly implicated in the reinforcing effects of cocaine and

amphetamine by studies employing IV self-administration of drugs. Rats

implanted with IV catheters and trained to self-administer cocaine with

limited access (3 hours/day) show a stable and regular drug intake over

each daily session. Rats are generally maintained on a low-requirement,

fixed-ratio (FR) schedule for IV infusion of the drug, such as an FR-1 or

FR-5. A special aspect of using these FR schedules and doses is that the

rats appear to regulate the amount of drug self-administered, showing an

inverse dose-effect function. Lowering the dose from the training level of

0.75 mg/kg per injection increases the number of self-administered

infusions and vice versa.

3
Low doses of DA receptor antagonists, when injected systemically,

reliably increase cocaine and amphetamine self-administration in rats

(Ettenberg et al. 1982; Yokel and Wise 1975). The animals seem to

compensate for decreases in the magnitude of reinforcement with an

increase in cocaine self-administration or a decrease in the interinjection

interval (ITI), a response similar to that produced by lowering the dose of

cocaine. This suggests that a partial blockade of DA receptors produces a

partial blockade of the reinforcing actions of cocaine.

In general, experiments investigating the effects of antagonists selective

for DA type 1 (D1) (Koob et al, 1987a) or DA type 2 (D2) (Bergman et al.

1990; Woolverton and Virus 1989) receptors on cocaine selfadministration suggest that both can decrease the reinforcing properties of

cocaine in rats and primates (Bergman et al., this volume) (figure 1).

Studies with intracranial microinjection of the D1 antagonist SCH 23390

have shown that the NACC (Maldonado et al. 1993) and subregions of

the NACC and the amygdala (Caine et al. 1993) may be particularly

sensitive to the D1 antagonist blockade of the reinforcing effects of

cocaine.

DA agonists typically have the opposite effect, decreasing cocaine

self-administration or increasing the ITI using these same parameters, an

effect similar to that produced by increasing the dose of cocaine (Hubner

and Koob 1990; Pulvirenti and Koob 1993). Recent results using a

selective DA type 3 (D3) agonist, 7-OHDPAT, show that this compound

potently decreases cocaine self-administration, suggesting a role for D3

receptors in cocaine reward (Caine and Koob 1993) (figure 2). This is

particularly intriguing, given the selective distribution of these D3

receptors in the terminal areas of the mesocorticolimbic DA system

(Levesque et al. 1992). These results suggest that D1 and D3 receptors in

the NACC may be particularly important for the reinforcing properties of

cocaine.

A role for mesocorticolimbic DA in the reinforcing properties of cocaine

and amphetamine was extended by the observation that 6-OHDA lesions

of the NACC produce extinction-like responding and a significant and

long-lasting decrease in self-administration of cocaine and amphetamine

over days (Lyness et al. 1979; Roberts et al. 1980). Not all animals

showed a clear extinction-like pattern of responding, suggesting that

factors other than the motivational aspects of cocaine reinforcement

might be altered.

4
1 2 3

Hours

1 2 3

Hours

FIGURE 1. Effects of subcutaneous injection of D, receptor

antagonist SCH 23390 (left side) and the D2 receptor

antagonist spiperone (right side) on cocaine selfadministration. Each point represents the average

hourly intake of cocaine by injection (n = 5). Doses are

in μg/kg. For SCH 23390, doses of 5, 10, and 20 μg/kg

significantly increased cocaine self-administration

(p < 0.05, Newman-Keuls test following analysis of

variance [ANOVA]). For spiperone, the dose of 10

μg/kg significantly increased cocaine self-administration (p < 0.05, paired t-test; overall ANOVA,

p > 0.05).

SOURCE: Taken with permission from Koob et al. (1987a)

5
0 4 8 12 16 20 24 28 32

Dose agonist per injection (μg)

FIGURE 2. (Panel a): Effects of D3 agonists on cocaine

self-administration in rats. Solid symbols indicate

doses significantly different from zero by independent

comparison (p < 0.05, Dunnett’s t-test following

ANOVA). (Panel b): The self-administration records

for a single animal. Each mark indicates delivery of a

cocaine infusion (0.25 mg of cocaine with 0-4 μg of

7-OHDPAT) after completion of five lever presses.

SOURCE: Taken with permission from Caine and Koob (1993)

6
To address this issue and to examine the anatomical specificity of this

effect, rats were trained to self-administer cocaine on a progressive ratio

schedule. In this procedure, the response requirement is increased after

each self-injection until each animal stops responding. This breakpoint

provides a reliable measure of the relative reinforcing value of a

self-administered drug. In rats with 6-OHDA lesions of the NACC, there

was a dramatic decrease in the FR value for which they continue to work

for cocaine (Koob et al. 1987b) (figure 3). Rats received continuous

reinforcement data averaged for the first 3 days postlesion (mean±SEM).

Rats received 8 μg 6-OHDA in 2 μL vehicle injected into the caudate

nucleus or NACC. Sham: vehicle (0.1 mg/mL ascorbic acid in saline)

injected controls. The middle dose (m) was 0.75 mg/kg 6-OHDA per

injection; M, twice this dose; L, half of this dose. These results show that

animals with the DA removed from the NACC (but not the corpus

striatum) fail to continue to work for cocaine, particularly when the work

requirements (e.g., cost in effort) are increased. Similar DA-depleting

lesions of the caudate nucleus failed to significantly alter performance on

the progressive ratio test, indicating the specificity of the effect to the

NACC. These results suggest that DA denervation of the region of the

NACC can significantly blunt the motivation to respond for cocaine

reward. In a further study of the behavioral specificity of this effect, rats

were trained on a multiple schedule for food and cocaine, with FR-15

components for food and cocaine alternating every 30 minutes for 2

hours. DA denervation of the NACC decreased responding for cocaine

but not food in this paradigm (Caine and Koob 1994).

A Role for Dopamine in the Motivational Aspects of

Withdrawal Associated With Psychomotor Stimulants

Cocaine withdrawal in dependent subjects is not characterized by the

obvious physical signs like those observed with opiates or sedativehypnotics. Evidence exists in humans, however, to show that following a

cocaine binge, abstinence produces severe depressive symptoms

combined with irritability and anxiety (Gawin and Kleber 1986). These

symptoms last several hours to several days and form the state described

as a “crash” associated with the cocaine dependence cycle.

Anhedonia, or the inability to derive pleasure from normally pleasurable

stimuli, is one of the more salient symptoms of the crash stage and may

be one of the major motivating factors in the etiology and maintenance of

the cocaine dependence cycle. An animal model for anhedonia is an

increase in reward thresholds as measured with the ICSS procedure. As

7
FIGURE 3.

KEY:

SOURCE:

Effects of 6-OHDA

lesions to the NACC

and caudate nucleus

(caudate) on responding in rats selfadministering cocaine.

(Top) continuous

reinforcement;

(middle) dose-effect

functions for each

group; and (bottom)

mean rewards and

mean highest ratio

obtained by each

group on the

progressive ratio

probe.

*Significantly different

from sham group,

p< 0.05 NewmanKeuls test.

Taken with permission

from Koob et al.

(1987b)

8
discussed above, cocaine, injected acutely, lowers self-stimulation

thresholds in rats (Kornetsky and Esposito 1981); this enhancement of

reward is likely to involve the mesocorticolimbic DA system.

One hypothesis is that the withdrawal from chronic self-administration of

cocaine may result in the opposite effect, that is, an increase in brain

stimulation thresholds. To test this hypothesis, rats were allowed to

self-administer cocaine IV for long periods, and reward thresholds were

monitored during the course of cocaine withdrawal (Markou and Koob

1991a). The animals were allowed to self-administer cocaine for

different time periods (3, 6, 12, 24, and 48 hours using a within-subject

design). Brain stimulation thresholds were determined at varying times

after the termination of the self-administration session (0, 1, 3, 6, 12, 24,

48, and 72 hours). Withdrawal from prolonged cocaine self-stimulation

resulted in elevated BSR thresholds, compared to predrug baseline levels

and compared to thresholds of control animals. The magnitude and

duration of the elevation in reward thresholds was proportional to the

amount of cocaine self-administered, that is, the duration of the

self-administration session (figure 4). The results are expressed as

percent change from baseline threshold levels: for the experimental

group, 37.4±2.5 μA, and for the control group, 35.9±3.1 μA

(mean±SEM). This elevation in reward threshold may reflect the state of

the brain’s motivational systems and, as such, may be homologous to the

anhedonia reported by human cocaine users (Gawin and Kleber 1986).

The effect of cocaine withdrawal on ICSS thresholds was opposite to the

effect of acute cocaine (Kornetsky and Esposito 1981), suggesting that

during the course of a cocaine self-administration bout and withdrawal

the drug can dramatically alter the substrates in the medial forebrain

bundle that mediate BSR. Similar elevations in reward thresholds have

been observed during withdrawal following chronic amphetamine

administration (Kokkinidis et al. 1980).

The neurochemical basis for the elevation in reward thresholds may, at

least in part, involve mesocorticolimbic DA. This would involve a

within-system adaptation; that is, an adaptation where the primary

molecular or cellular response responsible for the positive hedonic effects

of the drug would itself adapt to neutralize the effects of the drug, and

subsequent removal of the drug would produce the withdrawal effect.

The withdrawal effect in this case is reflected in an increase in reward

thresholds. Consistent with this hypothesis, recent data from

microdialysis studies using the same experimental design as that for

9
Hours Post Cocaine

FIGURE 4. Intracranial self-stimulation thresholds at

several time points after cocaine withdrawal following the self-administration of

cocaine for periods of 3 to 48 hours. The

asterisks indicate statistically significant

differences (p < 0.05) between control and

experimental groups (Dunnett’s test),

following a significant group x hours

interaction in an ANOVA. These results

show that prolonged chronic IV

self-administration of cocaine produces a

dose-related increase in reward thresholds

(anhedonia) that can persist for several

days after the highest dose.

SOURCE: Taken with permission from Markou and

Koob (1991a)

10
chronic cocaine reward threshold studies showed that chronic

self-administration of cocaine produces a decrease in DA release in the

NACC at the time points associated with the greatest increases in reward

thresholds (Weiss et al. 1992) (figure 5). As can be seen in figure 5, DA

release was significantly suppressed below basal levels between 2 to 6

hours postcocaine. Although DA levels tended to increase between 8 and

12 hours after onset of the withdrawal period, DA overflow remained

significantly below presession basal values for the cocaine group. The

dotted line represents mean presession basal DA levels for cocaine selfadministering rats. Control data in panels 5(b) and 5(c) correspond to the

mean duration of approximately 14 hours of self-administration for the

cocaine rats. Note also that precocaine basal DA levels in trained,

cocaine self-administering rats were significantly higher than in

drug-naive control rats (panel a). Control rats (n = 3) were drug-naive

animals placed in the self-administration chambers for 30 hours without

access to cocaine. Importantly, this decrease may account for the

observation that bromocriptine can reverse cocaine-induced increases in

reward threshold during cocaine withdrawal (Markou and Koob 1991b ).

This decrease in extracellular DA, however, is not of great magnitude

(approximately 50 percent). Other neurochemical systems may be

involved as a between-system adaptation; a different neurotransmitter

pathway and separate molecular and cellular apparatus would be triggered by the changes in the primary system responsible for the positive

hedonic effects of the drug. Removal of the drug would then unmask the

activity of this system to produce the anhedonia of withdrawal. Such a

between-system interaction may ultimately interface with the

mesocorticolimbic DA system to effect motivational changes.

Nondopaminergic Interactions With the Mesocorticolimbic

Dopamine System

The neurobiological interfaces of the mesocorticolimbic DA system with

the limbic system and the extrapyramidal motor system provide a rich

substrate for potential nondopaminergic interactions in cocaine

dependence. The region of the NACC (ventral striatum) receives

important limbic system (e.g., amygdala, hippocampus, and frontal

cortex) afferents that may be critically involved in reward. These

afferents appear to be glutamatergic, and they may modulate the function

of DA in the NACC. In fact, local intracerebral injection of glutamate

receptor antagonists into the NACC attenuates the locomotor-activating

11
FIGURE 5. Mean±SEM DA levels in microdialysate fractions

collected from the NACC of rats (n = 5) before, during,

and after an unlimited access cocaine selfadministration session. (Panel a): Basal DA levels

during two 1-hour periods in the home cage and 30

minutes in the self-administration chamber prior to

cocaine access. (Panel b): Response rates for cocaine

(inset) and DA levels during cocaine

self-administration averaged over the first 3 hours,

midsession (total self-administration session time

minus the first 3 hours and the last 1 hour), and the

final 1 hour of self-administration. (Panel c):

Dialysate DA concentrations during cocaine

withdrawal.

KEY: *p < 0.05, **p < 0.01; significantly different from

presession basal levels (Newman-Keuls posthoc tests

following a significant ANOVA).

*p < 0.02; significantly different from controls.

SOURCE: Taken with permission from Weiss et al. (1992)

The efferent connections from the NACC to the region of the substantia

innomiuat/ventral pallidum may be an important site in the subsequent

processing of the reinforcing effects of cocaine. Cell body lesions (kainic

acid) of the NACC block cocaine self-administration (Dworkin et al.

1988; Zito et al. 1985), and ventral pallidal/substantia innominata cell

12
properties of cocaine and cocaine reinforcement as measured by IV selfadministration (Pulvirenti and Koob 1993; Pulvirenti et al. 1991).

The efferent connections from the NACC to the region of the substantia

innominata/ventral pallidum may be an important site in the subsequent

processing of the reinforcing effects of cocaine. Cell body lesions (kainic

acid) of the NACC block cocaine self-administration (Dworkin et al.

1988; Zito et al. 1985), and ventral pallidal/substantia innominata cell

body lesions (ibotenic acid) have similar effects (Hubner and Koob

1987). Subsections of this region that appear to be critical for this

functional output of the NACC involve the medial parts of the ventral

pallidum/substantia innominata, also called the sublenticular extended

amygdala (Robledo and Koob 1993). Together these studies suggest that

certain subsets of neurons in the region of the NACC may be critical for

mediating the acute reinforcing properties of psychomotor stimulants and

that this NACC/sublenticular extended amygdala circuit (connection)

may be a second-order link for stimulant reinforcement.

Recent studies suggest that there are common neurochemical,

cytoarchitectural, and circuit connections between subparts of the NACC

(the shell), the bed nucleus of the stria terminalis, and the central nucleus

of the amygdala (Alheid and Heimer 1988; Koob et al. 1993). This has

led to the hypothesis that the extended amygdala may be of functional

importance for motivation in general and motivation for cocaine

self-administration in particular (Koob et al. 1993).

The afferents and efferents to the NACC DA system provide a rich

substrate for the development of means by which to modulate the

reinforcing actions of cocaine without directly acting on the mesocorticolimbic DA system. This may provide a key to understanding

the relationship of the behavioral properties of rewarding stimuli to the

subjective feelings of pleasure or emotion in humans. Such knowledge

may provide clues for the development of novel pharmacotherapies for

the treatment of cocaine dependence and the treatment of the psychopathology associated with cocaine intoxication and dependence.

13
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ACKNOWLEDGMENTS

This work was supported by grants DA 04398 (GFK), DA 07348 (FW),

DA 05478, and DA 05444 from the National Institute on Drug Abuse.

Luigi Pulvirenti was the recipient of a fellowship from the Istituto

Superiore di Sanita, Italy.

17
AUTHORS

George F. Koob, Ph.D.

Member (Professor)

Barak Came, B.A.

Predoctoral Fellow

Athina Markou, Ph.D.

Postdoctoral Fellow

Luigi Pulvirenti, M.D.

Visiting Assistant Professor

Friedbert Weiss, Ph.D.

Assistant Member (Assistant Professor)

Department of Neuropharmacology

The Scripps Research Institute

10666 North Torrey Pines Road

La Jolla, CA 92037

18
Dopamine, a Common Substrate

for the Rewarding Effects of Brain

Stimulation Reward, Cocaine, and

Morphine

Conan Kornetsky and Christine Duvauchelle

INTRODUCTION

Brain stimulation reward (BSR) is among the animal models used for

studying the neurobiology and neurochemistry of the rewarding effects of

abused substances. There have been numerous papers and reviews

demonstrating and attesting to the validity of BSR as a model for the

study of neuronal bases for the rewarding effects of abused substances

(Izenwasser and Kornetsky 1992; Phillips and Fibiger 1989; Steller and

Rice 1989; Unterwald and Kornetsky 1993). Cocaine, as well as most

other abused substances, increases the rate of response for intracranial

rewarding stimulation and lowers the threshold for the stimulation. The

most common sites for stimulation in these experiments were the medial

forebrain bundle (MFB) and the ventral tegmental area (VTA). The

thesis of this chapter is that BSR itself is a model for the rewarding

effects of cocaine and the abused opioids and that the underlying

mechanisms involved in BSR are similar to those of these abused

substances.

The first description of the effects of cocaine on BSR was published by

Crow (1970). Figure 1 is a tracing from the Crow paper of a cumulative

record of a rat’s rate of response after receiving 5.0 mg/kg of cocaine,

showing a marked increase in the rate of response caused by cocaine.

However, there are earlier reports of the facilitative effects of

amphetamine, a psychomotor stimulant with many of the same effects as

cocaine, on BSR (Killam et al. 1957; Stein 1964). The effect of cocaine

on BSR was replicated by Wauquier and Niemegeers (1974) using rate of

response (as in the Crow experiment) as the dependent variable. Since

these early papers, a number of investigators have shown that cocaine

(Esposito et al. 1978; Frank et al. 1988; Kornetsky and Esposito 1981;

Moody and Frank 1990) and other dopamine (DA) agonists (Cassens and

Mills 1973; Esposito et al. 1980; Izenwasser and Kornetsky 1989; Leith

and Barrett 1976) increase the rate of response or lower the threshold for

19
FIGURE 1. A tracing of the first published figure of the

effects of cocaine on BSR. Shown is the

cumulative record, continuous reinforcement

schedule, of 5 mg/kg of cocaine in a single rat on

rate of response

SOURCE: Crow (1970)

for rewarding brain stimulation. Figure 2 illustrates the thresholdlowering effects of cocaine on the BSR threshold.

The threshold-lowering effect of abused substances on BSR is a useful

predictive model for the abuse liability of various substances. The more

important questions, however, are why these abused substances increase

the sensitivity of an animal to this very artificial rewarding stimulation,

and whether there is similar activation of the same neuronal systems.

The threshold-lowering effects of cocaine or other abused substances are

clearly not the result of a general central nervous system (CNS)-

stimulating effect. The discrete trial psychophysical threshold method is

independent of motor effects (Esposito and Kornetsky 1977; Kornetsky

and Bain 1990; Markou and Koob 1992.) The abused opioids that have

marked dose-dependent depressant motor effects robustly lower the

threshold for rewarding brain stimulation (Hubner and Kornetsky 1992;

20
COCAINE (mg/kg)

FIGURE 2. Mean effects of various doses of cocaine on the

threshold for BSR. Saline levels are indicated by z =

2.0, and a z-score of ±2.0 indicates the 95 percent

confidence limits for individual animals. Scores in the

negative direction indicate a lowering of the

threshold,

SOURCE: Kornetsky and Esposito (1981)

Marcus and Kornetsky 1974). Furthermore, cocaine lowers the threshold

for rewarding brain stimulation at doses that raise the threshold for the

detection of nonrewarding intracranial stimulation (Kornetsky and

Esposito 198 1).

Although the facilitating effects of the psychomotor stimulants on BSR

were demonstrated relatively easily, the earliest experiment on the effects

of opioids on BSR yielded ambivalent results (Olds and Travis 1960).

The first published report demonstrating that an abused opioid increases

responding for rewarding brain stimulation was by Lorens and Mitchell

(1973). This was followed by a paper showing that morphine lowered

the threshold for BSR using a rate-independent procedure (Marcus and

21
Kornetsky 1974). A number of subsequent experiments confirmed these

early findings. Figure 3 illustrates the threshold-lowering effects of

heroin and its two metabolites, morphine and 6-acetylmorphine, on BSR

(Hubner and Kornetsky 1992).

Sensitization of the Effects of Cocaine and Morphine

A common effect of repeated doses of cocaine and other drugs with

known indirect DA agonist effects is sensitization to the motor effects

(Kalivas et al. 1988; Post and Weiss 1989). There are a number of

reports that argue for a role for DA in the cocaine-induced stereotypy

(Akimoto et al. 1989; Kalivas and Duffy 1990, 1993; Pettit et al. 1990).

However, there is some evidence indicating that behavioral sensitization

can occur without concomitant changes in extracellular DA. Kalivas and

Duffy (1993) concluded that the expression of increases in extracellular

DA was a function of both the dose of chronic cocaine administration and

the length of time between the end of chronic treatment and the cocaine

challenge. Although DA antagonists block the development of the

cocaine sensitization, they do not block the expression of previously

developed sensitization (Post et al. 1992).

Less well known is the sensitization to morphine-induced stereotypy

resulting from chronic high doses (Pollock and Kornetsky 1989). Three

high doses of morphine (10, 20, and 20 mg/kg) administered within a 24-

hour period result in repetitive oral stereotypy characterized by selfbiting or biting of the cage floor. There have been reports of this oral

stereotypy in the literature at least since 1963 (Martin et al. 1963).

Evidence of sensitization is seen in the reexpression of the biting

behavior caused by a 4 mg/kg dose of morphine as long as 6 months after

the initial three high-dose treatments with morphine (Pollock et al. 1990).

The results of this experiment are shown in table 1.

This sensitization to the stereotypic effects of morphine can be blocked

by the DA type 1 (D1) antagonist SCH 23390 (Pollock and Kornetsky

199 1). More recent experiments have demonstrated that the N-methyl-daspartate (NMDA) antagonist MK 801 blocks not only the development

of the sensitization but the expression of it, and suggests that DA’s role in

the etiology of this opiate-induced sensitization is mediated by action of

glutamate on the DA system (Livezey et al. 1993).

22
HEROIN (mg/kg)

MORPHINE (mg/kg)

6-ACETYLMORPHINE (mg/kg)

FIGURE 3. Mean±SEM standard score (z-score)

changes in the threshold for BSR for

heroin, morphine, and 6-

acetylmorphine.

SOURCE: Hubner and Kornetsky (1992)

23
TABLE 1. Incidence (# of rats in each group) of morphine-induced oral

stereotypy independent groups

Initial Rx 30 days 90 days 180 days 183 days

MS (N = 4)

SAL (N = 4)

MS (N = 4)

SAL (N = 4)

MS (N = 4)

SAL (N = 4)

KEY: * p = 0.03

** Although stereotypy was observed in 2 of the animals, it did

not meet the criterion of 5 consecutive minutes.

MS = morphine sulfate

SAL = saline

Although sensitization to the motor and stereotypic effects of both

cocaine and morphine has been demonstrated, there is less evidence of

sensitization to the effects of these drugs on BSR. Frank and colleagues

(1988) reported that cocaine administered for 18 consecutive days to rats

consistently lowered the BSR threshold but did not result in tolerance or

sensitization. Kokkinidis and McCarter (1990), however, found evidence

of sensitization that was dependent on the dosing schedule. The

difference in findings also could be the result of differences in the time of

testing after chronic cocaine administration.

Figure 4 illustrates the dose-response curves (Kornetsky and Bain 1982)

of the effects of morphine determined prior to chronic administration and

after 14 to 38 days of daily doses up to 30 mg/kg. The original purpose

of the figure was to illustrate the lack of tolerance to the thresholdlowering effects of morphine on BSR. Not only does the figure indicate

that there is no tolerance, but also that there is evidence of sensitization.

The dose-effect curve was displaced to the left, and the maximum

lowering of the threshold was greater after chronic administration.

24
FIGURE 4. Percent change in threshold (pre to post) from that of

saline before and after chronic morphine treatment (14

to 38 days) in the same animals (N = 9).

SOURCE: Kornetsky and Bain (1982)

Blocking of Opioid Effects by DA Antagonists and

Psychomotor Stimulant Effects by Opioid Antagonist on BSR

The threshold-lowering effect of morphine on BSR can be blocked by the

DA type 2 (D2) antagonist pimozide (Kornetsky and Porrino 1992; Sarkar

et al. 1992). The mu receptor agonist tyr-d-ala-gly-nme-phe-gly-ol

(DAMGO), applied directly to the nucleus accumbens (NACC) or the

olfactory tubercle (OT), lowers the BSR threshold (Duvauchelle et al.

1993) as robustly as subcutaneously administered morphine. Evidence

that this effect is DA-mediated was suggested by the blockade of this

effect by the D1

-D2 blocker cis-flupenthixol. This effect is illustrated in

figure 5.

25
CIS-FLU (mg/kg)

FIGURE 5. The reversal of the effects on the BSR threshold of intra

accumbens DAMGO by various doses of intraperitoneal

cis-flupenthixol (CIS-FLU) in a single animal. A z-score

of 0 indicates the saline threshold level. On the right are

given the equivalent stimulation levels in microamperes.

Only the 0.78 mg/kg dose of CIS-FLU, by itself;

significantly raised the threshold.

SOURCE: Duvauchelle and Kornetsky (1993)

The corollary to the finding that DA antagonists block the BSR

threshold-lowering effects of opioids is seen in experiments showing that

a number of the psychomotor stimulants can be blocked by opiate

antagonists (Bain and Kornetsky 1987; Esposito et al. 1980; Knapp and

Kornetsky 1989; Kornetsky and Bain 1990).

Self-Administration of Cocaine or Morphine, Common

Mechanism?

Using the self-administration paradigm, experimental evidence

suggesting similar mechanisms for the reinforcing effects of the

psychomotor stimulants and the abused opioids is less convincing than

the evidence derived from BSR experiments. Ettenberg and coworkers

(1982) were unable to alter cocaine self-administration by the

26
administration of an opiate antagonist, and a DA antagonist had little

effect on the self-administration of heroin. Pettit and colleagues (1984)

found that 6-hydroxydopamine (6-OHDA) lesions of the NACC had a

relatively greater effect than heroin in blocking self-administration of

cocaine. Zito and colleagues (1985) found that kainic acid lesions of the

NACC, which destroy cell bodies but leave fibers of passage intact,

blocked both cocaine and heroin self-administration. Koob and Goeders

(1989), in reviewing these experiments, suggest “that neurons in the

region of the nucleus accumbens-ventral pallidum circuit (connection)

may be a common second-order link for both stimulants and opiate

reward” (p. 232).

Most of the conflicting evidence suggesting that DA does not play a role

in the rewarding effects of opioids has used the drug self-administration

model. There has been a great deal of variability in results using the selfadministration model, despite the fact that it is probably the most

homologous model of human drug-taking behavior. Among the reasons

for this variability is the extent to which this behavior is scheduledependent. Changes in the reinforcement schedule can result in major

differences in drug intake (e.g., fixed-ratio [FR] 5 versus a progressive

ratio schedule).

The Role of Dopamine in BSR

Using in vivo microdialysis and in vivo voltometry, researchers have

found considerable evidence that rewarding brain stimulation to the VTA

results in an increase in DA release in the NACC (Blaha and Phillips

1990; Fibiger et al. 1987; Phillips et al. 1987). Further evidence for DA’s

importance in BSR is seen in lesion studies. Ipsilateral lesions, but not

contralateral 6-OHDA lesions, of the DA pathways in the lateral

hypothalamus blocked rewarding stimulation to the VTA but had little

effect on responding for stimulation to the NACC (Phillips and Fibiger

1989). The direct application of a DA agonist into projection sites of the

mesocorticolimbic system causes facilitation of BSR. Olds (1990)

induced DA receptor activation by intracerebral injections of DA,

d-amphetamine, and pargyline into the NACC and measured the selfstimulation rate of response from electrodes implanted in the MFB. This

intracerebral treatment resulted in facilitation of rates of response for

rewarding brain stimulation. There have been two preliminary reports of

increased sensitivity to amphetamine when applied directly into the

accumbens, as determined by the curve-shift method of determining BSR

27
changes. The stimulating electrodes were in the VTA (Colle and Wise

1986; Spencer and Steller 1986).

If DA is mediating BSR, then DA antagonists should decrease the rate of

response or raise the threshold for rewarding brain stimulation. Although

it is much easier to conclude that a lowering of the BSR threshold is the

result of increased sensitivity to the rewarding stimulation, it is more

difficult to prove that drugs that raise the threshold are not doing so

because of an effect on motor function. A number of experiments, both

rate-independent and rate-dependent, show that DA antagonists decrease

the sensitivity of animals to rewarding brain stimulation. A summary of

much of this work is found in the review by Steller and Rice (1989).

Using the rate-independent threshold method, the D2 antagonist pimozide

raises the threshold for BSR at doses that have no effect on the animal’s

ability to recognize the presence or absence of nonrewarding stimuli via

the same stimulating electrode (Bird and Kornetsky 1990). This effect is

shown in figure 6. The D1-D2 antagonist cis-flupenthixol has been found

to raise the BSR threshold in a dose-dependent manner (Duvauchelle et

al. 1993).

Although all of these experiments implicate DA in BSR, they do not rule

out a role for other neurotransmitters either acting independently or

altering the DA system. For example, the absolute threshold for BSR

from the ventral tegmental nuclei of Gudden (VTG) was only slightly

higher than that obtained from the MFB (Sarkar et al. 1991). Although it

was believed that this site was primarily serotonergic, recent

immunocytochemistry studies indicate that the VTG does not contain

DA, serotonin, or noradrenergic cell bodies (Sarkar et al., unpublished

data). Figure 7 shows the lack of significant difference between threshold

levels obtained from both the MFB and the VTG.

Effects of BSR, Cocaine, and Morphine on Metabolic Rates of

Glucose Utilization

Further evidence that BSR, cocaine, and morphine have rewarding effects

that may be mediated by similar mechanisms was obtained in

experiments employing the quantitative 2-deoxyglucose method for

determining metabolic rates in specific brain structures. These

experiments determined the effects of BSR, cocaine alone, and morphine

alone, as well as the effects of BSR in the presence of each of these drugs

in the rat (Kornetsky et al. 1991; Porrino et al. 1990).

28
Dose Pimozide (mg/kg)

FIGURE 6. Mean z-score changes in the threshold for detection

of nonrewarding and rewarding intracranial

stimulation. Note that at doses that significantly

raise the BSR threshold, the detection threshold is

not significantly altered.

SOURCE: Bird and Kornetsky (1990)

Local cerebral metabolic rates of glucose utilization (LCMRglu) in rats

were determined under four conditions: control (saline), cocaine,

morphine, and BSR. A comparison of the metabolic rates under these

conditions yielded both similarities and differences. There was a strong

trend for BSR to increase metabolic rates throughout the brain, with a

similar but lesser trend after the administration of cocaine. This trend for

increases in LCMRglu was not seen after morphine. Morphine tended to

decrease metabolic activity throughout the brain with the exception of the

29
MFB VTG

Stimulation Site

FIGURE 7. A comparison of the BSR threshold obtained from

stimulation of the medial forebrain bundle (MFB) and

ventral tegmental nuclei of Gudden (VTG) in the same

animals. Although the VTG threshold was significantly

higher than that obtained from the MFB, acquisition of

the BSR behavior was acquired as easily as that for

MFB stimulation.

SOURCE: Sarkar et al. (1992)

OT, a finding not dissimilar to that of other investigators (Ito et al. 1983;

London et al. 1987). The OT was the only structure in which there was a

significant increase in metabolic activity caused by all three treatments.

The mesocorticolimbic structures, in which there were significant

changes from control levels, are illustrated in figure 8. Although the

increase in metabolic rate in the NACC did not reach a significant

statistical level (P < .05), it is included in the figure because of the

interest in the NACC as a major site implicated in rewarding effects of

abused substances. The distribution of the effects of BSR on metabolic

rates are not dissimilar to those seen in other reports of the effects of

30
FIGURE 8. A comparison of the LCMRglu rates for animals treated

with saline, morphine (4mg/kg, SC), cocaine (10 mg/kg,

ip), and lever-pressing for rewarding brain

stimulation. Data are presented for the nucleus

accumbens (NACC), the olfactory tubercle (OT), and

the medial prefrontal cortex (MFC)

SOURCE: Data from Porrino et al. (1990) and Kornetsky et al.

(1991)

cocaine (Porrino 1992) or in which BSR was obtained from other brain

reward sites (Esposito et al. 1984; Porrino et al. 1984).

Is BSR Itself a Model for the Rewarding Effects of Drugs?

If brain stimulation, cocaine (or other psychomotor stimulants), or

morphine (or other abused opioids) are affecting similar systems, are

there similarities in the subjective effects of the experiences?

Theoretically, the question could be answered using the drug

discrimination (DD) procedure. Is there generalization between

rewarding electrical stimulation and cocaine? Because of the marked

differences between the physical characteristics of brain stimulation (e.g.,

duration of stimulation and the pharmacokinetics of cocaine), it is highly

31
unlikely that generalization from one to the other could be established.

Lepore and Franklin (1992), however, modeled the kinetics of drug

effects with frequency-modulated trains of brain stimulation. These

trains of stimulation had a time course that resembled the time course of

drugs in the brain. Thus, there would be an increment in frequency of

stimulation to model the gradual increase in drug brain levels after drug

administration, followed by a delay in frequency that modeled the

elimination half-life of a drug. Under these conditions, as opposed to a

fixed frequency, increasing the increment in the stimulation train (dose)

resulted in a decrease in response rate. This is illustrated in figure 9.

Is Electrical Stimulation to Humans Rewarding, and Does It

Mimic Drug Effects?

A more direct validation of the reinforcing effects of BSR and its

similarity to the rewarding effects of drugs is found in the reports of

human subjects who have received electrical stimulation to the brain.

The use of electrical stimulation to discrete brain sites has been carried

out in human subjects for the control of intractable pain and in the belief

that such brain stimulation might have a palliative effect on the symptoms

associated with schizophrenia, These studies were carried out in the early

1950s (Heath and Mickle 1960; Sem-Jacobsen and Torkildsen 1960).

Many of the patients in these clinical experiments reported positive

feeling from such stimulation, with some of them alluding to its feeling

like sexual stimulation. Sem-Jacobsen and Torkildsen (1960), in

reviewing their finding with depth intracerebral electrical stimulation in

human subjects, stated that subjects reported pleasant as well as

unpleasant sensations. These sensations were dependent on the

placement of the electrodes. “In some regions they like to keep the

stimulus on for a prolonged period, only interrupted by short breaks. In

other areas; they seem to get the most pleasure by frequently starting and

stopping the stimulus” (p. 284). They also reported a patient in whom the

stimulation “evoked a fluttering in a muscle group in the pelvis which

tickled the patient and she responded with joy and laughter” (p. 284).

Whether these feelings are similar to those elicited by cocaine could only

be determined if a subject had experienced both the drug and electrical

stimulation. Certainly cocaine elicits feelings of well-being and a rush

that has been described by some as sexual in nature. Freud (1974), in his

treatise on cocaine, Uber Coca, did not let this effect escape him. He

wrote, “Among the persons to whom I have-given coca, three reported

violent sexual excitement which they unhesitatingly attributed to coca”

32
Log “Dose” (Hz)

FIGURE 9. Relationship between the size of the

increment in frequency of the BSR

(“dose”) and the self-administration

response rate.

SOURCE: Lepore and Franklin (1992)

(p. 73). Although opioids tend to cause relaxation in abusers, they often

report that the rush after an intravenous (IV) injection is similar to that of

an orgasm (Chessick 1960), a report not dissimilar to that of the

cocaine/crack user.

SUMMARY AND CONCLUSIONS

These experiments suggest that the neuronal mechanisms involved in the

rewarding effects of BSR are similar to those for cocaine and, to a

significant degree, those of morphine. Although there is considerable

evidence that DA plays a significant role in the mechanisms involved in

these reinforcing effects of abused substances and BSR, it is highly

unlikely that the reinforcing effects can be explained by DA alone.

Although many studies suggest that DA is at least necessary but not

sufficient, there is other evidence discussed in this monograph suggesting

a major role for other neuronal systems.

33
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ACKNOWLEDGMENTS

This work was supported in part by grant nos. DA02326 and DA05100

from the National Institute on Drug Abuse (NIDA) and by Research

Scientist Award no. DA00099 from the NIDA to Conan Kornetsky.

AUTHORS

Conan Kornetsky, Ph.D.

Professor, Departments of Psychiatry and Pharmacology

Division of Psychiatry

Boston University School of Medicine

80 East Concord Street

Boston, MA 02118

Christine L. Duvauchelle, Ph.D.

Research Associate

Psychology Department

Arizona State University

Tempe, AZ 85287-2702

39
Neurobehavioral Pharmacology of

Cocaine: Role for Serotonin in Its

Locomotor and Discriminative

Stimulus Effects

Kathryn A. Cunningham and Patrick M. Callahan

INTRODUCTION

The highly abused psychostimulant cocaine elicits psychological

manifestations in humans (e.g., mood elevation, euphoria) that have been

well described and are similar to those of the amphetamines (Fischman et

al. 1976). With continued use or high doses of cocaine, psychiatric

disorders such as anxiety, panic attacks, depression, and paranoid

psychosis, as well as toxic physiological reactions, have been reported

(Lowenstein et al. 1987; Post 1975). In rodents, cocaine stimulates

locomotor activity at low doses and stereotypy and convulsions at higher

doses (Kilbey and Ellinwood 1976; Post and Comel 1983; Robinson and

Becker 1986; Scheel-Kruger et al. 1976). Repeated treatment with

cocaine results in the development of either tolerance or a progressive

enhancement of these behaviors (i.e., sensitization) (Post and Contel

1983; Robinson and Becker 1986). In addition to these effects on motor

activity, cocaine is also a highly efficacious reinforcer that maintains

operant responding (de Wit and Wise 1977; Pettit et al. 1984; Roberts et

al. 1980) and produces interoceptive stimulus effects easily discriminable

from saline (Callahan and Cunningham 1993a; Callahan et al. 1991;

Colpaert et al. 1979; Witkin et al. 1991).

The behavioral effects of acute and chronic cocaine administration clearly

depend upon intact dopamine (DA) function, particularly within

mesolimbic pathways that originate in the DA somata of the ventral

tegmental area (VTA) and terminate in limbic forebrain nuclei, including

the nucleus accumbens (NACC) (Fallon and Moore 1978; Swanson

1982). Cocaine binds to the DA transporter (Ritz et al. 1987) and inhibits

DA reuptake from the synapse (Koe 1976), prolonging the normal

stimulation of DA receptors. The potentiation of mesolimbic DA

transmission appears to mediate the locomotor stimulatory (Delfs et al.

1990; Kelly and Iversen 1976; Kilbey and Ellinwood 1976;

Scheel-Kruger et al. 1976), rewarding (de Wit and Wise 1977; Pettit et al.

40
1984; Roberts et al. 1980), and discriminative effects of cocaine

(Callahan et al. 1991, 1994; Colpaert et al. 1979; Dworkin and Smith

1988; Witkin et al. 1991; Wood and Emmett-Oglesby 1989), as well as

play a critical role in the development of cocaine sensitization (Henry and

White 1991; Kalivas and Duffy 1990; Pettit et al. 1990; Post and Contel

1983; Robinson and Becker 1986).

While both presynaptic DA somata and terminals, as well as postsynaptic

DA receptors located on non-DA neurons, are vital targets for its indirect

DA agonist actions, cocaine is not a selective DA reuptake inhibitor and

does not share an identical behavioral profile with such compounds,

particularly with regard to abuse liability (Bergman et al. 1989; Lamb and

Griffiths 1990).

The differentiation between cocaine and selective DA reuptake inhibitors

could be related to other pharmacological actions of cocaine. This

psychostimulant is a local anesthetic (Ritchie and Greengard 1966) and

inhibits the reuptake of serotonin (5-hydroxytryptamine [5-HT]) and

norepinephrine (NE) (Koe 1976) with at least equal potency and efficacy

as that of DA reuptake. In addition, cocaine has affinity for the 5-HT3

receptor (Kilpatrick et al. 1989), M1 and M2 muscarinic receptors

(Sharkey et al. 1988a), and u-receptors (Sharkey et al. 1988b). Thus, the

actions of cocaine on each of these non-DA systems probably contribute

to cocaine’s overall behavioral profile.

The purpose of this chapter is to review evidence to support the

contribution of 5-HT to two well-characterized behavioral effects of

cocaine in rodents: its hypermotive and discriminative stimulus effects.

It is the authors’ intent to address this question in light of available data

and to indicate gaps in the current knowledge of this topic.

ROLE FOR 5-HT IN THE MOTOR STIMULATORY EFFECTS OF

ACUTE COCAINE

Of the behavioral effects of cocaine, modifications in motor behavior

have been studied extensively over the last 15 years. Cocaine dosedependently increases horizontal and vertical (rearing) motor activity and

induces stereotypies (e.g., sniffing, head weaves, forepaw treading) at

high doses or upon chronic administration (Berman et al. 1982; Post and

Contel 1983; Robinson and Becker 1986; Scheel-Kruger et al. 1976).

The ability of cocaine and its structural analogs to induce hyperactivity

41
correlates with its actions as a DA reuptake blocker (Heikkila et al. 1979),

while 6-hydroxydopamine (6-OHDA) lesions (Kelly and Iversen 1976)

and DA antagonists (Spealman et al. 1992) block this behavioral effect.

Thus, DA is clearly a prominent mediator of motor activation elicited by

cocaine.

Appraisal of cocaine-induced hyperactivity following administration of

5-HT agonists and antagonists or depletion of 5-HT comprises the chief

pharmacological approach to studying the involvement of 5-HT in this

behavior (table 1). In early studies, the 5-HT precursor 5-hydroxytryptophan (5-HTP) was reported to reduce cocaine-evoked hyperlocomotion and stereotypies (Pradhan et al. 1978; Scheel-Kruger et al.

1976; Taylor and Ho 1979). The nonselective 5-HT antagonist

metergoline potentiated cocaine-induced hyperactivity and converted the

mild stereotypy observed following cocaine administration to the more

intense forms typically seen upon amphetamine administration (gnawing,

biting) (Scheel-Kruger et al. 1976), although another ergot derivative,

methysergide, had no effect on cocaine-induced hyperactivity in mice

(Reith 1990).

Induction of biting and licking was also seen following pretreatment with

the nonselective 5-HT antagonist cyproheptadine (Berman et al. 1982).

These authors suggested that cyproheptadine unmasked behaviors that are

putatively mediated by DA (intense gnawing, grooming), suggesting that

the expression of these DA stereotypies is inhibited by a serotonergic

action of cocaine (Berman et al. 1982; Taylor and Ho 1979). Following

pretreatment with p-chlorophenylalanine (PCPA), which depletes 5-HT

through inhibition of 5-HT synthesis, cocaine hypermotility was also

enhanced (Scheel-Kruger et al. 1976).

In sum, the decrease in cocaine-evoked hyperactivity induced by 5-HTP

and the increases elicited by blockade of 5-HT release or 5-HT depletion

are in keeping with the hypothesis that inhibitory 5-HT mechanisms may

influence cocaine-induced hyperactivity, as appears to be the case for

amphetamine. For example, global destruction of the raphe increases

spontaneous activity (Geyer et al. 1976; Lorens 1978) and levels of DA

metabolites in forebrain (Herve et al. 1979, 1981), raising the possibility

that both locomotion and DA mesolimbic function are under the control

of raphe neurons. These lesion-induced effects are in part related to a

loss of 5-HT neurons as psychostimulant-induced hyperactivity and

stereotypy are increased following selective 5-HT depletion (Gately et al.

1985; Geyer et al. 1976; Lorens 1978; Scheel-Kruger et al. 1976),

42
TABLE 1. Effect of 5-HT compounds on motor activity elicited by

cocaine*

5-HT Compound

Reuptake inhibitor

Effect on Cocaine-Induced

Motor Activity

Fluoxetine

Fluvoxamine

Paroxetine

Sertraline

Synthesis inhibitor

NC hyperactivity16

hyperactivity16

NC hyperactivity16

NC hyperactivity16

PCPA

Precursor

hyperactivity17’

18

5-HTP

5-HT1A agonists

hyperactivity14,17,19

stereotypy14

Gepirone (partial)

NAN 190 (partial)

5-HT3 antagonists

hyperactivity13

hyperactivity7

ICS 205,930

MDL 72222

Ondansetron

Zacopride

Nonselective antagonists

hyperactivity [rats18; mice15]

hyperactivity18

NC hyperactivity8

hyperactivity [rats18; mice15]

NC hyperactivity6

Cyproheptadine

Metergoline

induced gnawing, biting2†

hyperactivity17

induced biting, licking17†

Methysergide NC hyperactivity (mice)15

NOTE: * In most cases, a single dose of the 5-HT cormpound was

administered prior to assessment of motor behavior induced by one

acute injection of cocaine. All studies were conducted in rats

unless otherwise noted: and NC indicate increase, decrease,

and no change, respectively. Superscript numbers refer to citations

found in table 3.

KEY: † These stereotypies are not typically observed following injection

of cocaine alone.

43
although specific loss of raphe 5-HT neurons does not yield consistent

alterations in spontaneous locomotion (Geyer et al. 1976; Lorens 1978).

Serotonin neurons may, therefore, exert an inhibitory effect upon

cocaine-induced, DA-dependent hyperactivity and stereotypy.

Until recently, only nonselective 5-HT compounds had been assessed for

their effects on cocaine-elicited motor behavior, so the extent to which

the 5-HT transporter and specific 5-HT receptors might contribute to the

observed effects of 5-HT compounds on cocaine-induced behavior was

impossible to determine. In addition to the 5-HT transporter,

approximately 14 5-HT receptors have been identified, many of which

have been localized to the brain (5-HT1 [5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E,

5-HT1F], 5-HT2 [5-HT2A, 5-HT2B, 5-HT2C], 5-HT3, 5-HT4, 5-HT5 [5-HT5A,

5-HT5B], 5-HT6, 5-HT7) (Branchek 1993). Selective agonists and

antagonists that allow differentiation among these receptor subtypes are

unavailable in many cases, although selective 5-HT reuptake inhibitors

have been developed. Several recent attempts have been made to

characterize cocaine-induced motor activity following pharmacological

manipulations of the 5-HT system, using such compounds as the 5-HT1A

partial agonist gepirone, 5-HT reuptake inhibitors (e.g., fluoxetine), and

5-HT3 antagonists (e.g., zacopride).

The 5-HT1A receptor is found in abundance on 5-HT somata and

dendrites in the raphe nuclei; stimulation of this receptor by 5-HT1A

agonists results in a suppression of impulse activity of 5-HT neurons

(Sprouse and Aghajanian 1986) and a significant and reversible reduction

of 5-HT release in terminal areas (Adell et al. 1993; Sharp et al. 1989).

While most other compounds with affinity at this site are described as

partial agonists (e.g., gepirone, ipsapirone, NAN 190), 8-hydroxy-2-(din-propylamino) tetralin (8-OHDAPAT) is a reasonably selective agonist

for 5-HT1Areceptors.

Analogous to the case with PCPA, which depletes 5-HT preferentially in

terminal regions, 5-HT1A agonists might be expected to increase cocaineinduced behaviors based upon somatodendritic autoreceptor activation

and consequent reduction in 5-HT terminal release (Adell et al. 1993;

Sharp et al. 1989). To test this hypothesis, the partial 5-HT1A agonist

gepirone (7.5 mg/kg intraperitoneally [IP]) was administered 15 minutes

prior to a dose of cocaine (10 mg/kg, IP); this dose of gepirone did not

alter activity levels alone but did enhance acute cocaine-stimulated

hyperactivity (figure 1) (Paris et al. 1992).

44
Effects of Gepirone (7.5 mg/kg) on

Activity Induced by Cocaine (10 mg/kg)

Time (min)

FIGURE 1. The effects of the partial 5-HT1A agonist gepirone on

the activity induced by cocaine. Rats habituated to the

locomotor chamber were injected (thin arrow) with

saline (SAL) or gepirone (GEP; 7.5 mg/kg, IP),

followed 15 minutes later (thick arrow) by SAL or

cocaine (COC; 10 mg/kg, IP). Data are presented as

means of horizontal activity (±S.E.M.) measured in the

center and periphery of an open field chamber

equipped with a 4x4 photobeam matrix. Cocaine

(SAL-COC) elicited an increase in activity over saline

(SAL-SAL) or gepirone-treated rats (GEP-SAL), while

gepirone pretreatment (GEP-COC) significantly

enhanced the activity elicited by cocaine (* p < 0.05

versus SAL-COC). Gepirone (GEP-SAL) at this dose

did not alter activity from saline controls (SAL-SAL).

SOURCE: Adapted from Paris et al. (1992)

45
These data support the concept that the action of cocaine to enhance

5-HT availability normally counteracts the maximal output of the DA

system and, hence, maximal increase in motor activity. When the

impulse activity of 5-HT neurons is halted and 5-HT release diminished

due to pretreatment with 5-HT1A agonists, this normally dampening effect

of 5-HT is not apparent, and the locomotor stimulatory actions of cocaine

are enhanced.

In support of this hypothesis, King and colleagues have recently shown

that pretreatment with the putative 5-HT1A antagonist NAN 190 reduced

cocaine-induced hyperactivity (King et al. 1993). However, because both

gepirone and NAN 190 arc partial agonists, it is difficult to attribute their

stimulatory and antagonistic effects, respectively, to either agonism

(presynaptic) or antagonism (postsynaptic) at the 5-HT1A receptor. For

this reason, it will be necessary to reassess the effects of cocaine

following pretreatment with the full 5-HT1A agonist 8-OHDAPAT versus

a full antagonist (e.g., Way 100135) (Cliffe et al. 1993) to help establish

whether the relevant action of the partial agonist gepirone to enhance

cocaine hyperactivity is as a presynaptic agonist or postsynaptic

antagonist.

In a comprehensive study in mice, Reith and colleagues (Reith et al.

1991) investigated the hypothesis that selective 5-HT reuptake inhibitors

might antagonize the acute motor-activating effects of cocaine due to the

increased 5-HT available to activate 5-HT postsynaptic receptors (similar

to 5-HTP) (Pradhan et al. 1978; Taylor and Ho 1979). However, with the

exception of a high dose of fluvoxamine that enhanced this behavior,

cocaine-induced locomotion in mice was unaffected by several doses of

fluoxetine, paroxetine, or sertraline (Reith et al. 1991). These compounds

are selective and efficacious 5-HT reuptake inhibitors that increase

extracellular 5-HT levels in terminal regions. However, in comparison to

precursors (Rivot et al. 1983) and the 5-HT releaser fenfluramine

(Sarkissian et al. 1990; Schwartz et al. 1989), the magnitude of the

enhancement is more modest following administration of the 5-HT

reuptake inhibitors (Caccia et al. 1993; Perry and Fuller 1992; Rutter and

Auerbach 1993). This finding may be related to the preferential action of

selective 5-HT reuptake inhibitors to indirectly stimulate 5-HT1A

somatodendritic autoreceptors and concurrently and significantly reduce

5-HT neural firing (Chaput et al. 1986; Clemens et al. 1977; Cunningham

and Lakoski 1990); synthesis (Bohmaker et al. 1992), and release

(Wilkinson and Middlemiss 1992). Thus, the enhancement of 5-HT

transmission in 5-HT terminal regions that is elicited by selective 5-HT

46
reuptake inhibitors is self-limiting (Hjorth 1993; Reith et al. 1991), which

may explain why these drugs did not consistently decrease cocaineinduced activity as predicted by the findings with 5-HTP.

A systematic comparative study of cocaine with and without 5-HT

precursors (e.g., 5-HTP), releasers (e.g., fenfluramine), and reuptake

inhibitors in intact and 5-HT-depleted rats may help to determine which

aspects of motor activity are related to DA versus 5-HT reuptake

inhibition induced by cocaine. Because some behaviors elicited by high

doses and chronic administration of cocaine (Berman et al. 1982; Taylor

and Ho 1979) are similar to those seen upon administration of some 5-HT

agonists (i.e., forepaw treading, head weaves) (Glennon et al. 1991),

particular attention must be given to a separation of horizontal activity

(locomotion, ambulation), vertical activity (rearing), and stereotypies

(which can be expressed as stereotyped locomotion or rearing as well as

sniffing, head weaves, and forepaw treading). This microanalysis is

necessary to establish whether the effects of 5-HT compounds on the

generation of cocaine-induced behaviors are related to neural mediation

by 5-HT or competition among expressed behaviors.

The 5-HT antagonists cyproheptadine and metergoline were reported to

increase cocaine-induced hyperactivity or to unmask more intense DA

stereotypies such as gnawing and biting in rats (Berman et al. 1982;

Scheel-Kruger et al. 1976), although methysergide did not alter cocaine

behaviors in mice (Reith 1990). The nonselectivity of these antagonists

makes determination of the 5-HT receptor subtype(s) involved in the

overall enhancement of cocaine-evoked behaviors difficult; to date, very

few attempts to do so have been made. Of note, an interest in the

potential role of 5-HT3 receptors in locomotor hyperactivity induced by

cocaine has been generated by a number of findings. First, cocaine has

affinity at the 5-HT3 receptor (Kilpatrick et al. 1987) and was found to

inhibit 5-HT-induced stimulation of adrenergic and cholinergic

autonomic neurons via competition at the 5-HT3 receptor (Fozard et al.

1979). Yet, while these data support an antagonistic effect of cocaine on

5-HT3 receptors, several 5-HT3 antagonists including ICS 205-930,

MDL 72222, and zacopride have recently been found to reduce cocaine

hyperactivity (Reith 1990; Svingos and Hitzemann 1992).

One proposed mechanism of action for 5-HT3

 antagonists to block motor

activity induced by cocaine is via a reduction in the 5-HT-mediated

stimulation of DA release in forebrain areas thought to mediate the

stimulatory actions of cocaine, such as NACC (Chen et al. 1991;

47
McNeish et al. 1993). The fact that depletion of 5-HT with PCPA

blocked the ability of zacopride to reverse cocaine-induced hyperactivity

demonstrates the dependence of this antagonism on endogenous 5-HT

stores (Svingos and Hitzemann 1992). However, the reliance of this

phenomenon specifically on modulation of DA release via 5-HT3

receptors is less clear. At a dose of zacopride (0.1 mg/kg, IP) that

completely abolished cocaine hyperactivity, only a modest (27 percent)

reduction in cocaine-elicited increases in extracellular DA in NACC was

observed (McNeish et al. 1993).

Because PCPA pretreatment blocked the ability of zacopride to

antagonize cocaine, actions of 5-HT at 5-HT receptors other than the

5-HT3 subtype probably contribute to the observed effects of zacopride.

However, the generality and reproducibility of the 5-HT antagonist

blockade of cocaine hyperactivity is in doubt, given that both zacopride

(De La Garza and Cunningham 1993) and ondansetron (King et al. 1994)

failed to alter cocaine-induced hyperactivity in other studies. The reasons

for discrepancies among studies are not clear, although the type of

activity measured (horizontal and vertical versus stereotypy), species,

route of administration, doses of cocaine, and doses and receptor affinity

profiles of different 5-HT3 antagonists are suspect. If 5-HT3 antagonists

can be shown to block cocaine hyperactivity in a reproducible and

consistent fashion, further neurochemical studies will be necessary to

identify the contribution of 5-HT3 receptor modulation of DA release to

the antagonistic actions of 5-HT3 antagonists.

Because of the complexity of the 5-HT system and the relatively obscure

manner(s) in which 5-HT and DA systems interact, the specific

mechanisms by which 5-HT contributes to motor activation elicited by

cocaine are difficult to pinpoint. Cocaine inhibits reuptake of both DA

and 5-HT (as well as NH), and its actions to increase synaptic availability

of 5-HT may actually dampen the maximal responsivity of the DA

system to cocaine. The ability of 5-HT depletion to enhance cocaineinduced hyperactivity and the ability of nonselective 5-HT antagonists to

unmask more intense forms of DA-mediated stereotypies support this

contention. Similar processes are presumably involved in the

psychostimulant actions of amphetamine, although these may not be

identical because of the manner in which cocaine and amphetamine act:

While the actions of cocaine to enhance extracellular levels of

monoamines are impulse dependent, those of amphetamine are impulse

independent (Carboni et al. 1989). Manipulations that can be viewed as

reducing 5-HT function, such as decreased 5-HT content (e.g., PCPA),

48
terminal release (e.g., gepirone), or blockade of 5-HT receptors (e.g.,

cyproheptadine) enhance the acute motor-activating effects of cocaine.

Several 5-HT receptors are most likely to be involved, including the

5-HT1A and 5-HT3 receptors, while others remain to be studied.

ROLE FOR 5-HT IN THE DISCRIMINATIVE STIMULUS

EFFECTS OF COCAINE

Serotonin and DA interactions may also underlie other behavioral effects

of cocaine in addition to its locomotor stimulatory effects. Humans

experience subjective effects that include euphoria, mood elevation,

increased confidence, and a heightened sense of awareness as well as

anxiety, dysphoria, and nervousness following administration of cocaine

(Fischmari and Schuster 1982; Post 1975). If the interoceptive effects of

cocaine are perceived as pleasurable, this state can initiate and help to

maintain a pattern of drug-seeking behavior (Childress et al. 1988).

Drug discrimination (DD) procedures have been used to model the

subjective effects of psychoactive drugs in animals for the last 20 years.

In these tasks, the drug serves as a stimulus (cue) that signals the

availability of reinforcement conditional upon the occurrence of some

operant response (Appel et al. 1982). After acquiring such a

discrimination, various pharmacological manipulations can be conducted

in an effort to discern the mechanism(s) that underlie the discriminative

stimulus properties of the psychoactive compound.

The DD procedure has several positive aspects that make this assay

attractive, and these techniques have gained wide acceptance and some

measure of popularity. Its primary value for neuropharmacology is

derived from its specificity within a given drug class; drugs do not

substitute solely on the basis of psychoactive effects, nor do randomly

selected compounds mask the stimulus effects of a drug (Appel et al.

1982). However, two notes of caution are in order. In some instances, a

test compound only partially mimics or antagonizes a cue; these partial

substitutions and antagonisms are difficult to interpret. Furthermore, as is

the case with all pharmacological procedures, DD specificity often

depends upon the selectivity of agents that act on particular

neurotransmitter systems or at specific receptor subtypes.

One possible drawback to DD studies is the necessity of maintaining

trained animals for many months with drug(s) and vehicle(s)

49
administered frequently. In general, tolerance to the discriminative

effects of drugs develops only under chronic regimens of drug treatment

in the absence of continued training (Wood et al. 1984). Nonetheless,

these procedures have provided significant information concerning

psychostimulant mechanisms in vivo.

With regard to cocaine, substitution and antagonism tests have revealed

that both dopamine type 1 (D1) and dopamine type 2 (D2) receptors are

important mediators of the interoceptive effects of cocaine. Agonists for

the D2 receptor (e.g., quinpirole) and selective DA reuptake inhibitors

(e.g., GBR 12909) substitute fully for the cocaine stimulus, while D1

agonists (e.g., SKF 38393) partially substitute; both D1 (e.g., SCH 23390)

and D2 antagonists (e.g., haloperidol) attenuate the stimulus effects of

cocaine in rats (Callahan and Cunningham 1993a; Callahan et al. 1991;

Colpaert et al. 1979; McKenna and Ho 1980; Witkin et al. 1991).

Microinjection of cocaine into NACC fully mimics the stimulus effects of

systemic cocaine (Callahan et al. 1994; Wood and Emmett-Oglesby

1989), while both 6-OHDA lesion of NACC (Dworkin and Smith 1988)

and intra-NACC microinjection of the D1 antagonist SCH 23390 block

the discriminability of cocaine (Callahan et al. 1994). Thus, the

neuropharmacological profile supports the overall importance of DA

systems, specifically mesoaccumbens, in elicitation of the interoceptive

effects of cocaine.

Few systematic studies of 5-HT agonists and antagonists have been

undertaken in rats trained to discriminate cocaine from saline (tables 2

and 3). In early research, neither direct (mescaline, d-lysergic acid

diethylamide [LSD]) (Colpaert et al. 1979) nor indirect 5-HT agonists

(e.g., fenfluramine) (McKenna and Ho 1980; Wood and Emmett-Oglesby

1988) mimicked cocaine. Several nonselective 5-HT antagonists

(cinanserin, cyproheptadine, methysergide) did not block the cue

(Colpaert et al. 1979). These data suggested the lack of importance of

5-HT in this behavioral effect of cocaine. However, these studies in

general failed to assess the hypothesis that pharmacological enhancement

(e.g., 5-HTP) and reduction (e.g., PCPA, 5-HT antagonists) of 5-HT

neurotransmission might block and enhance, respectively, the

discriminability of cocaine as suggested by studies of cocaine-evoked

hyperactivity (above).

50
TABLE 2. Effect of 5-HT compounds on the stimulus effects of cocaine*

5-HT Compounds Substitutes Enhances Antagonizes

5-HT reuptake inhibitor

Citalopram

Fluoxetine

Imipramine

5-HT releaser

Fenfluramine

5-HT1A agonists

8-OHDPAT

Gepirone

Other 5-HT agonists

LSD (5-HT2A/2C)

Mescaline (5-HT2A/2C)

MCPP (5-HT1B/2C)

MK 212 (5-HT1B/2C)

TFMPP (5-HT1B/2C)

5-HT3 antagonists

ICS 205-930 (5-HT3)

MDL 72222

Ondansetron

Nonselective 5-HT

antagonists

Cinanserin

Cyproheptadine

Metergoline

Methysergide

NOTE: * Complete and partial substitutions

(SUBSTITUTES) are defined as >80 percent and 60-79

percent cocaine-lever responses, respectively. An enhancement ENHANCES) is defined as a significant increase in

the percentage of cocaine-lever responses upon coadministration of the compound with cocaine. A complete

and partial antagonism are defined as < 30 percent and

31-60 percent cocaine-lever responses following the combination of the 5-HT compound and cocaine. An X and ?

indicate that the drug had no effect or was not tested, respectively. Superscript numbers refer to citations found in table 3.

51
TABLE 3. Effects of 5-HT compounds on the stimulus effects of cocaine

citations

No. Reference

1 Baker et al. (1993)

2 Berman et al. (1982)

3 Callahan and Cunningham (1993b)

4 Colpaert et al. (1979)

5 Cunningham and Callahan (1991)

6 De La Garza and Cunningham (1993)

7 King et al. (1993)

8 King et al. (1994)

9 Lamb and Griffiths (1990)

10 Lane et al. (1992)

11 McKenna and Ho (1980)

12 Paris and Cunningham (1991)

13 Paris et al. (1992)

14 Pradhan et al. (1978)

15 Reith (1990)

16 Reith et al. (1991)

17 Scheel-Kruger et al. (1976)

18 Svingos and Hitzemann (1992)

19 Taylor and Ho (1979)

20 Wood and Emmett-Oglesby (1988)

Substitution tests with selective 5-HT reuptake inhibitors indicated that

citalopram (Baker et al. 1993), fluoxetine (Baker et al. 1993;

Cunningham and Callahan 1991), and imipramine (Baker et al. 1993) did

not mimic cocaine. In contrast, fluoxetine pretreatment did potentiate the

cocaine cue, shifting the dose-effect curve for cocaine to the left

(Cunningham and Callahan 1991). Other selective 5-HT reuptake

inhibitors, such as sertraline and fluvoxamine, share this ability (Callahan

et al., unpublished observation). Perhaps specific 5-HT receptors

activated by the increased synaptic 5-HT account for the enhancement

afforded by 5-HT reuptake inhibitors.

The manner in which 5-HT might control the interoceptive effects of

cocaine appears to differ from the serotonergic contribution to its

locomotor stimulating effects, since fluoxetine and other 5-HT reuptake

52
inhibitors in general failed to alter locomotor activity induced by cocaine

in mice (Keith et al. 1991). Note that the NE reuptake inhibitor

desipramine also effectively enhanced the cocaine cue (Cunningham and

Callahan 1991), and nonspecific pharmacokinetic processes cannot be

ruled out (e.g., increased brain cocaine levels induced by reuptake

inhibitors, possibly as a result of inhibition of cocaine metabolism

[(Misra et al. 1986; Tella and Goldberg 1993]).

The potentiation of the cocaine cue with 5-HT reuptake inhibitors

prompted a further pharmacological analysis to test the hypothesis that

other 5-HT agonists may mimic, potentiate, or antagonize the cocaine

cue. The full 5-HT1A agonist 8-OHDPAT and the partial 5-HT1A agonist

gepirone were without effect, despite evidence that gepirone effectively

enhanced the locomotor stimulatory actions of cocaine (Paris et al. 1992),

once again suggesting a differentiation in the manner in which 5-HT

modulates the locomotor versus discriminative effects of cocaine. The

5-HT agonists m-chlorophenylpiperazine (MCPP), MK 212, and

1 -(m-trifhroromethylphenyl) piperazine (TFMPP) were not perceived as

similar to cocaine, although TFMPP did elicit persistent 30 to 60 percent

drug-lever responding (Callahan and Cunningham 19933). Like

fluoxetine, TFMPP enhanced the discriminability of low doses of cocaine

(figure 2) (Callahan and Cunningham 1993b). On the other hand, MCPP

and MK 212 neither mimicked nor potentiated cocaine, but dosedependently blocked the stimulus effects of cocaine (figure 3) (Callahan

and Cunningham 1993b). Surprisingly, the efficacy of MCPP and MK

212 was similar to that of many DA antagonists (Callahan et al. 1991).

Of note, these compounds do not have appreciable affinity for DA

receptors (Hamik and Peroutka 1989; Neale et al. 1987). Thus, two

groups of piperazine derivatives can be distinguished: One group

(TFMPP) that serves to potentiate, and a second group (MCPP, MK 212)

that blocks the cocaine cue.

The piperazines MCPP, MK 212, and TFMPP are considered 5-HT

agonists; however, each differs with regard to its profile of interactions

with the 5-HT transporter and various 5-HT receptors. While the

structurally similar compounds MCPP and TFMPP have similar affinity

for 5-HT1B and 5-HT2C receptors (Curzon and Kennett 1990; Sills et al.

1985), TFMPP has a greater affinity for the 5-HT transporter than does

MCPP (Curzon and Kennett 1990; Sills et al. 1985). Therefore, TFMPP

(like fluoxetine) may potentiate the effects of cocaine via 5-HT reuptake

inhibition.

53
TFMPP (0.5 mg/kg) Potentiate of the Cocaine Cue

Dose of Cocaine (mg/kg)

FIGURE 2. The effects of the 5-HT agonist TFMPP on

the stimulus properties of cocaine. Rats

were trained to discriminate cocaine (10

mg/kg, IP) from saline in a two-lever,

water-reinforced drug discrimination task

(Callahan and Cunningham 1993b).

During combination tests, rats were

pretreated with TFMPP (0.5 mg/kg, IP) 15

minutes prior to an injection of cocaine

(0.313, 0.625, or 1.25 mg/kg) and were

placed in operant chambers 15 minutes

later. Bars denote the mean percentage of

cocaine-appropriate responses (±SEM)

observed following a dose of cocaine given

in the absence (-; filled bars) or presence

(+; hatched bars) of TFMPP pretreatment.

Data points are the mean of 8/8 rats [n/N:

number of subjects (n) completing at least

20 responses out of the number of subjects

tested (N)]. Asterisks denote values

significantly different than the indicated

dose of cocaine alone (p < 0.05). Control

points are found on the left side of graph

and show the degree of stimulus control

engendered by 10 mg/kg of cocaine. (C 10;

filled bar), saline (S; open bar), and 0.5

mg/kg of TFMPP (T 0.5; plaid bar).

54
5-HT Compounds Antagonize the Cocaine Cue

Dose of MCPP or MK 212 (mg/kg,ip)

FIGURE 3. The effects of the 5-HT agonists MCPP and MK 212 on

the stimulus properties of cocaine. Rats were trained to

discriminate cocaine (IO mg/kg, IP) from saline in a twolever, water-reinforced drug discrimination task

(Callahan and Cunningham 1993b). During combination

tests, rats were pretreated with MCPP or MK 212 (0.25-2

mg/kg, IP) 15 minutes prior to an injection of cocaine

(5 mg/kg) and were placed in operant chambers 15

minutes later. Closed symbols denote the mean

percentage of cocaine-appropriate responses (±SEM; left

ordinate); open symbols denote the mean response

rate/minute (±SEM; right ordinate). Data points are the

mean of 5-7/7 rats. Asterisks denote values significantly

different than cocaine (5 mg/kg) alone p < 0.05). At a

dose of 0 mg/kg, the degree of stimulus control

engendered by 5 mg/kg of cocaine is shown.

Further evidence that the in vivo actions of TFMPP can be distinguished

from those of MCPP is suggested by the finding that, in rats trained to

discriminate MK 212 from saline, MCPP (but not TFMPP) produces a

full substitution (Cunningham et al. 1986). While it is difficult to

propose one neural mechanism to account for these potentiations based

upon 5-HT reuptake inhibition, one possibility might be an enhancement

55
of DA release; in fact, intra-VTA injection of TFMPP has been shown to

increase release of NACC DA, an action that would be expected to

enhance the behavioral effects of cocaine (Guan and McBride 1989).

The compounds MCPP and MK 212, which blocked the cocaine cue,

share affinity at a number of 5-HT receptors including the 5-HT1B and 5-

HT2C receptors. Since the 5-HT2A/2C antagonist LY 53857 does not alter

the cocaine cue (Callahan and Cunningham, unpublished observation),

5-HT1B receptors may be involved in the antagonistic effects of these

compounds. These 5-HT1B receptors are found in DA cell body areas and

accumbens and are thought to modulate 5-HT release at terminals

(Bobker and Williams 1989; Pazos and Palacios 1985). An action ‘of

these compounds to modulate DA release at the level of the raphe, VTA,

or limbic sites may be possible. Furthermore, a potential role for NE in

mediating these antagonistic actions of MCPP and MK 212 requires

investigation. However, the potency order for antagonism of the cocaine

cue does not correlate with the affinity of these compounds for either

or adrenoceptors (Hamik and Peroutka 1989; Neale et al. 1987).

Few 5-HT antagonists with selectivity at 5-HT receptors have been

assessed for substitution, potentiation, or antagonism of cocaine (tables 2

and 3). Because of the affinity of cocaine for the 5-HT3 receptor

(Kilpatrick et al. 1987) and the interest in the role of 5-HT3 receptors in

controlling DA function (Costall et al. 1987), several 5-HT3 antagonists

have been assessed in rats trained to discriminate cocaine from saline.

Neither MDL 72222, ICS 205-930 (Paris and Cunningham 1991) nor

ondansetron (Lane et al. 1992) substituted or blocked cocaine; the ability

of such compounds to potentiate the cocaine stimulus has not yet been

studied. Although 5-HT3 antagonists inhibit a variety of DA-mediated

events, including (in some studies) cocaine-evoked hyperactivity (Reith

1990; Svingos and Hitzemann 1992), the stimulus effects of cocaine

appear to be resistant, thus providing further evidence that the 5-HT

modulation of cocaine behaviors is not identical for its locomotor

stimulatory and discriminative stimulus effects.

CONCLUSION

While the bidirectional modulatory effects of 5-HT agonists on the

stimulus effects of cocaine probably reflect the fact that these 5-HT

agonists have distinctive profiles with regard to affinity and action at

56
multiple 5-HT receptors, it appears that the locomotor and discriminative

effects of cocaine can be augmented or reduced by manipulations of

5-HT tone. In general, these behavioral studies support the hypothesis

that 5-HT may modulate DA output at the level of the 5-HT soma

(raphe), DA soma (VTA), or the terminals of mesolimbic DA circuits that

are critical to these behaviors. Unfortunately, assimilation of these

studies into one conceptual framework is difficult because of the relative

lack of a concrete understanding of how and where 5-HT and DA interact

in the brain to control behavior, and an incomplete knowledge of the

complexity of the 5-HT system, including the large number of 5-HT

receptors and the relative lack of specific and selective ligands for each

site.

One long-held hypothesis is that 5-HT, under normal conditions,

tonically inhibits DA systems; many of the research findings discussed in

this chapter support this hypothesis. However, alternate hypotheses (e.g.,

5-HT tonically excites DA activity) appear to explain other behavioral

findings (Nader and Barrett 1990; Paris et al. 1992). Nevertheless, it is

apparent that a full appreciation of how cocaine produces its behavioral

effects is dependent upon a better understanding of the mechanisms and

loci at which 5-HT modulates DA mesolimbic systems and how cocaine

biases this balance.

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ACKNOWLEDGMENTS

Grant support was provided by the National Institute on Drug Abuse

(DA 05708 and DA 065 11) and the National Alliance for Schizophrenia

and Affective Disorders.

AUTHORS

Kathryn A. Cunningham, Ph.D.

Associate Professor

Patrick M. Callahan, M.A.

Faculty Associate

65
Department of Phamacology and Toxicology

University of Texas Medical Branch

Route J31, 10th and Market

Galveston, TX 77555-1031

66
A Review of the Effects of

Dopaminergic Agents in Humans:

Implications for Medication

Development

Richard B. Rothman

INTRODUCTION

The purpose of this chapter is to expand on issues related to the

mechanism or mechanisms of cocaine’s addictive and euphorogenic

effects that were discussed in previous papers (Rothman 1990; Rothman

et al. 1989).

THE DOPAMINE HYPOTHESIS OF COCAINE’S REINFORCING

EFFECTS

The hypothesis that mesolimbic dopamine (DA) plays a critical role in

mediating the reinforcing effects of cocaine is well supported by a wide

variety of data. An article by Johanson and Fischman (1989)

comprehensively reviews much of the data. There is a high degree of

correlation between the potency of cocaine-like drugs as inhibitors of DA

reuptake and their potency in tests of self-administration (Madras et al.

1989; Ritz et al. 1987; Spealman et al. 1989) and observations that

lesions of the mesolimbic DA system disrupt cocaine self-administration

(Dworkin et al. 1988; Koob et al. 1987a; Roberts and Koob 1982;

Roberts et al. 1977).

Further support for the DA hypothesis comes from observations that DA

antagonists disrupt cocaine self-administration in a predictable manner

(De La Garza and Johanson 1982; Ettenburg et al. 1982; Johanson et al.

1976; Koob et al. 1987b; Roberts and Vickers 1984; Wilson and Schuster

1972; Woods et al. 1978) and that DA agonists such as apomorphine,

bromocriptine, and piribedil are self-administered (Baxter et al. 1974;

Woolverton et al 1984; Yokel and Wise 1978), as are the DA reuptake

blockers bupropion (Woods et al. 1983), mazindol (Wilson and Schuster

1976), and nomifensine (Spyaki and Fibiger 1981). It should be noted,

however, that some investigators suggest that disruption of cocaine

67
self-administration by DA antagonists results from a nonspecific

rate-reducing effect (Johanson and Fischman 1989; Woods et al. 1987;

Woolverton and Balster 1981; Woolverton and Virus 1989).

EFFECT OF DOPAMINERGIC AGENTS IN HUMANS

Although these data are convincing, they are puzzling. There are

apparent incompatibilities between the animal data and clinical

experience with regard to medicines that increase DA or block its actions.

These drugs can be informally classified as DA reuptake inhibitors, direct

DA agonists, DA increasers, and DA antagonists. Although DA-releasing

agents such as amphetamine produce euphoria in humans, these are not

discussed in this chapter.

The exact relationship between reinforcement, as measured in animal

studies, and the subjective and addictive effects of cocaine in humans is

not completely understood. It is reasonable to suppose that the ability of

cocaine to produce euphoria in humans is probably related to its addictive

effects. After all, most people take cocaine, at least initially, because it

makes them feel good. Cocaine produces euphoria in humans after

intravenous (IV), oral, and inhalational administration (Johanson and

Fischman 1989). Moreover, cocaine produces euphoria in the great

majority of people who take it (Johanson and Fischman 1989).

A direct prediction of the DA hypothesis is that dopaminergic agents that

produce cocaine-like effects in animals should produce cocaine-like

effects in humans. Cocaine produces a number of subjective and

objective effects in humans, but it is not clear which cocaine-like effects

one would want to see successfully predicted by animal studies. This

chapter focuses on euphoria, or a feeling of well-being; as mentioned

earlier, this is an effect of cocaine that is likely to be related to its

addictive properties. However, the relationship between euphoria and

reinforcement is not necessarily straightforward, since drugs can exert

reinforcing effects in the apparent absence of euphoria. Indeed, it could

be argued that an alternative relevant measurement of a drug’s reinforcing

effect is its actual abuse by humans. Although dopaminergic agents do

produce some cocaine-like effects, these effects do not include euphoria,

and they do not occur in the majority of patients who are administered

these drugs. Moreover, these dopaminergic agents are not known to be

drugs of abuse.

68
DA Reuptake Inhibitors

There are four DA reuptake blockers that are, or have been, marketed in

the United States: bupropion, nomifensine, mazindol, and benztropine.

As noted in table 1, bupropion is an antidepressant. Nomifensine, an

antidepressant, was taken off the market because it produced severe

allergic reactions in some patients. Mazindol is used for the treatment of

obesity. Benztropine is commonly prescribed for the treatment of

movement disorders (Bianchine 1980).

As shown in table 2, all four of these medications are more potent than

cocaine in inhibiting [

3H]dopamine ([3H]DA) reuptake into striatal

synaptosomes (Andersen 1987). Setting aside pharmacokinetic

considerations, one would predict that these agents, like cocaine, would

produce euphoria in humans. However, the prescribing literature for

these drugs do not mention the occurrence of euphoria as either a primary

effect or as a side effect (Bianchine 1980; Chait et al, 1987; Hadler 1972;

Rickels et al. 1982; Stem et al. 1982; Yakabow et al. 1984). Moreover,

with the exception of mazindol, these agents are all Schedule V drugs,

indicating a very low abuse liability. Since mazindol is dysphoric in

humans (Chait et al. 1987), it is surprising that it is classified as a

Schedule IV drug. If these drugs could produce euphoria, one would

TABLE 1. DA reuptake inhibitors marketed for use in humans

Agent Indication

Bupropion Antidepressant

Euphoria/Addiction?

None reported’

Nomifensine Antidepressant None reported2

Benztropine Movement disorders None reported3

Mazindol Anorectic

1

Stern et al. (1982)

2 Rickels et al. (1982)

3

Bianchine (1980)

4 Chait et al. (1987); Hadler (1972)

None reported4

69
think this would have been readily observed, since these medicines have

been collectively prescribed to millions of people.

This common-sense notion has stood up to scientific scrutiny. As

summarized in table 3, when the subjective effects of bupropion and

nomifensine were specifically examined, there was no mention of

drug-induced euphoria (Hamilton et al. 1983; Miller and Griffith 1983;

Parrott et al. 1982; Peck and Hamilton 1983; Shekim et al. 1989;

Yakabow et al. 1984). The studies of Peck and Hamilton (1983) showed

that oral administration of 200 mg of bupropion or 100 mg of

nomifensine did not produce amphetamine-like central nervous system

stimulant activity in normal volunteers. Supporting these results were

studies (Griffith et al. 1983; Miller and Griffith 1983) demonstrating that

at oral doses up to 400 mg, bupropion did not produce amphetamine-like

subjective effects in experienced amphetamine abusers.

Direct DA Agonists

DA agonists available for use in humans include pergolide and

bromocriptine, which act equally at DA type 1 (D1) and type 2 (D2)

receptors. Their primary therapeutic use is in the treatment of

Parkinson’s disease, acromegaly, and hyperprolactinemia. Since they are

TABLE 2. IC50 values for drugs as inhibitors of [

3H]DA reupake in vitro

Drug IC50 (nM)

Cocaine 690

Bupropion 648

Benztropine 175

Nomifensine 134

Mazindol 29

NOTE: IC50 values for inhibition of [3H]DA reuptake into striatal

synaptosomes (Andersen 1987).

70
TABLE 3. Studies that reported on the subjective effects of DA reuptake

inhibitors in humans

Drug Citations

Bupropion and

nomifensine

1

Benztropine 2

Mazindol 3

1 Hamilton et al. (1983); Miller and Griffith (1983); Parrott et al.

(1982); Peck and Hamilton (1983); Shekim et al. (1989); Yakabow et

3

al. (1984)

2 Bianchine (1980)

Chait et al. (1987)

self-administered by animals (Woolverton et al. 1984), one might expect

them to produce cocaine-like effects in humans. Although these agents

do produce a variety of psychiatric side effects, as shown in table 4,

euphoria is not among them.

DA Increasers

The DA increasers include the monoamine oxidase (MAO) inhibitors and

levodopa. The MAO inhibitors commonly used in the United States are

phenelzine, tranylcypromine, and selegiline. Whereas phenelzine and

tranylcypromine inhibit both MAO types A and B, selegiline is a

selective inhibitor of MAO type B (Murphy 1978; Murphy and Kalin

1980; Murphy et al. 1984). Phenelzine and tranylcypromine are effective

antidepressants (Baldessarini 1990). Selegilme is approved by the Food

and Drug Administration only for the treatment of Parkinson’s disease

(Cedarbaum and Schleifer 1990). Preliminary data suggest it might also

have antianxiety and antidepressant properties (Tariot et al. 1987).

Selegiline’s mechanism of action in the treatment of Parkinson’s disease

is thought to result from inhibition of MAO type B, which metabolizes

DA and results in an increase in the synaptic concentration of DA

(Cedarbaum and Schleifer 1990). In support of this hypothesis, in vivo

71
TABLE 4. Neuropsychiatric (plus some general) side effects of

pergolide and bromocriptine

Pergolide Bromocrintine

Dyskinesia

Dizziness

Hallucinations

Dystonia

Confusion

Somnolence

Insomnia

Anxiety

Tremor

Depression

Abnormal dreams

Personality disorder

Psychosis

Abnormal gait

Akathisia

Extrapyramidal syndrome

Incoordination

Paresthesia

Akinesia

Hypertonia

Neuralgia

Speech disorder

Nausea

Headache

Dizziness

Fatigue

Lightheadedness

Vomiting

Abdominal cramps

Nasal congestion

Constipation

Diarrhea

Drowsiness

microdialysis studies in rats have shown that MAO inhibitors increase the

concentration of extracellular DA (Colzi et al. 1990; Imperato and

Di Chiara 1984; Miller and Gold 1988). Moreover, studies of

Alzheimer’s disease patients (Sunderland et al. 1987) demonstrated that

administration of selegiline decreased the cerebrospinal fluid (CSF) levels

of the DA metabolite homovanillic acid (HVA), presumably as a result of

MAO inhibition. Similar results were observed in the CSF of monkeys

treated chronically with the selective MAO type A inhibitor clorgyline

(Cox et al. 1991).

Since MAO inhibitors increase synaptic concentrations of DA, the DA

hypothesis would predict that they should have cocaine-like effects.

Indeed, in rats trained to discriminate 5 mg/kg of cocaine from saline,

72
Colpaert and colleagues (1980) found that the cocaine interoceptive cue

was generalized to selegiline and tranylcypromine, consistent with the

notion that these agents act to increase DA. However, as indicated in

table 5, the side-effect profile does not include euphoria. In fact, these

drugs are quite dysphoric. Similarly, levodopa is prescribed to patients

with Parkinson’s disease because it increases synaptic DA, yet it does not

produce euphoria (Cedarbaum and Schleifer 1990).

DA Antagonists

The DA antagonists include the relatively large number of medicines

used mainly in the treatment of schizophrenia. The reader is referred to a

textbook for a more thorough description of the antipsychotic drugs

(Baldessarini 1990). Although the recent description of DA types 3, 4,

and 5 (D3, D4, and D5) receptors (Sokoloff et al. 1990; Sunahara et al.

1991; van Tol et al. 1991) complicates the task of deciding which DA

receptor or receptors might mediate the reinforcing effects of cocaine in

animals, the data demonstrate that antipsychotics, which are prescribed to

humans, attenuate cocaine self-administration in animals as predicted by

the DA hypothesis.

Evidence that antipsychotics block cocaine-induced euphoria in humans

is negative, lacking, or inconclusive. As summarized in table 6, Gawin

(1986) contributed a case report in which he noted that “four cocaine

abusers with histories of stimulant-induced paranoid psychoses reported

selective reduction in psychotic symptoms but not euphoria when treated

with dopamine blockers. This provides preliminary evidence against

efficacy of neuroleptics in cocaine abuse prevention, and suggests

euphoria and paranoia may have discriminable neurophysiological

substrates” (p. 142).

Sherer and colleagues (1989) reported that haloperidol (8 mg

intramuscularly [IM]) partially reduced the high, but not the rush,

induced by IV cocaine. This finding is difficult to interpret, since it is not

clear if the sedating effect of haloperidol contributed to the partial

amelioration of the cocaine-induced high. In an open-label study of the

effectiveness of flupenthixol deconoate for treating cocaine abuse in

crack addicts, Gawin and colleagues (1989) noted that “subjects treated

informally before this trial at higher doses (30 to 80 mg) . . . often

reported diminished intensity or duration of cocaine’s euphoric effect, but

not complete blockade, when cocaine smoking was resumed . . . [This]

73
TABLE 5. Neuropsychiatric side effects of MAO inhibitors

Phenelzins

Dizziness

Headache

Drowsiness

Sleep disturbances

Fatigue

Weakness

Tremors

Twitching

Hyperreflexia

Myoclonic movements

Selegiline

Hallucinations,

Dizziness

Confusion

Anxiety

Depression

Drowsiness

Dreams/nightmares

Tiredness, delusions

Disorientation

Lightheadedness

Impaired memory*

Increased energy*

Transient high*

Hollow feeling

Lethargy/malaise

Apathy

Overstimulation

Vertigo

Personality change

Sleep disturbance

Restlessness

Weakness

Transient irritability

Behavior/mood change

KEY: * At doses greater than the usual 10 mg/day. Rate of occurrence

not specified.

may not occur in a clinically meaningful magnitude in the low doses used

in this study” (p. 17).

Indirect evidence that antipsychotic medications do not attenuate the

euphoric effects of cocaine comes from studies that indicate that

schizophrenic patients, many of whom are taking antipsychotic

medication, abuse cocaine (Brady et al. 1990; Bunt et al. 1990; Dixon

et al. 1991; Schneier and Siris 1987; Sevy et al. 1990). Thus, although

74
TABLE 6. Summary of studies reporting on the effects of antipsychotic

drugs on cocaine-induced subjective effects in humans

Gawin (1986)

“Four cocaine abusers with histories of stimulant-induced paranoid

psychoses reported selective reduction in psychotic symptoms but not

euphoria when treated with dopamine blockers. This provides

preliminary evidence against efficacy of neuroleptics in cocaine abuse

prevention, and suggests euphoria and paranoia may have discriminable

neurophysiological substrates.”

Sherer et al. (1989)

Haloperidol 8 mg IM partially reduced the “high” but not the rush

induced by IV cocaine. This finding is difficult to interpret, since it is not

clear if the sedating effect of haloperidol contributed to the partial

amelioration of the cocaine-induced high.

Gawin et al. (1989)

In this open-label study, 10 crack addicts were given 10 or 20 mg of

flupenthixol decanoate IM. Dr. Gawin noted that:

". . . subjects treated informally before this trial at higher doses (30 to 80

mg) . . . often reported diminished intensity or duration of cocaine’s

euphoric effect, but not complete blockade, when cocaine smoking was

resumed . . . [This] may not occur in a clinically meaningful magnitude in

the low doses [used in this study.”

Unfortunately, this finding must be classified as anecdotal.

the hypothesis that DA antagonists block cocaine-induced subjective effects

in humans has not been rigorously tested, the currently available data suggest

that they do not. Clearly, this issue calls for careful study by clinical

investigators.

75
INITIAL CONCLUSIONS

The data reviewed here raise more questions than they answer. Nevertheless,

some tentative conclusions can be reached. Although animal studies

demonstrate that DA is a key neurochemical mediator of the reinforcing

effects of cocaine, the interpretation of the human data is less clear. With the

exception of cocaine and amphetamine-like drugs, the various dopaminergic

agents reviewed here do not produce euphoria in humans and are not drugs of

abuse. Although factors other than the ability to produce euphoria play a role

in determining abuse liability (Balster 1991), the simplest explanations for the

fact that these medicines are not abused drugs is that they do not produce

euphoria and are weak reinforcers.

Although various arguments can be made as to why any particular

dopaminergic agent might not produce cocaine-like effects in humans, the

lack of cocaine-like effects produced by this relatively broad mechanistic

spectrum of dopaminergic agents is difficult to reconcile with the DA

hypothesis as specifically formulated in this chapter. This interpretation

suggests that the DA hypothesis may be too simple to completely explain the

human subjective (euphoria) and objective (actual abuse) response to cocaine

administration.

The ability of a drug to support self-administration behavior in animals using

a substitution paradigm is often predictive of its abuse liability in humans

(Johanson 1990; Johanson and Balster 1978; Johanson and Fischman 1989;

Schuster 1991). Although behavioral pharmacologists acknowledge the

limitations of the method (Johanson 1990), the simplistic notion that

self-administration of a drug means the drug has significant abuse liability

seems to have become almost a dogma among scientists not trained in the

subtleties of behavioral pharmacology. The results of the self-administration

substitution paradigm are often used to predict the abuse liability of test

drugs. Like any diagnostic test, the self-administration (substitution)

paradigm can be expected to have measurable rates of false positives and

false negatives. Drugs such as lysergic acid diethylamide and marijuana,

which are not self-administered by animals, are often used as examples of

false negatives (Johanson 1990).

Table 7 lists drugs that the author feels are false positives. These data are

adapted from the paper of Iwamoto and Martin (1988). These agents are

self-administered by animals in the substitution paradigm, but do not produce

cocaine-like effects in humans. For example, bupropion (Woods et al. 1983),

mazindol (Wilson and Schuster 1976), nomifensine (Spyraki and Fibiger

76
TABLE 7. Drugs that are self-administered (substitution procedure) but do

not produce euphoria in humans

Opioids Dopaminergic agents Misc. agents

Ketocyclazocine

Ethylketocyclazocine

Apomorphine

Piribedil

Bromocriptine

Mazindol

Bupropion

Procaine

Clonidine

SOURCE: With the exception of mazindol, nomifensine, and bupropion, the

data are from the review of Iwamoto and Martin (1988).

1981), bromocriptine, and pergolide (Woolverton et al. 1984) all support

self-administration behavior in animals yet do not produce cocaine-like

effects in humans. Similarly, the alpha, agonist clonidine and the local

anesthetic procaine support self-administration behavior but do not produce

euphoria in humans.

In addition to the false-positive drugs, there are drugs such as the MAO

inhibitors that one would expect to be self-administered by animals but which

presumably are not (based on the lack of published data on this class of drugs

in the self-administration literature). These agents behave consistently in

animals and humans. In that both cocaine and MAO inhibitors increase

synaptic levels of the biogenic amines, it is puzzling why the former produces

euphoria and is a drug of abuse while the latter agents do not.

An implication of this assessment is that the self-administration substitution

paradigm, as applied to cocaine-like drugs, does not always accurately predict

the ability of a drug to produce euphoria or cocaine-like effects in humans.

Assuming that this is true, one would also question the ability of the

self-administration paradigm to predict the activity of a cocaine antagonist in

humans. Indeed, as reviewed earlier, the apparent inability of DA antagonists

to block the euphoric effects or abuse of cocaine in humans supports this idea.

The significance of this interpretation for efforts to develop effective

pharmacotherapeutics for cocaine abuse is that preclinical drug development

programs are generally structured so that the self-administration substitution

paradigm is used to select candidate drugs for possible use in humans. Thus,

researchers may be selecting medications that will not work or, alternatively,

77
ruling out medications that may work. These considerations point to the need

for developing animal models that can detect the difference between

dopaminergic drugs that are and are not abused by humans.

A STRATEGY FOR DRUG DEVELOPMENT

Viewed collectively, these data and their interpretations might lead one to

take a pessimistic view of researchers’ ability to develop effective

medications for cocaine abuse. However, it is the opinion of this author that

the problem lies not with the models that have been developed, but probably

with the fact that there is a tendency to overinterpret the data resulting from

the models.

Take, for example, the self-administration paradigms referred to earlier. As

generally practiced, IV self-administration studies in animals use a

substitution procedure in which the animal is first trained to self-administer

cocaine, and then the ability of a drug to substitute for the cocaine is

quantitated. Behavioral pharmacologists mostly agree that this

rate-dependent approach is not the best one possible for measuring the

reinforcing efficacy of the drug (Johanson and Fischman 1989). That is, the

substitution method does not measure if a drug is less reinforcing than

cocaine, but only determines whether the animal will self-administer the drug

when denied access to cocaine. Indeed, it seems reasonable, though perhaps

simplistic, to suggest that a cocaine-addicted monkey that is denied access to

cocaine will self-administer any drug that will increase synaptic DA even if

the drug is not as intrinsically reinforcing as cocaine. In other words, if the

monkey cannot have cocaine, it will take the next best thing.

Thus, in the opinion of this author, the self-administration substitution

paradigm functions as a pharmacological assay that detects drugs that have

direct or indirect dopaminergic activity. It does not always detect the

property of the drugs that produce euphoria in humans. When viewed in this

context, it is not an unexpected result that dopaminergic drugs that are

self-administered in substitution procedures do not produce euphoria in

humans.

A hypothesis consistent with both the human and animal data is that

mesolimbic DA does mediate the addictive and euphorogenic effects of

cocaine, but only certain dopaminergic agents can produce euphoria in

humans (Rothman 1990). Although this hypothesis creates secondary

research questions as to why these differences among dopaminergic agents

78
exist, it also creates the possibility of pharmacotherapeutic intervention.

There are several possible reasons for these differences. Limited data support

the hypothesis that the rate at which an addictive drug enters the brain is

important to its addictive properties (Balster and Schuster 1973; Hemingfield

and Keenan 1993). On this basis, heroin is thought to be more addictive than

methadone.

According to this hypothesis, dopaminergic agents in humans, which are

generally taken orally, may not rapidly achieve the brain concentrations

required to produce the rapid increase in mesolimbic DA that is hypothesized

to be necessary for the production of euphoria. Although this hypothesis has

intuitive appeal, it has not (to this author’s knowledege) been rigorously

tested. Nevertheless, this hypothesis does suggest that a high-affinity DA

transporter ligand with slow pharmacokinetic characteristics might actually

block the effects of cocaine or substitute for cocaine. Alternatively, direct

agonists might not stimulate the appropriate DA receptors. Another

possibility is that unpleasant side effects of these drugs in humans prevent

attainment of doses that would be required to produce cocaine-like effects.

Perhaps these agents have other effects in humans that somehow cancel out

their effects on mesolimbic DA. It may be that, in humans, the drugs never

achieve high enough brain levels to produce euphoria. Finally, perhaps

cocaine is doing something that is not completely understood.

A paper focused primarily on the DA reuptake inhibitors (Rothman 1990)

proposed dividing DA reuptake inhibitors into two classes. Type 1 blockers

are drugs that produce addiction and euphoria in humans, such as cocaine-like

drugs. Type 2 blockers are drugs such as mazindol, nomifensine, and

bupropion that do not produce euphoria or addiction. Assuming that the

initiating event for cocaine-induced euphoria is the binding of cocaine to the

DA transporter, administration of a D2 reuptake blocker should block the

binding of cocaine to the DA transporter, and thereby attenuate

cocaine-induced euphoria.

The identification of a such a competitive antagonist would undoubtedly

provide an important research tool. However, it might have limited

therapeutic uses as a medication. A patient could overcome the drug

inhibition by self-administering more cocaine, thereby increasing the

probability of increased toxic side effects that would not be blocked by the

competitive antagonist.

An alternative approach is to develop a type 2 agent that binds with high

affinity to the DA transporter and dissociates slowly. If the dissociation rate

79
were slow enough, the agent would behave as a noncompetitive inhibitor,

creating insurmountable inhibition of those cocaine effects initiated by its

binding to the DA transporter. A sustained increase in mesolimbic DA

produced by such an agent might provide a cocaine addict with some relief

from cocaine craving, which some investigators suggest is related to a relative

deficiency of DA (Dackis and Gold 1985). Thus, such a drug might act as a

substitute-type medication.

A key issue is how a D2 reuptake inhibitor might be identified prior to its

administration to humans. In this author’s opinion, the answer may be to

measure its reinforcing efficacy, relative to cocaine, in animals. This can be

done by performing self-administration studies designed according to either a

progressive-ratio paradigm or a choice paradigm (Johanson and Fischman

1989). One possible set of criteria for identifying a D2 reuptake inhibitor is

that it should have low reinforcing efficacy, act as a classical locomotor

stimulant (i.e., stimulate locomotor activity), generalize to a cocaine-induced

interoceptive cue, and be self-administered in a substitution paradigm.

However, prior to the validation of these methods, good judgment and luck

will probably dictate the correct choice of a putative type 2 agent.

These and additional considerations (see. below) led to investigation of the

high-affinity DA reuptake inhibitor 1-[2-[bis(4-fluorophenyl)

methoxy]ethyl]-4-[3-phenylpropyl]piperazine (GBR12909) and its analogs

(Rothman et al. 1989, in press) as possible prototypical noncompetitive

inhibitors. Published data have shown that GBR12909 is about 700-fold

more potent than cocaine in inhibiting DA reuptake in vitro (IC50 = 1 nM)

(Andersen 1989); GBR12909 is a relatively selective inhibitor of DA

reuptake (Andersen 1989); the behavioral profile of GBR12909 in animals is

somewhat different from that of other locomotor stimulants (Nielsen and

Scheel-Kroger 1988); and after systemic administration, GBR12909 binds

persistently to the DA transporter and attenuates the ability of cocaine to

increase extracellular DA (Rothman et al., in press).

CONCLUSION

According to the hypothesis of D1 and D2 reuptake inhibitors, cocaine

antagonists already exist. However, researchers have not yet fully developed

and validated animal models that predict the antagonists’ ability (or absence

thereof) to produce euphoria in humans. With a little luck and considerable

effort, work with analogs of GBR12909 will advance the understanding of

80
the mechanisms of cocaine-induced euphoria and also lead to successful

development of pharmacotherapeutics for cocaine abuse.

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ACKNOWLEDGMENT

Current collaborative research in this area is supported in part by NIDA’s

Medication Development Division. This program includes synthesis of new

86
agents by Dr. Rice’s group in the Laboratory of Medicinal Chemistry,

NIDDK; behavioral evaluation of agents by Dr. Agu Pert’s group in NIMH;

binding profiles of the agents by Dr. Richard Rothman’s group at the ARC;

and the determination of the reinforcing efficacy of these new drugs in rhesus

monkeys by Dr. John Glowa’s group at NIDDK. The author thanks David

Gorelick, M.D., Ph.D., and Agu Pert, Ph.D., for reading the manuscript.

AUTHOR

Richard B. Rothman, M.D., Ph.D.

Chief

Laboratory of Clinical Psychopharmacology

National Institute on Drug Abuse Addiction Research Center

P.O. Box 5180

Baltimore, MD 21224

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Use of Rodent Self-Administration

Models to Develop Pharmacotherapies for Cocaine Abuse

Steven I. Dworkin and Raymond C. Pitts

INTRODUCTION

The search for a therapeutic agent to treat cocaine abuse has been

identified as one of the major goals of the National Institute on Drug

Abuse (NIDA). Although one may question the probability of

discovering a “magic bullet” for cocaine abuse, this behavior has been

reinforced in the past, albeit on a very lean schedule of reinforcement.

The early development and growth of the field known as behavioral

pharmacology has been credited to the discovery of chlorpromazine, the

“magic bullet” for the treatment of severe psychotic behavior (Carlton

1983).

The demonstration that a pharmaceutical agent could be used to

normalize complex psychotic behaviors resulted in a significant

investment by the Federal Government and private industry in the

development of behavioral pharmacology. This investment was based on

the assumption that additional drugs could be developed to treat other

behavioral disorders. A discipline that combined the expertise of

pharmacology (founded on the idea that drugs could be developed to treat

diseases) with an experimental analysis of behavior was considered

ideally suited to aid in the identification and development of these

compounds.

The early success in finding compounds that could be beneficial in the

treatment of depression, anxiety, and schizophrenia firmly established the

field of behavioral pharmacology. The acknowledgment of this field

included accepting the notion that nonhuman models could be used to

predict the clinical efficacy of psychoactive compounds. The

development of nonhuman models of drug abuse and the discovery of

compounds that are effective in the treatment of heroin addiction

88
(i.e., methadone, naltrexone, buprenorphine) support the notion that

pharmaceuticals could be developed to treat cocaine abuse (Schuster

1986).

DRUG SELF-ADMINISTRATION

The initial impetus for determining if psychoactive compounds could

maintain operant responding was to provide a behavioral approach to the

analysis of physical dependence (Thompson and Schuster 1964). Early

research demonstrated that the self-administration model could be used in

monkeys (Thompson and Schuster 1964; Yanagita et al. 1965) and rats

(Davis 1966; Weeks 1962). It was almost immediately realized that drugmaintained responding was similar to behavior maintained by other

environmental events (i.e., food and water) and that drug delivery could

serve as a reinforcer to engender and maintain drug-seeking and drugtaking behaviors (Kelleher and Goldberg 1977). Thus, animal studies of

drug self-administration could be an important model of human drug

abuse. These demonstrations and technical refinements paved the way

for using the self-administration procedure for a variety of research

endeavors (Brady and Lukas 1984; Young and Herling 1986).

The drug self-administration model has been shown to be an exquisite

animal model of substance abuse and dependence (Goudie 1991; Hartnoll

1991; Sanger 1991). Johanson and Schuster (1981) elucidated six areas

of research that were initiated as a result of the development of drug selfadministration procedures. The first area of research was the

determination of factors related to engendering, maintaining, and

influencing the patterns of drug seeking and drug taking. A second area

was to investigate pharmacologic and environmental manipulations that

could decrease drug taking. The third and fourth areas were the

elucidation of the mechanisms of clinical problems associated with drug

abuse therapy and the determination of the biochemical correlates of drug

abuse, respectively. The fifth and sixth areas were the development of

screening tests for preclinical assessment of abuse potential and toxicity,

respectively. Much of the research using the self-administration model

can be listed under one or more of these six areas, and a significant

amount of information on all of these areas has been accumulated. The

self-administration model has provided a screening test to evaluate the

potential abuse liability of novel compounds, a behavioral bioassay to

investigate the neurobiology of reinforcement, and a simulation of a

major behavior disorder.

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The demonstration that drugs could serve as reinforcers in operant

paradigms provides a new class of environmental events for researchers

to investigate. Initial studies were directed toward determining the

similarities and differences between the reinforcing effects of drug and

nondrug reinforcers (i.e., food and water). These studies resulted in the

realization that drug-maintained responding is influenced by the same

variables that altered responding maintained by nondrug reinforcers

(Johanson 1978; Johanson and Schuster 1981; Katz 1989; Kelleher and

Goldberg 1977; Spealman and Goldberg 1978; Young and Herling

1986). For example, different schedules of reinforcement (Ferster and

Skinner 1957) could be used to maintain schedule-appropriate rates and

patterns of self-administration (see figure 1).

However, there are some important differences in behavior maintained by

a drug compared to responding maintained by other environmental

events. One of the major differences is the relationship between

magnitude of reinforcement and increases in dose and response rates.

While studies with nondrug reinforcers generally result in an increase in

responding as the magnitude of reinforcement is increased, responding

maintained by pharmacologic agents generally shows an inverted

U-shaped function. Figure 2 shows dose-effect curves for response rates,

interinjection intervals, and absolute amount of cocaine self-administered

under a fixed-ratio (FR) schedule during 4-hour sessions. As the dose of

cocaine increases, responding first increases and decreases while the total

amount of the drug and the mean interinfusion interval increases.

At least three different mechanisms for the descending limb of the selfadministration dose-effect curve have been suggested (Katz 1989). The

first was that the descending limb was the result of the subject titrating

the level of drug to produce a consistent drug effect. This notion

followed the observation that inter-injection intervals maintained by

stimulants were relatively constant and directly related to dose. Studies

that attempted to predict or model drug levels at the time when drug

seeking starts to occur provide some support for this hypothesis. Studies

that correlated the blood levels of amphetamine (Yokel and Pickens

1974) with amphetamine self-administration or the extracellular levels of

dopamine (DA) in the nucleus accumbens resulting from cocaine selfadministration (Pettit and Justice 1991) indicated that rats did maintain a

relatively constant level. However, the level maintained was related to

the dose of the drug.

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FIGURE 1. Cocaine self-administration under different

schedules of reinforcement

A second explanation for the decreasing limb of the dose-response curve

was that the self-administered drug has direct effects on subsequent

responding independent of, and in addition to, its reinforcing effects.

These direct effects should decrease responding maintained by other

reinforcers or be attenuated with experimenter-imposed timeout periods if

they are independent of the reinforcing effect of the drug. Studies that

have evaluated the potential influence of the direct effects of selfadministered drugs suggest that the direct effects can result in a decreased

rate of responding maintained by other reinforcers (Pickens and

Thompson 1968; Spealman and Kelleher 1979) or can be attenuated by

using experimenter-imposed minimum interinjection intervals (Griffiths

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FIGURE 2. Dose-response curves for cocaine self-administration

under an FR-10 schedule

et al. 1979). These studies are not conclusive; however, relatively large

doses of a drug can increase self-administration at doses that suppress

ongoing behavior maintained by other reinforcers (Balster and Schuster

1973; Spealman and Kelleher 1979). However, the patterns of selfadministration (at least in rats) are consistent over several hours and do

not indicate an increasing direct effect of the drug as more drug is selfadministered.

The third explanation proposed was that the descending limb was a result

of a change in the reinforcing effects of the self-administered compound.

Larger doses are not as reinforcing as lower doses, or they may have

some aversive component associated with their administration. Although

extremely large doses of amphetamine (Sanger et al. 1980) and cocaine

(D’Mello et al. 1981; Foltin et al. 198 1) can result in a conditioned taste

aversion, these doses are typically in excess of those that are on the

descending limb of the dose-effect curve for self-administration. In

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addition, results from studies using a dose-choice procedure indicate that

larger doses of cocaine are preferred to lower doses (Iglauer and Woods

1974; Johanson 1975). Moreover, larger doses are preferred to lower

doses even when the choice of the higher doses also results in the

presentation of electric shocks (Johanson 1977). Satiation has also been

proposed to account for the decreasing limb of the dose-effect curve.

Like food-maintained responding, after the subject has received a

sufficient amount of the drug, additional injections are not as reinforcing.

It is unlikely that any single mechanism is responsible for the descending

limb of the dose-response curve for all species and drugs for which it

occurs. There are data that support or refute all of the hypotheses

presented. However, one must appreciate the difficulty in interpreting

changes in the rate of self-administration, especially following the

administration of a potential treatment compound. These compounds

may alter the direct effects, the bioavailability, or the reinforcing effects

of the self-administered compound. The use of any single procedure is

not sufficient for the screening or characterization of a potential

pharmacotherapy for drug abuse.

PROCEDURES USED TO CHARACTERIZE THE

THERAPEUTIC POTENTIAL OF PUTATIVE

TREATMENT COMPOUNDS

One of the most commonly used procedures to evaluate the effects of

putative treatment compounds on drug self-administration is to

investigate the effects of these compounds on responding maintained by

FR schedules of drug administration. The FR schedule does not impose

significant constraints on the amount or frequency with which an animal

can receive drug infusions. In fact, both rats (Bozarth and Wise 1985;

Dworkin et al. 1987) and monkeys (Johanson et al. 1976) will selfadminister lethal quantities of cocaine if given unlimited access to the

drug under FR schedules. Therefore, most investigators limit access to

the drug to only a few hours each day.

A second problem associated with the use of FR schedules, as discussed

above, is the inverted “U” dose-effect curve that is obtained when

appropriate doses are evaluated. This necessitates evaluating several

different doses of a drug to determine if a treatment compound increases

or decreases the reinforcing effects or whether it alters the unconditioned

effects of the drug (Katz 1989). For example, the DA type 1 (D1) agonist

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SKF 38393 decreased responding maintained by low doses of cocaine,

increased responding maintained by moderate doses, and had no effect on

responding maintained by the two largest doses evaluated (Katz and

Witkin 1992). Thus, the examination of a putative treatment on a range

of doses of the drug of interest increases the likelihood of determining a

potential therapeutic effect of the test compound.

A second procedure that has been used to evaluate the compound’s

efficacy in the treatment of drug abuse is the progressive-ratio (PR)

schedule. This schedule is similar to the FR schedule, except that the

ratio value increases after the delivery of each infusion. The ratio value

at which responding does not occur for a specified period of time is

termed the breakpoint, and it has been suggested to provide a measure of

reinforcing efficacy (Hodos 1961). Studies investigating serotonergic

involvement in the reinforcing effects of cocaine have shown that

modulation of the serotonergic system alters the breakpoint and rate of

responding maintained by cocaine under PR schedules.

Depletion of forebrain serotonin with 5,7-dihydroxytryptamine lesions of

the amygdala or medial forebrain bundle has been reported to augment

cocaine reinforcement by increasing the breakpoints under a PR schedule

(Loh and Roberts 1990). Fluoxetine pretreatment decreased these

breakpoints, suggesting that serotonin may inhibit the reinforcing effects

of cocaine (Richardson and Roberts 1991). However, there is still some

ambiguity regarding the interpretation of data from PR studies. Since

responding is maintained by a ratio schedule, the unconditioned effects of

a compound could influence the breakpoint independent of a change in

reinforcing efficacy.

A major concern of studies that demonstrate a particular compound alters

drug-maintained responding is the behavioral specificity of any changes

observed. Since drug self-administration is viewed as conceptually

similar to responding maintained by conventional environmental events

that serve as reinforcers, food-maintained responding has been used as a

control to evaluate the behavioral specificity of putative treatment

compounds. For example, chlorpromazine was shown to decrease both

food-maintained responding and responding maintained by small cocaine

doses under a second-order schedule of reinforcement. However,

responding maintained by larger doses of cocaine was increased by the

same doses of chlorpromazine that decreased responding maintained by

the lower doses (Herling and Woods 1980). Both the decrease in the selfadministration of the lower doses and the increase in the self94
administration of larger cocaine doses was suggested to result from the

drug effects on response rates and not a change in reinforcing efficacy.

A similar strategy was employed to evaluate the potential specific effects

of the opiate buprenorphine on cocaine self-administration. It was shown

that daily buprenorphine pretreatment reduced cocaine self-administration

by rhesus monkeys to a much greater extent (e.g., 70 to 90 percent below

baseline) than food-maintained responding (Mello et al. 1989). In

subsequent investigations, tolerance to the effects of buprenorphine on

food-reinforced responding was reported to develop following repeated

testing with the drug, while cocaine self-administration remained

suppressed (Mello et al. 1990, 1992). A more recent study further

illustrates the utility of comparing the effects of a putative treatment

compound on responding maintained by the drug of interest and food

(Katz and Witkin 1992). In that study, doses of the D1 agonist

SKF 38393 had little or no effect on food-maintained responding at doses

that resulted in a significant decrease in responding maintained by

cocaine.

In addition to using food-maintained responding, some investigators have

evaluated the effects of a putative treatment compound on several drugs

of abuse. The concurrent maintenance of heroin and cocaine selfadministration on alternate days was used to demonstrate the specificity

of dopaminergic involvement in the reinforcing effects of cocaine and not

heroin (Ettenberg et al. 1982; Pettit et al. 1984). The effects of

buprenorphine on responding maintained by different drugs have not

been as unequivocal; buprenorphine attenuates cocaine selfadministration but also suppresses behavior maintained by other drugs

(e.g., phencyclidine, ethanol) and nondrug reinforcers (e.g., saccharin

solutions, food) in both rats (Carroll and Lac 1992) and rhesus monkeys

trained to smoke cocaine base (Carroll et al. 1992a). It has also been

reported that buprenorphine does not result in a shift to the right of the

dose-effect curve but does result in a downward shift of the curve

(Winger et al. 1992). This same downward shift was also observed

following the administration of heroin and nalbuphine, two other opioid

agonists. Moreover, the dose of buprenorphine required to decrease

cocaine self-administration was much greater than doses of the drug

required to maintain self-administration or suppress alfentanil selfadministration (Winger et al. 1992).

Thus, investigations of the effects of putative treatment compounds on

responding maintained by more than one drug provide information on the

95
specificity of the observed effects. These studies can isolate compounds

that may have indirect effects from those that result in a decrease in the

reinforcing effects of a drug or drug class.

DEVELOPMENT AND TESTING OF NOVEL TROPANE

ANALOGS

Recently, a number of novel cocaine derivatives have been developed and

used to define the pharmacophore responsible for the pharmacologic,

neurobiologic, and behavioral actions of cocaine (Abraham et al. 1992;

Bergman et al. 1989; Boja et al. 1990; Carroll et al. 1992b, 1992c; Cline

et al. 1992; Davies et al. 1993; Kozikowski et al. 1991; Lewin et al. 1992;

Madras et al. 1989). An example of the utility of this approach is the

development of a series of compounds in which the 3 P-ester linkage of

cocaine has been replaced by direct 3ß-aryl derivatives (Clarke et al.

1973). Some of these analogs have a much greater potency than cocaine

for binding at the DA transporter (Carroll et al. 19926). Furthermore, the

4-fluorophenyl derivative WIN 35,428, or CFT, (Madras et al. 1989) and

the 4-iodophenyl derivative RTI-55 (Boja et al. 1991) are currently used

to identify DA transport sites. The synthetic scheme used to develop

these compounds, however, is limited because it requires the use of (-)-

cocaine as the starting material.

An alternative synthetic strategy using the reaction of vinylcarbenoids

with pyrroles (Davies et al. 1991) was used to synthesize novel

2ß-methyl ketone and 2ß-ethyl ketone cocaine analogs (Davies et al.

1993). One of these compounds, 2ß-propanol-3ß-(4-toluyl)-tropane

(PTT), has been evaluated for its effects on cocaine self-administration.

The compound PTT (30 to 90 μg/inf) substituted for cocaine in single

substitution sessions during which the compound was used to replace

cocaine (0.33 mg/inf) during a 3- or 6-hour period (Dworkin et al. 1992).

In these studies, rats were trained to self-administer cocaine (0.33 mg/kg)

under an FR-10 schedule for 3 hours a day. PTT was substituted for

cocaine during these sessions.

Figure 3 depicts the effects of substituting different doses of PTT for

cocaine during single 3-hour sessions. The data are means and standard

errors from five subjects that were exposed to each dose at least twice.

These doses of PTT were able to maintain self-administration in this

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FIGURE 3. The self-administration of PTT during acute

substitutions for cocaine

acute substitution paradigm. The compound was also able to engender

and maintain self-administration in drug-naive subjects (Dworkin et al.

1992).

The temporal pattern of responding maintained by PTT, however, was

qualitatively different from the regular intake pattern maintained by

cocaine (see figure 4). Responding maintained by PTT consists of

periods of low-rate responding at the start of the session, followed by a

period of very rapid responding. After several infusions are taken at a

very high rate there is a long pause and the pattern is repeated.

The effect of PTT pretreatment on cocaine self-administration was also

investigated. Three subjects were trained to self-administer cocaine

(0.33 mg/inf) under an FR-10 schedule of drug presentation. Each

infusion was followed by a 20-second timeout during which responses

were counted but had no programmed consequences. Sessions were

97
FIGURE 4. Cumulative records depicting the effects of acute

substitutions of PTT doses for the 0.33 mg/infusion

dose of cocaine

98
3 hours in duration, and occasional double sessions (6 hours) were

scheduled. Each session began with a response-independent infusion of

cocaine. The effects of PTT (1.0 and 3.0 mg/kg, intraperitoneally [IP])

and cocaine (30.0 mg/kg, IP) were investigated. Presession

administration of cocaine and both doses of PTT resulted in a substantial

decrease in cocaine self-administration for the first 3 hours following

administration (figure 5). The largest effect was observed following the

administration of the 3.0 PTT dose. With the exception of this dose,

responding returned to baseline during the second 3-hour period.

FIGURE 5. Effects of IP pretreatment with cocaine (30 mg/kg) or PTT

(1 mg/kg and 3 mg/kg) on cocaine self-administration

Representative cumulative records shown in figure 6 depict the effects of

the presession administration of cocaine and PTT on cocaine selfadministration. The effects of cocaine and PTT pretreatment on

responding maintained by food pellet presentation was also evaluated to

determine the selectivity of the effects of PTT on cocaine selfadministration (figure 7). Six rats were trained on a discrete-trial, FR-10

schedule of food presentation, with a 6-minute intertrial interval (ITI). At

the start of the sessions, a light above a response lever was illuminated,

and the 10th responses resulted in the delivery of a food pellet. The light

was darkened, and a 6-minute ITI was scheduled during which responses

99
FIGURE 6. Cumulative records showing the effects of presession

administration of PTT on cocaine self-administration

were counted but had no programmed consequences. The start of the

ratio schedule was signaled by illumination of a lever light following the

6-minute ITI. This schedule was used to maintain rates and patterns of

food-maintained responding that were similar to those maintained by

cocaine self-administration.

Figure 7 depicts the effects of cocaine (30.0 mg/kg, IP) and PTT (1.0 and

3.0 mg/kg, IP) on food-maintained responding. Data are means plus

standard deviation (SD). Both cocaine and the larger dose of PTT

resulted in a significant decrease in food-maintained responding. Unlike

responding maintained by cocaine, the lower dose did not decrease foodmaintained responding. Representative cumulative records of responding

100
FIGURE 7. Effects of cocaine and PTT on food-maintained

responding

maintained by this schedule and the effects of cocaine and PTT are

displayed in figure 8. The bottom pen was deflected downward during

the ITI. Responses during the ITI resulted in momentary upward

deflections of the bottom pen. The 3.0 dose of PTT decreased

responding maintained by food but increased the number of ITI responses

from a mean of 40±17 (SD) to a mean of 407±623.

The results of these studies evaluating the effects of PTT suggest that the

compound is reinforcing and can decrease both cocaine selfadministration and food-maintained responding. However, decreases in

cocaine self-administration occurred at a dose that did not alter foodmaintained responding. These results demonstrate the ability to

investigate the effects of potential treatment compounds for cocaine

abuse.

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FIGURE 8. Cumulative records of the effects of PIT on foodmaintained responding

USE OF DELAY OF REINFORCEMENT TO EVALUATE

CHANGES IN THE REINFORCING EFFICACY OF A DRUG

A number of variables can influence the effectiveness of a given event as

a reinforcer. As suggested earlier, many parallels exist between drugs

and other reinforcers (Young and Herling 1986). One variable that has

not been studied nearly as extensively with drug reinforcers as with

nondrug reinforcers (such as food presentation) is delay of reinforcement.

In a typical delay-of-reinforcement procedure, some time elapses between

the response that results in reinforcement and the actual delivery of the

reinforcer. In general, imposing a delay between responding and

reinforcement reduces the effectiveness of an event as a reinforcer, and

the reduction in reinforcing effectiveness is a positive function of delay

value (Catania and Keller 1981). While this relation appears to hold with

102
drug reinforcers like cocaine (Stretch et al. 1976), the effects of

reinforcement delay on drug-reinforced responding is an underdeveloped

research area. The purpose of this line of experiments is twofold: to

examine some effects of reinforcement delay on behavior maintained by

cocaine delivery, and to provide a possible set of procedures that may

help characterize the effects of manipulations designed to reduce the

reinforcing effects of abused drugs.

The subjects were six male Fischer F-344 rats implanted with jugular

catheters. The rats were studied in standard one- or two-lever operant

chambers. Lever pressing was maintained under FR-10 schedules of

cocaine injections (0.33 mg in 2.0 mL delivered over 5.6 seconds). Each

cocaine injection was accompanied by a tone and was followed by a

20-second timeout.

In three rats (R4, R5, and R6), effects of unsignaled, nonresetting delays

were assessed across experimental phases. The delay value for each rat

began at 0 seconds (immediate reinforcement) and was increased by 60

seconds until responding was, or nearly was, eliminated. The O-second

delay condition was then reinstated. Thus, the schedule of cocaine

presentation was a tandem FR-10 FT, with the FT value equal to the

programmed delay. Experimental sessions were 4 hours in duration.

For all rats, imposing a delay eventually reduced response rates and the

number of injections received during experimental sessions. For rat R4

(figure 9), this decrease did not occur until the programmed delay (FT)

value reached 240 seconds; for rats R5 and R6, this decrease occurred at

the 60-second delay value. Decreasing the delay value to 0 seconds and

reducing the FR value to 1 resulted in a moderate regeneration of

responding in rats R4 and R6. Responding by rat R5 did not recover

following this manipulation.

Imposing an unsignaled, nonresetting delay (i.e., adding a tandem FT

requirement) resulted in a decline and eventual cessation of responding

maintained by cocaine injections. These results are similar to those

obtained with other reinforcers and thus provide another parallel between

nondrug and drug reinforcement processes. In the present study, the

effects of this manipulation sometimes persisted long after the delay was

removed. This was especially true with rat R5, suggesting the possibility

of a permanent change in the reinforcing efficacy of cocaine.

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FIGURE 9. Effects of increasing the scheduled delay of

reinforcement on cocaine self-administration

In a second delay of reinforcement study, three rats (N2, N6, and N10)

were exposed to a progressive-delay schedule. Under this arrangement,

the first injection occurred with a O-second delay, after which each

successive injection was followed by a signaled delay. The duration of

the delay began at 30 seconds and doubled with each succeeding

injection until 30 minutes passed without a response, or until a 5-hour

session time limit was reached. During the delay periods, the

experimental chamber was dark, and the response lever was retracted.

This procedure (a chained FR-10 FT schedule with progressively

increasing FT values) could be seen as providing a measure of the

reinforcing effectiveness of cocaine. After several sessions under this

procedure at the training dose (0.33 mg/inj), other doses (.083 mg/inj to

0.83 mg/inj) were occasionally substituted during selected sessions. Each

dose tested was substituted at least twice.

For all rats, responding under the progressive delay procedure was well

maintained by the training dose (0.33 mg/inj) of cocaine. Breakpoints

104
ranged between 4,000 and 8,000 seconds. On many occasions the rats

would respond throughout the session, terminating the session via the

time limit.

Substitution of other cocaine doses resulted in a monotonically increasing

dose-effect function for rats N2 and N10 and an inverted U-shaped

function for rat N6 (see figure 10). At the higher doses, the sessions for

rats N2 and N10 nearly always terminated via the time limit.

FIGURE 10. Dose-response curve indicating the effects of the

progressive delay schedule on cocaine selfadministration

The results from the progressive-delay schedule show that responding can

be maintained when extremely long delays occur between responding and

the presentation of cocaine. At the peaks of the dose-effect functions,

responding was maintained when delays of over 2 hours occurred. There

are a number of possible reasons why responding was maintained at such

long delay values. Cocaine is a potent reinforcer, capable of sustaining

behavior under extreme circumstances. The delay period was signaled,

thus stimuli during the delay period could serve as conditioned

reinforcers for responding during the FR-10 schedule component. Also,

because relatively short delays always occurred during the early portions

of each session, the conditioned reinforcing capacity of the delaycorrelated stimuli may have been maximized. Responding could not

105
occur during the delay (the response lever was retracted). Thus,

responding during the long delays could not undergo extinction. The

progressive-delay procedure has potential utility as a tool for the

assessment of manipulations designed to alter the reinforcing

effectiveness of abused drugs.

This procedure may possess advantages over other more commonly used

procedures in that breakpoint-like data can be obtained without increasing

response requirements. This may be advantageous when assessing the

effects of pharmacological agents on self-administered drug with

behavioral effects that may themselves depend on response requirement.

Increasing dose-effect functions can be obtained over dose ranges that

normally produce decreases in most response measures.

CONCLUSION

Studies investigating the reinforcing effects of response-dependent

electric shock (Morse and Kelleher 1977) and nicotine administration

(Goldberg and Spealman 1983; Spealman 1983; Spealman and Goldberg

1982) demonstrate that almost any environmental stimulus can serve as a

reinforcer or punisher under the right environmental conditions. It has

been suggested that drugs with the highest abuse potential are those that

serve as reinforcers under a wide range of conditions (Johanson and

Schuster 1981). A treatment corollary to that assumption would be that

an efficacious treatment compound should attenuate self-administration

under a wide range of experimental conditions. Since a positive model

for the detection of a treatment compound for cocaine abuse has not been

found, researchers should continue to pursue a broad behavioral approach

toward understanding the important issues.

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ACKNOWLEDGMENT

Research and manuscript preparation supported by U.S. Public Health

Service grant nos. DA-03628 and DA-06634 and NIDA contract no. 271-

90-7402.

AUTHORS

Steven I. Dworkin, Ph.D.

Department of Physiology and Pharmacology

Bowman Gray School of Medicine

Winston-Salem, NC 27157-1083

Raymond C. Pitts

Department of Psychology

University of North Carolina

Chapel Hill, NC 27599-3270

112
Pharmacological and Behavioral

Treatment of Cocaine Addiction:

Animal Models

Marilyn E. Carroll

Two animal models of drug abuse are reviewed: a rat model in which

cocaine is self-administered via indwelling intravenous (IV) catheters,

and a primate model in which rhesus monkeys are trained to smoke

cocaine base. Two methods have been used to reduce cocaine-reinforced

behavior: pharmacological methods or pretreatment with potentially

therapeutic drugs, and behavioral methods in which the environment is

enriched with alternative nondrug reinforcers. These methods have also

been extended to other drugs that are delivered IV in rats or orally in

rhesus monkeys, and to behavior maintained by potent nondrug

reinforcers.

The results of these animal models have been promising, but they have

raised some important methodological issues that have to be considered

when designing preclinical treatment studies. First, drug treatment may

not selectively alter cocaine-reinforced behavior. It is important to

examine the effects of a potential treatment drug on behavior rewarded by

food and other nondrug substances. Second, drug and behavioral

treatments interact with the behavioral economics of procuring the drug.

Their effectiveness depends on how hard the animal works for each

milligram (mg) of the drug that is delivered. Thus, it is necessary to test a

potential treatment under a range of response requirements. Finally, it is

important to evaluate the potential treatment at several phases of the

addiction process, such as acquisition, maintenance, withdrawal, and

relapse, as treatments may be differentially effective at different stages.

Most previous animal work has concentrated on the maintenance phase.

There are a few studies that provide animal models of acquisition,

withdrawal, and relapse; however, the effects of potential treatment

strategies on these behaviors have not yet been determined.

113
INTRAVENOUS DRUG SELF-ADMINISTRATION IN RATS

Behavioral Treatment

An experiment was conducted to determine whether a nondrug alternative

reinforcer, a drinking solution of glucose (3 percent weight by volume

[wt/vol]) and saccharin (0.125 percent wt/vol) (G+S), which is a highly

preferred substance for rats (Valenstein et al. 1967), would ‘alter the

self-administration of IV cocaine. Great difficulty was encountered in

training the rats to self-administer G+S and cocaine simultaneously

(Carroll et al. 1989). Many of the rats selected one substance and did not

self-administer the other, although both were concurrently available. For

a subset of the rats, G+S self-administration prevented the acquisition of

cocaine self-administration; for another group, cocaine selfadministration prevented the acquisition of G+S self-administration

(Carroll et al. 1989).

Extensive exposure was necessary to obtain stable baselines for both

substances. In the rats that achieved stable behavior, G+S or cocaine

access was systematically added or removed to examine the effect on

self-administration of the other substance. Figure 1 shows that, in rats

that had access to IV cocaine and water to drink (left panels), the addition

of G+S for 5 days resulted in a significant decrease in cocaine selfadministration. In a group of rats that had access to both cocaine and

G+S (center panels), the baseline G+S intake was reduced compared to

those without G+S (right panel); when G+S was replaced with water, the

cocaine intake more than doubled. When G+S was reinstated, cocaine

infusions were again reduced. In a third group that had been

self-administering cocaine, when cocaine was temporarily (10 days)

replaced by saline, saline infusions were minimal (right panels). They

also had access to G+S. When the saline was temporarily (10 days)

replaced with cocaine, the number of infusions markedly increased, and

G+S intake was reduced by more than half. These findings show that

G+S and cocaine compete as reinforcers, and each interferes with

maintenance levels of self-administration of the other substance.

A recent attempt was made to more systematically examine this

phenomenon using an autoshaping program to objectively and

quantitatively measure the rate of acquisition of cocaine

self-administration (Carroll and Lac 1993). Under an autoshaping

program, a pigeon key is lighted or a rat lever is extended into the

chamber (Brown and Jenkins 1968; Messing and Sparber 1983). After a

114
FIGURE 1. Data are shown for three groups of five rats over

successive 5-day blocks. The group on the left initially

had access to IV cocaine and water to drink. G+S was

substituted for water for 5 days, and then water

replaced G+S for 5 days. The group in the center had

cocaine and G+S, and then water was substituted for

G+S for 5 days, The group on the right was trained to

self-administer IV cocaine but was temporarily

maintained on saline infusions and G+S was available

to drink; then cocaine was substituted for saline for 5

days. Each point represents a mean of 5 rats for 5

days (+ the mean SE across days).

few seconds, the light is extinguished or the lever is retracted, and a food

reinforcer is delivered. In a few sessions animals learn to associate

responding on the manipulandum with delivery of the reinforcer.

Responses on the response key or lever also result in the light being

extinguished or the lever retracting and the reinforcer being delivered

immediately.

In the present experiment, rats were autoshaped to press a lever that

resulted in a 0.2mg/kg cocaine infusion. There were six autoshaping

sessions each day when 60 infusions (10 per hour) were automatically

delivered according to a random 90-second schedule. This component

was followed by a daily 6-hour self-administration component when the

115
lever remained extended and every lever press (except those during the

infusions) resulted in an infusion. The criterion for acquisition of

cocaine-reinforced behavior was arbitrarily defined as 5 consecutive days

when the mean number of infusions was 100 or more for the 6-hour

self-administration sessions. The experiment was terminated when the

acquisition criterion was reached or at 30 days following startup.

Five groups of 12 to 14 rats were compared. The first four groups were

factorially arranged according to whether they had G+S and water or only

water to drink during autoshaping, and whether they had G+S and water

or only water in the home cage for 3 weeks prior to autoshaping in the

operant chamber (table 1). These groups all had free access to water in

the home cage and operant chamber, and their food intake was limited to

20 g. A fifth group had no G+S, either in the home cage or during

autoshaping in the operant chamber, and their food intake was unlimited.

This allowed for a comparison of feeding conditions on acquisition of

cocaine self-administration.

The results indicated that access to the G+S solution in the operant

chamber substantially delayed autoshaping. In group 1 (which had access

to G+S in both the home cage and the operant chamber), half of the 12

rats did not acquire cocaine self-administration within 30 days. A history

of access to G+S in the home cage but no access in the operant chamber

(group 3) did not interfere with acquisition of cocaine self-administration.

Figure 2 shows collapsed data for the two groups that had G+S in the

operant chamber during autoshaping sessions (N = 24) and for the two

groups that had only water during autoshaping (N = 24). The presence of

G+S in the operant chamber clearly increased the number of days to

acquire cocaine self-administration, and 9 of the 24 rats in this combined

group did not acquire cocaine self-administration within 30 days.

Autoshaping in group 5, which had free access to food was highly

variable, but a high positive correlation (t = 7.74, df = 12, p < 0.01) was

found between the amount of food consumed and the number of days to

meet the acquisition criterion. Thus, the acquisition of cocaine-reinforced

behavior was reduced or prevented in environments enriched with

alternative nondrug substances such as food and a preferred liquid (G+S),

compared with an impoverished environment that contained only water

and limited access to food (Carroll and Lac 1993). Others have shown

that acquisition of cocaine self-administration is enhanced by prior

exposure to caffeine (Horger et al. 1991) and naltrexone (Ramsey and

116
TABLE 1. Experimental design

Group no. Home cage

Group 1 G+S and water

Operant chamber

G+S and water

Group 2 Water only G+S and water

Group 3 G+S and water Water only

Group 4 Water only Water only

Group 5* Water only Water only

KEY: * Group 5 had unlimited access to food, while groups 1-4 were

limited to 20 g.

Van Ree 1990) and that acquisition of amphetamine self-administration is

related to individual differences in locomotor activity (Piazza et al. 1989).

Pharmacological Treatments

Another series of experiments examined pharmacological effects of

potential treatment drugs on IV cocaine self-administration in rats.

Group designs were used in which separate groups of rats selfadministered different doses of cocaine (0.1, 0.2, or 0.4 mg/kg unit

doses), Other groups self-administered only G+S. In the first experiment

(Carroll et al. 1990a), fluoxetine, a serotonin uptake inhibitor, was

examined as a potential treatment drug; similar treatments were found

effective at reducing amphetamine self-administration in rats (Smith et al.

1986).

Separate groups of rats were injected with three doses of fluoxetine (2.5,

5, or 10 mg/kg) IV twice daily. The rats were allowed to self-administer

cocaine during continuous 24-hour sessions, with each infusion

contingent upon four responses on the lever (fixed-ratio [FR] 4 [FR-4]).

Responding during the 4-second infusion was counted but had no

programmed consequences. The groups self-administering G+S

responded on a tongue-operated, automatic drinking device that delivered

0.1 mL per tongue-contact response. The basic procedure was to allow

all self-administration behavior to stabilize for at least 10 days, and the

last 5 days of that period served as the pretreatment baseline. The

117
Days to Acquisition Criterion

FIGURE 2. A frequency distribution shows that number of days

until the autoshaping criterion was met divided into six

5-day intervals. The number of rats in each group

within that interval is represented by the height of each

bar. In the bin depicting 26-30 days, all of the rats did

not reach the criterion by the 30-day limit.

treatment drug was then given IV twice daily for 5 days, and behavior

was allowed to stabilize for at least 10 days after treatment. Saline

control injections were not given to minimize interference with the

cannula system; previous research indicated that saline pretreatment had

no effect on cocaine self-administration (Carroll et al. 1986).

Fluoxetine produced dose-dependent decreases in cocaine infusions and

G+S intake, while food intake in both the cocaine and G+S groups was

unaltered by these doses of fluoxetine (Carroll et al. 1990a). The cocaine

dose-response function was shifted downward and to the left. Fluoxetine

had the greatest effect at the lowest cocaine doses and almost no effect at

the highest cocaine dose (Carroll et al. 1990a). Unit dose and the

response requirement under the FR-4 schedule can be combined and

118
considered as a single variable (Bickel et al. 1990), unit price (responses

per mg). In this case, the drug pretreatments were most effective when

the unit price of cocaine was high.

To examine the generality of fluoxetine’s suppressant effects, the

experiment was replicated with groups of rats that self-administered

fentanyl, a potent mu receptor agonist (2.5, 5, and 10 μg/kg). Similar

results were obtained; fluoxetine produced dose-dependent decreases in

fentanyl self-administration at low and moderate fentanyl doses, but it

had little effect at the highest fentanyl dose.

Another means of increasing serotonin levels is to increase the amount of

L-tryptophan in the diet (Smith et al. 1986). The cocaine selfadministration experiment was replicated in other groups of rats that had

2, 4, or 8 percent L-tryptophan added to their standard chow, which

already contained 0.29 percent L-tryptophan (Carroll et al. 1990b). This

dietary manipulation produced concentration-dependent decreases in

cocaine and G+S self-administration. The effect of L-tryptophan was

greatest at the lowest cocaine dose, and there was almost no effect at the

highest dose.

Buprenorphine is a partial mu receptor agonist that has been shown to

reduce cocaine craving in methadone patients (Kosten et al. 1989) and to

reduce IV cocaine self-administration in rhesus monkeys (Mello et al.

1990). Buprenotphine pretreatment was examined in rats

self-administering a range of cocaine doses as well as in groups

self-administering G+S (Carroll and Lac 1992). Three buprenorphine

doses (0.1, 0.2, and 0.4 mg/kg) were tested in separate groups that

self-administered 0.1, 0.2, or 0.4 mg/kg cocaine. Buprenorphine

produced dose-dependent decreases in cocaine self-administration at the

two lower cocaine doses; however, there was only a minimal effect at the

highest cocaine dose. Buprenorphine also produced dose-dependent

decreases in G+S self-administration, but there was no effect on food

intake in the cocaine groups and only a small decrease in food intake in

the G+S groups.

Buprenorphine and fluoxetine were effective at reducing cocaine

self-administration in rats, but behavior maintained by the nondrug

substance G+S was reduced as well. Food intake was not altered in the

present experiment. In the previous study with monkeys, food delivery

was contingent on operant responding, and buprenorphine produced a

119
small but temporary decrease in food-maintained responding (Mello et al.

1990).

Figure 3 summarizes the results of some of the behavioral and

pharmacological treatments tested in rats in this laboratory.

Cyproheptadine, a serotonin antagonist, did not alter cocaine

self-administration; this may have been due to a ceiling effect. Other

researchers have found amphetamine self-administration was increased

by the serotonin antagonist metergoline (Lyness and Moore 1983).

Fentanyl pretreatment increased cocaine self-administration only in a

group of rats that had recently acquired cocaine self-administration and

had not yet reached the maximum number of cocaine infusions. It had no

effect once cocaine infusions stabilized at the maximum level (Carroll et

al., unpublished data). Naltrexone increased cocaine self-administration;

these results agree with those of other researchers who used similar

cocaine and naltrexone doses (Ramsey and Van Ree 1990). Another drug

that has been tested in this paradigm is an opioid peptide, dynorphin

(1-13), but it had no effect on cocaine self-administration at an IV dose

range of 0.12 to 1 mg/kg (Carroll and Lee, unpublished data). The lower

frames of figure 3 indicate that free access to food and G+S also reduced

cocaine self-administration.

Self-Administration of Smoked Cocaine Base and Orally

Delivered Drugs in Rhesus Monkey

Behavioral Treatments. Similar behavioral and pharmacological

treatments have been tested in rhesus monkeys. Four monkeys were

trained to smoke cocaine base by first training them to self-administer

liquids from a lip-operated drinking spout, then replacing the drinking

spout with a smoking tube that was similar in appearance to the drinking

spout (Carroll et al. 1990c). Each smoke delivery was contingent upon

completion of a progressive ratio response requirement on a lever. A

maximum of eight smoke deliveries (2 mg/kg each) was available, and

each smoke delivery was followed by a 15-minute timeout. After

behavior stabilized when the monkeys were maintained at 80 percent of

their free-feeding body weight, weights were increased or decreased in a

nonsystematic manner to examine the effect on cocaine selfadministration. Figure 4 shows that cocaine self-administration increased

as body weights decreased, and the lowest number of cocaine

120
FIGURE 3. Data are shown for groups of five rats in 5-day blocks.

The first bar in each frame represents the no-treatment

condition, the second bar is the 5 days of the

particular treatment described on the label above the

graph, and the third bar is the first 5 days back on the

nontreatment condition. Drug treatment doses are

indicated in parentheses, and the treatment drugs were

administered IV. L-tryptophan was given in ground

laboratory chow.

deliveries was obtained when free access to food was allowed

(100 percent of their free-feeding body weight).

Earlier work with orally delivered etonitazene, phencyclidine (PCP),

ketamine, amphetamine, and methohexital as self-administered drugs

showed similar results due to food deprivation and satiation (Carroll and

Meisch 1984; Meisch and Carroll 1987). In addition, when the drug

concentration was varied, the suppressant effects of food satiation

increased. A similar interaction occurred when PCP self-administration

was suppressed by concurrent access to saccharin (0.03 percent wt/vol) or

121
8 percent ethanol (Carroll et al. 1990d). As was the case with the drug

pretreatment effects on IV cocaine self-administration in rats, the higher

the unit price of the self-administered drug (responses per mg), the

greater the suppressant effect of the potential treatment drug or nondrug

reinforcer.

In a recent experiment, the unit price concept was studied by varying the

FR or price of PCP while keeping the drug concentration constant

(Carroll et al. 1991), and the effect of a nondrug alternative reinforcer,

saccharin, was examined at a range of PCP prices. As PCP price or FR

increased from 4 to 128 responses, the number of deliveries decreased.

This function is referred to as a demand curve, and the demand for PCP

steadily decreased with increases in price. The price of saccharin

deliveries remained fixed at 16, and intake was high and did not change

as a function of fluctuations in PCP price. When saccharin instead of

water was concurrently available with PCP during the daily 3-hour

sessions, the demand curve shifted downward in a parallel manner.

However, if the percentage of reduction in PCP deliveries due to

concurrent saccharin was considered as a function of the PCP price,

concurrent saccharin reduced PCP deliveries by only 20 percent at the

lowest PCP price (FR-4), and it reduced PCP deliveries by 90 percent at

the highest PCP price (FR-128). This relationship would hold if the data

were transformed into unit price, because the dose (mg) per delivery

remained constant. Thus, the higher the unit price (responses per mg),

the greater the suppressant effect of a concurrent nondrug reinforcer.

Pharmacological Treatments. Drug pretreatment experiments also

have been conducted using the monkey models of drug selfadministration. Four monkeys that had stable cocaine base-smoking

behavior were administered a range (0.01 to 0.8 mg/kg) of buprenorphine

doses intramuscularly 30 minutes before their daily smoking sessions for

5 days. Buprenorphine produced dose-dependent decreases in cocaine

base smoking. When saline was injected, all monkeys received the

maximum allowable (eight) smoke deliveries. Dose-dependent decreases

in smoke deliveries resulted when buprenorphine injections were given

(Carroll et al. 1992). The same buprenorphine doses were tested in other

groups of monkeys self-administering orally delivered PCP, ethanol, and

saccharin. Under each of these conditions, buprenorphine produced

dose-dependent decreases in self-administration. Thus, buprenorphine’s

effects were not specific to cocaine-reinforced behavior.

122
% Free Feeding Body Weight

FIGURE 4. Progressive ratio responses for cocaine smoke are

presented as a function of percentage of free-feeding

body weight for four monkeys. Each condition was held

constant for at least 10 days, and each point represents

a mean (±SE) for the last 5 days at that condition.

Other groups of monkeys were given access to concurrent PCP and

saccharin or PCP and ethanol, then treated with buprenorphine to

determine whether buprenorphine’s suppressant effects would be

enhanced under conditions when PCP self-administration was already

reduced by a concurrent drug or nondrug reinforcer (Carroll et al. 1992).

When PCP and water were concurrently available, the maximum

suppression due to buprenorphine was a 65-percent reduction compared

to saline pretreatment; however, when saccharin was concurrently

available with PCP, buprenorphine reduced PCP self-administration by

90 percent compared to saline pretreatment. These findings indicated that

there was an additive effect of behavioral and pharmacological

treatments. While concurrent ethanol also suppressed PCP

self-administration, buprenorphine did not produce any greater

suppressant effect when ethanol was concurrently available than when

water was concurrently available (Carroll et al. 1992).

123
Recent experiments were conducted to determine whether buprenorphine

would modify behavioral disruptions due to drug withdrawal. Operant

responding for food has served as a sensitive baseline for measuring

withdrawal effects when administration or self-administration of many

drugs of abuse is terminated. A model of PCP withdrawal was used to

examine the effects of buprenorphine (Carroll and Carmona 1991). Food

pellets were delivered under an FR-64 schedule, and PCP and water were

concurrently available under FR-16 schedules. When behavior had

stabilized for at least 10 days, water was substituted for PCP for 8 days.

Figure 5 shows that the number of pellet deliveries decreased by almost

90 percent, and there was a slow recovery over the 8-day period. When

PCP was reinstated, food deliveries returned to baseline levels. In

subsequent replications, either saline or buprenorphine was injected twice

daily during the 8-day PCP withdrawal period. Two buprenorphine

doses (0.2 and 0.8 mg/kg) were used that had been very effective at

reducing cocaine, PCP, ethanol, and saccharin self-administration. Figure

5 shows that the 0.2 mg/kg dose did not alter the course of PCP

withdrawal, and the 0.8 mg/kg dose had a similar lack of effect. In earlier

work a drug that is similar to PCP, (+) N-allylnormetazocine, eliminated

the PCP withdrawal effect on food-maintained behavior when

administered under similar conditions (Carroll 1988). In a recent

experiment another drug that is similar to PCP, dizocilpine, an N-methylD-aspartate (NMDA) antagonist, almost completely reduced the PCP

withdrawal effect at doses of 0.05 and 0.1 mg/kg (figure 6) (Carroll et al.,

in press).

Behavioral disruptions due to drug withdrawal also are affected by

behavioral economic conditions and the availability of alternative

reinforcers. In a recent study it was reported that the PCP withdrawal

effect (disruption in the food baseline) became more severe as the price of

food (FR) was increased from 64 to 128 to 258 responses. As the price

was increased even further to 5 12 and 1,024, the severity of the

disruption did not increase further. At these high response requirements

the monkeys were beginning to show weight loss (Carroll and Carmona

1991). Thus, two variables, price of food and body weight, were

changing at once.

In a subsequent experiment, the economic conditions were examined

further by repeating the withdrawal condition under an open and closed

economy (Carroll and Carmona 1991). The monkeys were still allowed

to earn food pellets under an FR-1,024 schedule, but under the open

124
Days

FIGURE 5. Mean pellet deliveries as a percentage of baseline

(unconnected point) are presented as a function of

sequential days of PCP withdrawal (8) and

reinstatement (5). The frame on the left indicates that

the monkey was injected with saline twice daily during

the 8 days of PCP withdrawal, and the frame on the

right indicates that buprenorphine (0.8 mg/kg) was

injected twice daily. Data are presented for one

monkey (M-C). Filled circles indicate that PCP was

available concurrently with water, and open circles

indicate that only water was available.

economy their earned food was supplemented each day with 100 g of free

food delivered by the experimenter. They did not show weight loss under

these conditions. Under the closed economy, they earned all of their food

under the FR- 1,024 schedule; there was no supplement, and the animals

experienced weight loss. Under the open economy condition, which was

repeated twice, a typical PCP withdrawal effect was found. Pellet

deliveries were decreased by approximately 60 percent; however, no PCP

withdrawal effect occurred under the closed economy.

The same amount of food pellets were earned during PCP access and

PCP withdrawal, and this was also the same amount that was earned

when there was an open economy. Figure 7 is a hypothetical curve

summarizing these results. As the price of food was increased, a drug

withdrawal effect measured by disruption in food-reinforced responding

became more severe. When the price of food became so high that weight

loss began to occur, the PCP withdrawal effect decreased as the price of

food increased further. A U-shaped function describes the severity of the

withdrawal effect as the price of food increased. These results show that

125
FIGURE 6. Mean pellet deliveries as a percentage of baseline

(unconnected point) are presented as a function

sequential days of PCP withdrawal (8) and

reinstatement (5). The frame on the left indicates that

the monkey was injected with saline twice daily during

the 8 days of PCP withdrawal, and the frame on the

right indicates that MK-801 (0.1 mg/kg) was injected

twice daily. Data are presented for one monkey (M-C).

a withdrawal effect can range from nonexistent to severe depending upon

the price of food and the type of food economy that exists, suggesting

that the disruptions in operant behavior during withdrawal are related to

motivational deficits rather than physical illness. Thus, it is important to

assess withdrawal effects within a range of economic variables.

CONCLUSION

In summary, pharmacological and behavioral treatments were described

that reduce self-administration of cocaine and other drugs. The

magnitude of effects was similar across several drug classes, different

species, and drug and nondrug reinforcers. Factors that influence the

effectiveness of these treatments are the phase of the addiction process

(acquisition, maintenance, or withdrawal), availability of alternative

reinforcers, and the behavioral economics of food or drug reinforcement.

Drug and behavioral treatments have greater effects when the unit price

(responses per mg) of the drug is high and little or no effect when the unit

price is low.

126
Stable Body Weight Reduced Body Weight

(Food Deprived)

Price of Food

FIGURE 7. A hypothetical function is presented to describe the

relationship between the price of food (FR) and the

disruption in food-reinforced behavior due to PCP

withdrawal as a percent of baseline when PCP is

available. The vertical line and labels at the top

indicate that the biphasic function is also due to

reduced body weight. To the left of the vertical line the

free-feeding body weight is maintained while, to the

right of the line, body weight decreases as the price of

food increases. This function is based on previous

experimental results (Carroll et al. 1991a).

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129
ACKNOWLEDGMENTS

The assistance of Gilberto Carmona in the cocaine base smoking and

buprenorphine experiments with monkeys, and of Sylvie Lac with the IV

rat preparation, are appreciated. This research was supported by National

Institute on Drug Abuse grant nos. R01 DA 02486, R 37 DA 03240, and

R01 DA 05844.

AUTHOR

Marilyn E. Carroll, Ph.D.

Department of Psychiatry

University of Minnesota Medical School

Box 392 UMHC

Minneapolis, MN 55455

130
Preclinical Assessment of

Cocaine’ Antagonist Drugs in

Squirrel Monkeys

Jack Bergman

Stimulation of dopamine (DA) receptors resulting from the inhibition of

monoamine transport appears to play a prominent role in the behavioral

effects of cocaine. On this basis, the development of drugs to modify

these neurochemical actions of cocaine is a rational approach in

developing therapeutics for cocaine abuse and dependence. From a

pharmacological perspective, strategies used to develop therapeutics for

the treatment of opioid dependence might be applicable in this approach.

For example, compounds to serve as replacement therapeutics, much as

methadone is used in the treatment of opioid dependence, might be useful

pharmacological adjuncts in treatment programs.

The development of drugs to directly block the actions of cocaine

represents another strategy that may have clinical utility. This might

involve the development of compounds to block the actions of cocaine

directly at its presumably presynaptic binding sites or indirectly by

blocking the actions of DA at DA receptors. In an analogous manner,

opioid receptor antagonists such as naltrexone have been applied in the

treatment of problems associated with opioid dependence. More recently,

buprenorphine, a partial agonist that produces morphine-like or

morphine-antagonist effects under different conditions, is being evaluated

as a therapeutic for opioid dependence.

The author and coworkers at the New England Primate Research Center

have undertaken systematic studies of compounds that may have some

utility as blockers of the effects of cocaine. These experiments were

conducted primarily on squirrel monkeys and involved at least two stages

of evaluation. In the first stage, subjects responded under fixed-interval

(FI) schedules of reinforcement under which cocaine and related

compounds have characteristic rate-increasing effects, Drugs also were

studied in drug discrimination (DD) experiments in which cocaine and

compounds that are either structurally or functionally related to cocaine

dose-dependently increase responding on the cocaine-associated lever. In

studies involving FI performances or DD procedures, candidate

131
therapeutics are studied by determining how they might modify the doserelated effects of cocaine. In the second stage of evaluation, compounds

that may pharmacologically modify the effects of cocaine on FI

performance or in DD experiments are further evaluated for their ability

to alter the reinforcing effects of cocaine in drug self-administration

studies. In the latter studies, full dose-effect functions for cocaine selfadministration are determined in both the absence and the presence of

selected doses of the candidate therapeutic. It is important to emphasize

that, in each of the procedures, pharmacological antagonism is evaluated

on the basis of shifts in the cocaine dose-effect. function.

Using the methods described above, a number of compounds have been

evaluated that may regulate dopaminergic activity and thus alter the

effects of cocaine. For example, drugs that may bind to the cocaine

binding site on the DA transporter have been studied to determine

whether those compounds might block or accentuate the effects of

cocaine. Opioids and other compounds that may limit or modulate the

release of DA from the presynaptic neuron also have been evaluated.

However, most of the research has involved ligands for postsynaptic DA

receptors and, in particular, DA type 1 (D1) receptors. In this effort, the

research has focused on the effects of D1 receptor blockade by the D1

antagonist SCH 39166 and, more recently, by D1 agonists that have low

intrinsic activity and, as partial agonists, may act functionally as

antagonists. As shown in the left panels of figure 1, the D1 antagonist

SCH 39166 antagonizes the effects of cocaine on FI responding and in

DD experiments. Doses ranging from 0.03 mg/kg to 0.3 mg/kg of the D1

receptor blocker produce rightward shifts in the dose-effect functions for

cocaine in both studies.

The antagonism of cocaine’s effect by SCH 39166 appears to be mutual

and surmountable; that is, the rate-decreasing effects of the antagonist

itself are overcome by cocaine, after which higher doses of cocaine can

reproduce the cocaine dose-effect function to the right of its original

position. As shown in the bottom right panel of figure 1, the antagonism

of cocaine’s effects by SCH 39166 also is evident in studies of drug selfadministration in squirrel monkeys. In these experiments, squirrel

monkeys responded for consequent injections of cocaine under a secondorder FI lo-minute schedule of responding during which the completion

of each 30-response fixed ratio (FR-30) produced a visual stimulus

change. Under this schedule, the first visual stimulus change after the

elapse of 10 minutes was accompanied by intravenous (IV) drug injection

and followed by a brief timeout period. Daily sessions comprised five or

132
COCAINE (mg/kg)

FIGURE 1. Effects of cocaine in groups of squirrel monkeys

(n = 4-6 per group) in experiments involving FI

performance under an FI schedule of stimulus-shock

termination (top left, cocaine discrimination (bottom

left), and IV drug self-administration (bottom right).

Abscissae: cumulative dose or, in bottom right, unit

dose per injection, log scale; ordinates: rates of

responding shown as percentage of control rates (top

left) or responses/second (bottom right) and percentage

of responses on cocaine-associated lever (bottom left).

Open symbols represent the effects of cocaine alone.

Filled symbols represent the effects of cocaine

redetermined in the presence of the D1

 receptor blocker

SCH 39166.

133
six presentations of the second-order FI schedule. Pretreatment with

SCH 39166 served to antagonize the effects of cocaine and, in most

cases, produced a rightward shift in the entire dose-effect function for

self-administration, indicative of surmountable antagonism.

The antagonistic effects of SCH 39166 in all the above procedures are of

a magnitude comparable to or greater than that observed with DA type 2

(D2) receptor blockers and suggest that, at the least, D1 mechanisms play

a prominent role in the abuse-related effects of cocaine.

In subsequent experiments, the effects of D1 agonists that have been

shown to have limited efficacy relative to DA were evaluated. Perhaps,

as partial agonists at the D1 receptor, these compounds also could

attenuate the behavioral effects of an indirect agonist such as cocaine. In

ongoing studies, two D1-selective benzazepines that are thought to act as

partial agonists, SKF 75670 and R-SKF 38393, indeed have produced

rightward shifts in the dose-related effects of cocaine on schedulecontrolled responding, indicative of mutual and surmountable

antagonism. For comparison, the effects of SKF 81297, a D1-selective

agonist with actions that can be surmountably antagonized by SKF 75670

or R-SKP 38393, are also being evaluated. As shown in figure 2, SKF

8 1297 appears to have effects in combination with cocaine that differ

markedly from those of the D1 receptor blocker SCH 39166 or, thus far,

SKF 75670 or R-SKF 38393. That is, the dose-effect function for

cocaine is shifted downward rather than to the right, indicating that the

effects of cocaine, although attenuated, are not pharmacologically

antagonized by SKF 81297. These data suggest that efficacy may be an

important factor in determining how the effects of a D1 agonist modify

those of cocaine. To the extent that limited efficacy D1 agonists may not

have the side effects associated with receptor blockers, they might prove

to have therapeutic utility for the management of some aspects of cocaine

dependence and are an interesting class of compounds for further study.

As discussed above, in addition to the development of candidate

therapeutics that act at D1 receptors, another strategy for developing

cocaine antagonists also might involve compounds that modulate DA

release into the synapse. For example, attention recently has focused on

the involvement of opioid mechanisms in the regulation of DA activity.

A growing body of neurochemical evidence indicates that DA release can

be modulated in different ways by μ and K opioids. In this regard, μ

opioids may enhance the release of mesolimbic DA, whereas K opioids

may attenuate or diminish its release. Recently, it has been found that the

discriminative-Stimulus effects of cocaine in squirrel monkeys may be

134
COCAINE (mg/kg)

FIGURE 2. Effects of cocaine in squirrel monkeys (n = 4) under an

FI schedule of stimulus-shock termination. Abscissa:

cumulative dose, log scale; ordinate: rates of

responding as percentage of control rates. Open

symbols represent the effects of cumulative doses of i.m.

cocaine alone. Filled symbols represent the effects of

cocaine redetermined in the presence of the D1 agonist

SKF 81297. Open circles above C represent mean and

S.D. of control rates of responding during successive

components of the session.

enhanced by prior administration of μ opioids, and these modulatory

effects can be antagonized by the opioid antagonist naltrexone.

Consistent with these findings, ongoing experiments suggest that effects

of cocaine on schedule-controlled responding and in DD experiments can

be reliably modified by prior administration of K opioids such as

U 50,488. As shown in figure 3, doses of U 50,488 that previously have

been found to attenuate the effects of cocaine in DD studies also appear

to produce a rightward shift in the dose-response function for the effects

135
COCAINE (mg/kg)

FIGURE 3. Effects of cocaine in squirrel monkeys (n = 4) under an

FI schedule of stimulus-shock termination. Abscissa:

cumulative dose, log scale; ordinate: rates of

responding as percentage of control rates. Open

symbols represent the effects of cumulative doses of

intramuscular cocaine alone. Filled symbols represent

the effects of cocaine redetermined in the presence of

the K agonist U 50,488. Open circles above C represent

mean and S.D. of control rates of responding during

successive components of the session.

of cocaine on FI responding. Although K opioids have direct behavioral

effects that may preclude their development as therapeutics, these data

suggest that interfering with the regulation of DA release may be a useful

way of modifying the behavioral effects of cocaine.

CONCLUSION

Research results such as these provide further evidence that the

behavioral effects of cocaine are prominently mediated by its indirect

dopaminergic actions, including increased DA activity at D1 receptors.

Findings that the limited efficacy agonist SKF 75670 can antagonize the

136
behavioral effects of cocaine have provided an example of the

modification of the behavioral effects of an indirect agonist by a

postsynaptic receptor ligand with reportedly limited efficacy. Based upon

current findings with the use of the partial opioid agonist buprenorphine

for the treatment of opioid dependence, it may be that limited agonist

efficacy also is a useful feature for cocaine antagonist therapeutics.

Additionally, findings with the K-opioid agonist U 50,488 suggest that

another approach to the development of cocaine antagonists might be to

dampen the release of DA.

Collectively, these findings indicate that it is feasible to evaluate cocaine

antagonists in preclinical studies in monkeys. They illustrate, as well, the

importance of full dose-effect determinations for meaningful evaluation

of drug interactions. As shown, antagonism by these types of compounds

can be characterized as mutual and surmountable, and it is important to

keep in mind the limitations of such actions for the treatment of cocaine

dependence. First, drugs that antagonize the behavioral effects of cocaine

may have effects in their own right that, in turn, may limit their clinical

application. Second, the antagonism of cocaine’s effects can be

overcome by increases in the dose of cocaine, which may further limit the

utility of this approach. Nevertheless, antagonists may have a role in the

treatment of some cocaine-related problems. For example, antagonists

may be useful for the treatment of cocaine overdose and, in some cases,

as short-term pharmacological adjuncts for the management of cocaine

abuse. However, whether surmountable cocaine antagonists have a role

as long-term pharmacological adjuncts in treatment programs is less

certain. By analogy, the use of surmountable antagonists in the

management of opioid dependence has had only inconsistent success. In

this regard, the development of acceptable replacement therapeutics for

the management of cocaine dependence at least deserves consideration as

an alternative strategy.

ACKNOWLEDGMENT

This chapter was prepared with support from USPHS grant nos.

DA-03774, DA-00499, and RR-00168.

137
AUTHOR

Jack Bergman, Ph.D.

Associate Professor

Department of Psychiatry

Division of Behavioral Biology

New England Regional Primate Research Center

Harvard Medical School

1 Pine Hill Drive, Box 9102

Southborough, MA 01772-9102

138
Cocaine Self-Administration

Research: Treatment

implications

Richard W. Foltin and Marian W. Fischman

Treatment of cocaine abuse over the past decade has increasingly used

pharmacological adjuncts to behavioral interventions. Although few

double-blind, placebo-controlled research studies have been reported,

many case reports and open-label trials have appeared in the clinical

literature. A number of different strategies have been used in selecting

potential treatment medications, including reduction in cocaine craving,

blockade of cocaine-induced euphoria, and other changes in the

self-reported effects of cocaine (Kosten 1989). Use of these traditional

self-report measures is based on the generally held assumption that the

effects of a drug that maintain drug taking are related to drug-induced

changes in subjective state, and that what drug users say about the dose of

a drug they have just taken can be used to predict the likelihood that the

drug will be used excessively and nonmedically (Fischman 1989). As

reported elsewhere (Foltin and Fischman 1991a), however, the pivotal

feature of cocaine abuse is cocaine-taking behavior, and any potentially

useful medication must be shown to reduce cocaine-taking behavior

within the context of a treatment program.

Clinical research using patient populations is generally not the most

efficient design for evaluating potentially useful medications. The level

of control required for the collection of data showing both safety and

efficacy can best be achieved within a laboratory-based research study.

Under controlled laboratory conditions, self-reported effects of cocaine

can be measured concurrently with physiological measures and,

importantly, this can be carried out within the context of measuring

cocaine-taking behavior.

Such a research design is based on laboratory research with nonhumans,

where procedures have been developed to evaluate the controlling

variables in drug self-administration (Johanson and Fischman 1989).

Rhesus monkeys given continuous free access to cocaine readily

self-administer it in erratic bursts (or binges), in marked contrast to the

stable patterns of drug self-administration seen when the animals are

139
allowed access to the drug for only a few hours each day. They also fail

to eat and, therefore, become severely debilitated (Johanson et al. 1976).

Comparable patterns of multiple-dose cycles are seen in cocaine abusers

who take the drug repeatedly until their drug supply is exhausted. Since

this pattern is the norm for cocaine abuse, it is important that any

laboratory procedure attempting to evaluate potential treatments for

cocaine abuse incorporate a multiple-dose procedure into the assessment.

This chapter describes the development and utility of a multiple-dose

cocaine self-administration procedure in which volunteers were given the

opportunity to take repeated doses of cocaine, with doses and patterning

approximating those reported in the natural ecology. Of importance is

the integration of the more traditional single-dose methodology (Foltin

and Fischman 1991a), including self-reported and physiological effects,

with the most salient feature of cocaine abuse: cocaine selfadministration. The relationship between cocaine self-administration and

its self-reported effects is complex (Foltin and Fischman 1991a), and use

of only self-reported effects cannot provide sufficient information to

evaluate the potential utility of a new treatment medication.

In all the studies described, normal healthy volunteers with histories of

cocaine and other drug use (e.g., heroin, marijuana, alcohol, nicotine

cigarettes) participated in daily experimental sessions lasting 2 to 4 hours.

Subjects resided in a hospital clinical research unit for the duration of the

2- to 3-week studies and had access to nondrug-related recreational

activities. During their daily sessions, subjects were given the

opportunity to take multiple doses of cocaine or placebo. Few studies

evaluating the self-administration of cocaine by human subjects under

controlled conditions have been published (Foltin and Fischman 1991a).

Two laboratory self-administration procedures have been developed for

use with humans. In the first, essentially unlimited access to a single dose

is provided, and subjects can determine pattern of intake. The second

procedure measures choice between placebo and active drug options,

comparing all possible combinations.

In a study on intranasal cocaine self-administration (Foltin et al. 1988),

subjects were given access to 96 mg or 4 mg (a placebo dose) of cocaine

once every 35 minutes. When 96 mg cocaine was available, the subjects

requested the drug as soon as it was available and inhaled approximately

five doses. When 4 mg cocaine was available, the subjects requested the

drug as soon as it was available and inhaled approximately four doses.

The 96-mg dose sessions had to be stopped by the experimenters due to

140
the subjects’ elevated blood presssure, while the 4-mg sessions were not.

It is difficult to argue that 96-mg doses maintained more drug-taking

behavior than 4-mg doses because medical considerations constrained the

free-access design. Thus, with free-access procedures within a single

session, it is at times difficult to differentiate placebo from active drugmaintained behavior.

Fischman and Schuster (1982) provided data on the pattern of

intravenous (IV) cocaine self-administration in experienced cocaine users.

All subjects reliably self-administered cocaine with a 5- to lo-minute

inter-injection interval, resulting in about six doses per-hour. A similar

pacing of cocaine intake was observed for both 16-mg and 32-mg cocaine

doses. Thus, with free-access procedures within a single session, it is at

times difficult to differentiate behavior maintained by different doses.

Using free-access procedures, it is often difficult to interpret changes in

pattern of intake and amount of intake with respect to drug dose; short

sessions and limitations on the number of sessions hinder interpretation of

the results. Given these problems, it might be difficult to interpret the

effects of a treatment drug on free-access cocaine self-administration by

humans.

This chapter describes a series of studies using two dose-choice

procedures that circumvent many of the problems described in the

preceding paragraphs to analyze variables affecting IV and smoked

cocaine self-administration by humans. During each session, subjects

were allowed to choose between two unidentified IV injection solutions

(saline or different doses of cocaine). They were told that these solutions

could be an active or inactive drug. Each subject was told that the

right-hand response button and light were associated with a specific drug

solution and that the left-hand response button and light were associated

with a second drug solution. Subjects were allowed to choose repeatedly

between solutions each day in experimental sessions that lasted 2 to 4

hours. In nearly all cases, there was a 14-minute interval between drug

choices. This interval roughly corresponds to the interval that subjects

report using between IV injections outside the laboratory. Subjects were

instructed to sample each of the two available doses during the first two

choice trials. During the remaining four to six choices, subjects were

instructed to choose the dose of cocaine they preferred.

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Options

FIGURE 1. Percent of high cocaine dose choices as a

function of the two available doses

summarized across a series of studies

When one option consisted of active cocaine and the other placebo,

subjects almost exclusively chose to self-administer the active drug by

selecting the active dose in 80 to 100 percent of the trials within a session

(Fischman et al. 1990; Foltin and Fischman, unpublished observations).

Thus, even in single sessions, robust differences between active drug and

placebo were demonstrated in experienced drug users.

The choice of higher cocaine doses over lower doses in 60 to 100 percent

of the trials within a session was another robust phenomenon observed in

these studies (figure 1) (Fischman et al. 1990; Foltin and Fischman,

unpublished observations). Unlike free-access procedures, preferences

among available active doses are rapidly demonstrated using choice

procedures. Behavior observed under choice procedures provides a rapid

assessment of dose preference within a single session and should provide

a good behavioral baseline for the assessment of potential cocaine

treatment drugs or behavioral interventions.

While the above data indicate the sensitivity of choice procedures to dose,

it was also of interest to investigate behavioral factors that might

influence cocaine choice. In one study (Foltin and Fischman,

unpublished observations), subjects were given a choice between two

active doses of cocaine, and the response requirement for the high dose

was systematically manipulated. Subjects consistently chose the high

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dose of cocaine on four out of four choice opportunities regardless of the

response cost associated with that dose. For example, under the fixed

ratio 1600 condition, subjects had to respond three times a second for 8

minutes in order to obtain each high dose of IV cocaine. Data from a

representative subject are presented in figure 2(a), demonstrating the

consistent choice of the high cocaine dose (16 mg) regardless of the

response requirement for the high dose. Although all subjects

complained bitterly about the “stupid button pressing,” they continued to

choose the high dose. This relatively simple manipulation of increasing

the work necessary to obtain a dose of cocaine was ineffective in altering

dose choice. This points to the robust effects of cocaine as a reinforcer

and suggests that simply increasing the amount of effort necessary

(within limits, of course) to obtain a substantial dose of cocaine is not a

useful method for decreasing cocaine intake.

In another study (Foltin and Fischman, unpublished observations),

monetary gain was paired with low-dose choices with the prediction that,

if paid enough money, subjects would choose low doses paired with

money rather than a higher dose that was not associated with money.

However, the effects of pairing money with low doses on high-dose

choice were minimal. Data from a representative subject are presented in

figure 2(b), demonstrating the consistent choice of the high cocaine dose

(16 mg) even when choosing the low dose would have resulted in

low-dose administration and $10. Occasionally, pairing $10 with the

low dose did decrease high-dose choice, but these effects were variable.

Subjects were asked to indicate how much they would be willing to pay

for each of the tested doses. It is interesting to note that there was no

relationship between the amount that subjects said they would pay for a

high dose of cocaine and the effect of actually paying them on high-dose

choice. It might be expected that, if a larger sum of money than the

subjects reported the high dose was worth was paired with the lower

dose, they would take the lower dose and the money. This was not the

case. For example, one subject chose the high dose on three of four

opportunities, even when $10 was paired with the low dose. This means

that he had the option of receiving the high dose alone, or $10 plus the

low dose at each choice. When asked how much he would be willing to

pay for the high dose of cocaine, he said that he would not buy such lowquality cocaine.

As with increasing response cost, the relatively simple manipulation of

paying subjects to choose the lower dose of cocaine was ineffective in

altering dose choice. This suggests that simply increasing the monetary

143
U.S. Dollars Associated with Low Dose

FIGURE 2. (Panel A): Number of

high cocaine dose

choices as a function of

the response requirement to obtain the high

dose. (Panel B:)

Number of high

cocaine dose choices

as a function of the

amount of money

paired with the low

dose.

cost of the drug (within limits, of course) is minimally useful in

decreasing cocaine intake. In combination, these data suggest that

cocaine choice is a robust phenomenon that is not particularly sensitive to

these two behavioral manipulations.

Recently; the self-administration of cocaine by smoking has risen in

prominence and notoriety in the United States and Canada (Cheung et al.

1991; Gawin 1989; Johanson and Fischman 1989; Trebach and Zeese

1990). Cocaine smoking produces rapid rises and peaks in cocaine

plasma levels and subjective effects similar to IV administration (Foltin

and Fischman 1991b; Foltin et al. 1990; Hatsukami et al. 1990; Jeffcoat

144
et al. 1989; Jones 1990; Paly et al. 1982; Perez-Reyes et al. 1982).

Smoked cocaine produces many of the positive effects of IV cocaine (i.e.,

a rush) without some of the negative aspects: painful self-injection,

possible contact with the acquired immunodeficiency syndrome virus,

other health risks associated with IV drug use, and the stigma of being an

IV drug user. In addition, the widespread availability in some cities of

prepared, inexpensive, single-dose units of cocaine base (“crack,” “ready

rock”) has enhanced the probability of cocaine ingestion via smoking.

A previous report (Foltin and Fischman 1991b) indicated that the potency

of smoked cocaine was about 60 percent of that of IV cocaine; that is, a

50-mg dose of smoked cocaine had effects similar to a 32-mg dose of IV

cocaine. Visual analog scale (VAS) ratings of “stimulated,” “high,” and

“liking” were greater at similar plasma levels following smoked cocaine,

compared to IV cocaine. Other subjective effects of smoked and IV

cocaine were similar.

These differences in ratings of “stimulated,” “high,” and “liking” scores

suggested that smoked cocaine might have a modestly greater abuse

potential than IV cocaine. While such differences in subjective effects

provide important information about potential differences in abuse

liability (de Wit and Griffiths 1991; Preston and Jasinski 1991), studies

directly assessing drug self-administration provide a more effective

measure of relative abuse liability (Fischman and Foltin 1992). The first

purpose of this study was to investigate the relative reinforcing effects of

doses of smoked and IV cocaine that produced similar cardiovascular

effects. Both a smoked and an IV dose were available during daily

self-administration sessions, with subjects choosing which of the doses to

self-administer. The second purpose of the study was to compare

changes in subjective-effects measures with dose choice to estimate the

relationship between cocaine self-administration and the self-reported

effects of cocaine.

When given access to placebo IV cocaine and placebo smoked cocaine,

subjects chose each option equally often. When given access to placebo

IV cocaine and an active dose of smoked cocaine, subjects almost

exclusively chose the smoked dose (4.5 times, on average, out of a

possible 5 choice trials). Similarly, when given access to placebo smoked

cocaine and an active dose of IV cocaine, subjects almost exclusively

chose the IV dose. During sessions when subjects were given access to

25 mg of smoked cocaine and an active dose of IV cocaine, subjects

chose the low smoked dose on about three choice trials. Finally, when

145
subjects were given access to 50 mg of smoked cocaine and an active

dose of IV cocaine, subjects chose the high smoked dose on about four

choice trials. Thus, active doses were exclusively chosen over placebo

doses regardless of the route of administration, the low smoked dose was

chosen slightly more often than both IV doses, and the high smoked dose

was consistently chosen over both IV doses.

In addition to summarizing choice behavior based on the mean number of

smoked doses, the data also were summarized on the number of subjects

who demonstrated a preference for smoked cocaine, that is, who chose

the smoked dose on three or more of the five choice trials. These data

(figure 3) show clearly that, when an active dose was paired with a

placebo dose, all subjects preferred the active dose. Six subjects

preferred the low smoked dose over both IV doses, and at least eight

subjects preferred the high smoked dose over both IV doses. Using this

criterion, the high smoked cocaine dose was clearly preferred over both

IV doses (8 of 10 subjects), while even the low smoked dose was often

preferred over the high IV dose (6 of 10 subjects).

It is possible that during sessions in which two active doses were

available, choice may have been related more to the first cocaine

administration of the day rather than differences between the two doses

per se; that is, subjects may have perseverated with the dose that

produced the initial change from baseline. Each of the 10 subjects

experienced 4 active dose pairs (e.g., 25 mg smoked versus 16 mg IV

cocaine), resulting in a total of 40 such sessions. On 22 of these sessions,

subjects first chose IV cocaine, and only on 7 of these occasions (32

percent of the time) did subjects choose IV cocaine an additional 3 or

more times. In contrast, on 18 of these sessions subjects first chose

smoked cocaine, and on 14 of these occasions (78 percent of the time)

subjects chose smoked cocaine an additional 3 or more times. This

pattern of results supports a preference for smoked cocaine rather than a

perseveration of initial dose choice.

These results indicate clearly that the recent increase in cocaine smoking

is due, at least in part, to the high abuse liability of smoked cocaine. The

robust choice of the high smoked dose over both active IV doses by 80

percent of the subjects in the current study is particularly surprising in

that 80 percent of these subjects reported a preference for IV cocaine, not

smoked cocaine, during interviews prior to participation.

146
Preference for Smoked Cocaine

Smoked Dose

FIGURE 3. Number of subjects choosing the smoked

cocaine dose as a funcion of the dose of smoked

and intravenous cocaine available each session

KEY: Pbo = Placebo

The cardiovascular and subjective effects of cocaine repeatedly were

determined during each session in order to examine the possible

relationship between these effects and route choice. High cocaine doses,

regardless of route of administration, produced the typical spectrum of

cocaine effects: increases in systolic and diastolic pressure, heart rate,

and rate-pressure product; ratings of “stimulated,” “high,” and “anxious”

for the benzedrine group (BG), morphine-benzedrine group (MBG); and

lysergic acid diethylamide (LSD) scores of the Addiction Research

Center Inventory (ARCI) (Haertzen 1966); arousal and positive mood

scores of the Profile of Mood States (POMS) (McNair et al. 1971); and

decreases in pentobarbital-chlorpromazine-alcohol group scores of the

ARCI (Fischman et al. 1976, 1983a, 19833, 1990; Foltin and Fischman

1991b; Foltin et al. 1987, 1990; Kumor et al. 1989; Muntaner et al. 1989;

Resnick et al. 1977). With the exception of peak systolic pressure and

rate-pressure product following low doses, there were no significant

differences between acute doses of smoked and IV cocaine. The absence

of significant differences in subjective and cardiovascular effects between

routes of administration contrasts with the clear preference for smoked

147
cocaine. The subjective effects of acute doses of smoked and IV cocaine

were not predictive of subsequent route choice.

Analysis of the effects of repeated doses of cocaine across trials within a

session indicated that systolic and diastolic pressure, heart rate,

rate-pressure product, ratings of “stimulated” and “high,” and LSD scores

of the ARCI were increased above baseline during the entire session

following smoked and IV cocaine administration. As with the acute

effects, there were no significant main effects by route of administration.

There were a number of significant interactions between the route of

cocaine administration and the cumulative dose that indicate a

relationship between the subjective effects of cocaine and route choice.

There was a significant positive linear relationship between ratings of

“sedated,” LSD scores of the ARCI, confusion, elation, positive mood

scores of the POMS, and cumulative cocaine dose following smoked

cocaine, but not following IV cocaine. In addition, the predicted

increases in ratings of “high” with cumulative dosing were larger

following smoked cocaine than IV cocaine.

Although significant, the predicted increases in effect with increasing

smoked cocaine dose were small. With the exception of ratings of

“sedated,” increases in these measures commonly occur following

cocaine administration (Fischman et al. 1976, 1983a, 1983b, 1990; Foltin

and Fischman 1991b; Foltin et al. 1987, 1990; Kumor et al. 1989;

Muntaner et al. 1989; Resnick et al. 1977). These findings confirm a

previous report that indicated the ratings of “stimulated” and “high” were

greater at similar plasma levels following two doses of smoked cocaine,

as compared with two doses of IV cocaine (Foltin and Fischman 1991b).

Thus, only with repeated administration did several subjective-effects

measures differentiate smoked and IV cocaine and predict route choice.

In addition to using drug self-administration and subjective effects to

predict abuse liability, ratings of “quality” and “liking” and estimates of

street value also have been used to predict abuse liability of a drug (de

Wit and Griffiths 1991; Foltin and Fischman 1991a; Preston and Jasinski

1991). Both active doses of cocaine significantly increased ratings of

“potency,” “quality,” “high,” “liking,” and street value compared to

placebo.. The high smoked cocaine dose was associated with significantly

greater ratings of “liking” than the high IV cocaine dose. In a previous

study comparing the effects of smoked and IV cocaine (Foltin and

Fischman 1991b), smoked cocaine also was associated with significantly

148
greater ratings of “liking” than IV cocaine. In combination, these results

suggest that subjects’ estimates of drug “liking” are predictive of abuse

liability.

With the exception of the “liking” rating, there were almost no

relationships between after-session ratings of drug effect and route

choice. This issue was investigated further by examining ratings on the

days that subjects had access to an active dose of smoked cocaine and an

active dose of IV cocaine. With one exception, in spite of clear

preference for smoked cocaine, there were no significant differences in

after-session ratings of the two active cocaine doses. The after-session

ratings of “potency,” “quality,” “high,” and “liking,” but not street value,

were greater for 50 mg smoked cocaine than 16 mg IV cocaine. In

addition, no significant correlations between ratings of the smoked dose

and the number of smoked-dose choices were observed. It is possible

that, while absolute ratings were poor predictors of route choice, the

difference between the rating of the smoked dose and the rating of the IV

dose may have been predictive of route choice; the greater the difference,

the higher the probability of smoked dose choice. However, this was not

the case; with one exception, there were no significant correlations

between the difference in scores and smoked dose choice.

One purpose of this study was to examine the relationship between the

subjective effects of a drug and self-administration of that drug. If

smoked cocaine were a new drug, rather than a new route of

administration for an old drug, then it would be predicted to have

significant abuse liability based on the similarity of the subjective effects

to the effects of IV cocaine (de Wit and Griffiths 1991; Foltin and

Fischman 1991a; Preston and Jasinski 1991). In the present study,

despite using doses of smoked and IV cocaine that were matched for

initial cardiovascular and subjective effects, smoked cocaine was

preferred over IV cocaine, as determined by route choice. Analysis of the

effects of repeated cocaine dosing indicated that several subjective effects

and ratings of “liking” were predictive of route choice. While these

results clearly indicate the necessity of studying drug self-administration

in addition to subjective effects, there is a caveat. It is possible that the

standardized questionnaires used did not assess the relevant subjective

effects that would have predicted route choice. The inclusion of

self-report items specifically tailored to assess unique aspects of smoked

cocaine may have predicted route choice.

149
The self-administration model should thus be a useful tool for evaluating

the mechanisms of action of pharmacological interventions in the

treatment of cocaine abuse via both smoked and IV routes of

administration (Foltin and Fischman 1991b). Since separate measures

can be made of drug taking, cardiovascular effects, and subjective effects,

it is theoretically possible to parcel out specific effects of a treatment

medication, thereby eventually providing targeted treatment.

The two-dose choice procedure has been used to evaluate the effects of

the potential treatment drug desipramine on cocaine-taking behavior

(Fischman et al. 1990). Therapy with the tricyclic antidepressant

desipramine has been suggested as a pharmacological adjunct for the

treatment of cocaine abuse (Extein and Gold 1988; Gawin and Kleber

1984; Giannini and Billet 1987; Giannini et al. 1986). Although not

always a sucessful intervention (Amdt et al. 1990), in a double-blind

clinical trial (Gawin et al. 1989) about three times as many patients

maintained on desipramine as opposed to placebo-remained abstinence

for 3 to 4 weeks. Gawin and Kleber (1984) have proposed that repeated

cocaine use results in noradrenergic and dopaminergic receptor changes

that are similar to those seen in depression. Thus, if the antidepressants

are useful, particularly the tricyclic antidepressants, their utility may be as

therapeutic adjuncts rather than as pharmacological antagonists of

cocaine’s effects.

Choices between active doses of IV cocaine and placebo were recorded

before and during a period of maintenance on desipramine. Subjects

were outpatients during the desipramine maintenance period, reporting to

the laboratory daily; blood samples were taken to monitor desipramine

blood levels twice each week. Blood levels of desipramine were

maintained at approximately 125 ng/mL during the final determination of

cocaine dose choice. This protocol allowed evaluation of desipramine’s

effects on drug taking, dose preference, self-reported drug effects, and

cardiovascular effects under conditions in which the drug was taken

outside the laboratory (i.e., the opportunity for repeated dosing was

available).

As shown in figure 4(a), desipramine had no effect on cocaine-taking

behavior: Subjects almost exclusively chose cocaine over placebo both

before and during desipramine maintenance. Cocaine could not always

be administered because of medical considerations (i.e., diastolic blood

pressure above 100 mmHg or heart rate above 131 bpm), which were

generally related to the desipramine-induced elevations in baseline

150
Cocaine (mg)

FIGURE 4. (Panel A): Number of high cocaine

dose choices as a function of the

available cocaine dose (the alternative

was always a placebo injection) before

and during desipramine maintenance.

(Panel B): “I want cocaine” scores as

a function of cocaine dose before and

during desipramine maintenance.

Error bars represent SEMs.

cardiovascular measures. The self-administration of cocaine despite

potentially detrimental cardiovascular effects is clear evidence for the

toxicity of this drug.

Craving is a generally used measure in clinical studies, and decreases in

craving for cocaine have been reported for cocaine abusers being treated

with desipramine (Gawin and Kleber 1984; Gawin et al. 1’989). A VAS

labeled “I want cocaine” was administered as part of the self-report

questionnaires answered repeatedly during each session. As shown in

figure 5(b), before the period of maintenance on desipramine, subjects’

scores on this objective measure of craving were close to the maximum of

100, while scores on this scale were substantially and significantly lower

during desipramine maintenance. Despite such shifts in reports of

151
wanting cocaine, however, the subjects’ cocaine-taking behavior

remained unchanged. These results are evidence for the importance of

multiple measures in assessing the efficacy of potential treatment drugs,

and they provide an example of dissociations between changes in

subjective-effects measures and drug intake.

Although desipramine maintenance did not appear to affect the

self-administration of cocaine, it did modify some of cocaine’s

self-reported effects. Several patterns of changed effects emerged. The

first of these was evident on many of the scales that are sensitive to

stimulant drugs, including arousal and positive mood of the POMS and

the BG scale of the ARCI (figure 5[a]). Prior to desipramine

maintenance, the initial daily dose of cocaine increased these scores in a

dose-related fashion. Desipramine maintenance attenuated these

dose-related effects of cocaine.

A second pattern of interaction between cocaine and desipramine on other

subjective-effects scales was observed. These scales included the POMS

confusion and anger scales and the ARCI LSD scale (figure 5[b]),

measures of dysphoric drug effects. Desipramine maintenance resulted in

lower placebo scores and significantly higher scores in response to

cocaine, indicating an enhancement of cocaine’s effects on these more

negative scales.

Desipramine maintenance did not always change the self-reported effects

of cocaine. The effects measured by the series of questions answered at

the termination of each choice session (approximately 30 minutes after

the last cocaine injection, when blood levels were decreasing) were

among the most consistent in this regard. At that time, subjects were

instructed to rate the dose over the entire session. Regardless of the

presence or absence of desipramine, ratings of “high,” “liking,”

“potency,” and “How much would you pay?” all showed increases

withincreasing doses of cocaine. For example, as shown in figure 5(c),

subjects indicated that they would be willing to pay approximately

$40 for the 32-mg dose of cocaine. Therefore, there appear to be some

effects of cocaine that are dose related and do not change under

conditions of desipramine maintenance. This unchanged retrospective

rating of cocaine’s effects during desipramine maintenance suggests that

cocaine abusers maintained on desipramine might continue to take

cocaine, at least in the absence of a concomitant behavioral intervention.

152
FIGURE 5. (Panel A): BG scores of the ARCI as a

function of the available cocaine dose

before and during desipramine

maintenance. (Panel B): LSD scores

of the ARCI as a function of the

available cocaine dose before and

during desipramine maintenance.

(Panel C): After-session ratings of

street value of the cocaine dose

received that session as a function of

cocaine dose. Error bars represent

SEMs.

153
The dissociation between the effects of desipramine on cocaine

self-administration and the self-reported effects of cocaine clearly

suggests that desipramine alone is not an adequate pharmacological

intervention for treating cocaine abusers. Under conditions of

desipramine maintenance, cocaine remains a potent reinforcer. It is

possible, however, that the alteration in cocaine’s profile of effects may

modify its reinforcing effects so that users participating in a behavioral

treatment intervention can learn to use other reinforcers in their

environment rather than continuing to take cocaine. The absence of a

shift in cocaine choice during desipramine maintenance, paired with the

verbal reports of decreased cocaine craving, suggest that subjects would

have chosen less cocaine if a nondrug option had been available.

The last study to be described used a procedure involving three choices:

two different doses of cocaine and a nondrug option. The nondrug option

involved tokens exchangeable for reinforcers such as videotaped films,

candy bars, and cigarettes. Using tokens as a third nondrug option had

modest effects on cocaine choice. When 8 mg and 16 mg of cocaine

were available, increasing the number of tokens from one to two had

minimal effect on high-dose choice (figure 6). When 16 and 32 mg of

cocaine were available, however, increasing the number of tokens from

two to four did slightly decrease high-dose choice. Thus, there is some

evidence that this nondrug option can compete with cocaine choice.

The three-choice procedure has been used to evaluate the effects of the

potential treatment drug fluoxetine on cocaine-taking behavior. Like

desipramine, fluoxetine, a selective inhibitor of serotonin uptake (Fuller

et al 1991), has been suggested as a pharmacological adjunct in the

treatment of cocaine abuse (Pollack and Rosenbaum 1991). As in the

previous protocol, choice behavior was recorded before and during a

period of maintenance on the treatment drug. During the 3-week

maintenance period, subjects reported to the laboratory on weekdays,

completed self-report questionnaires, provided a urine sample for

determining drug use, and consumed a 20 mg capsule of fluoxetine.

Preliminary data obtained with five subjects suggest that fluoxetine

maintainence altered choice behavior when subjects had access to low

cocaine doses (4 and 8 mg/70 kg) but not when they had access to high

cocaine doses (16 and 32 mg/70 kg). When 4 and 8 mg doses of cocaine

were available, fluoxetine maintenance affected choice behavior in one

subject so that choice shifted to low doses (figure 7). When 8 and 16 mg

doses of cocaine were available, there was also a shift to low doses or

tokens during fluoxetine maintenance. But when 16 and 32 mg doses

154
Non-Drug Option and Cocaine Choice

High Dose Tokens High Dose Tokens

Choice

FIGURE 6. Choice of the high cocaine dose or tokens

as a function of the available cocaine doses

and the number of tokens delivered

following a request for tokens. Error bars

represent SEMs.

were available, fluoxetine maintenance had no effect on choice behavior.

While the results have been variable among subjects, choice behavior for

all subjects was altered during fluoxetine maintenance on days when 4

and 8 mg doses of cocaine were available.

In contrast to desipramine maintenance, fluoxetine had no effect on

subjects’ “I want cocaine” scores (figure 8[a]), which averaged between

30 and 50 (out of 100) before and during fluoxetine maintenance.

Cocaine administration produced dose-dependent increases in subjects’

ratings of “high” after the first dose (figure 8[b]). During fluoxetine

maintenance, ratings of “high” were greater after the administration of 4,

16, and 32 mg/70 kg doses of cocaine, suggesting a possible shift to the

left of the cocaine dose-response function for some of the behavioral

effects of cocaine. This pattern was not evident for other measures of

positive changes in mood associated with stimulant use, that is, BG and

MBG scores on the ARCI, arousal, and positive mood scores on the

POMS. An interesting pattern of changes in after-session ratings of drug

effects was evident during fluoxetine maintenance, as compared to before

155
FIGURE 7. Choice of the high or low cocaine dose or

tokens as a function of the available

cocaine doses and the number of tokens

delivered following a request for tokens

before and during fluoxetine maintenance.

Error bars represent SEMs.

fluoxetine maintenance. Fluoxetine maintenance increased subjects’

ratings of drug liking for the lowest dose of cocaine (4 mg/70 kg) without

affecting ratings of the highest doses (figure 8[c]). A similar pattern was

evident for subjects’ ratings of drug potency. As described above,

increased liking scores would be predictive of greater abuse liability (de

Wit and Griffiths 1991; Foltin and Fischman 1991b ; Preston and Jasinski

1991). When asked to estimate the street value of each dose, subjects’

estimated value of the lowest dose was $0 before fluoxetine maintenance,

but almost $3 during fluoxetine maintenance (figure 9[d]). In contrast,

the estimated values of the two highest doses decreased from $5 and $12

to $3 and $9 during fluoxetine maintenance.

156
FIGURE 8. (Panel A): Ratings of “I want cocaine” following the

first active dose as a function of cocaine dose before

and during fluoxetine maintenance. (Panel B):

Ratings of “high” following the first active dose as a

function of cocaine dose before and duringfluoxetine

maintenance. (Panel C): After-session ratings of

“liking” as a function of cocaine dose before and

duringfluoxetine maintenance. (Panel D): Aftersession ratings of street value as a function of

cocaine dose before and during fluoxetine

maintenance. Error bars represent SEMs.

These preliminary data on the effects of fluoxetine on cocaine choice and

subjective effects indicates that the interaction between fluoxetine and

cocaine is complex. As was observed with desipramine, maintenance on

an antidepressant had minimal effects on cocaine choice behavior in

subjects who were not seeking treatment. Fluoxetine may have altered

the discriminability of low doses, accounting for the change in choice

behavior at these dose levels. The subjective-effects data suggest that this

decrease in discriminability may indicate an enhancement of the effects of

the lowest dose of cocaine. Fluoxetine had no effect on cocaine craving,

which is in sharp contrast to the effects of desipramine. This absence of

an effect on craving suggests that fluoxetine may be less helpful in

controlling cocaine use than desipramine. Further data are needed to

157
interpret the relationship between changes in choice behavior and the

subjective effects of cocaine during fluoxetine maintenance. As shown

with the choice of smoked cocaine over IV cocaine, it is likely that these

relationships are complex.

In summary, this research demonstrates the way in which procedures

developed in the laboratory for use with nonhumans can be adapted for

use with humans and combined with measures of verbal report. Choice

procedures provide a rapid and sensitive measure of drug selfadministration. With respect to cocaine, active doses were chosen over

placebo, higher doses were chosen over lower doses, high-dose choice

was minimally affected by response cost, and pairing money with low

doses minimally decreased high-dose choice. The presence of a nondrug

option, however, altered cocaine choice at some dose levels.

Combining choice procedures with measures of cardiovascular and

subjective effects allows for comparisons across these measures and

provides information about factors affecting abuse liability of drugs. For

example, smoked cocaine was chosen over IV cocaine even when doses

were matched for cardiovascular and subjective effects after an acute

administration. However, subtle differences between the effects of

cocaine administered by different routes was evident only after repeated

dosing. This finding indicates that multiple-dose paradigms should be

used to study the effects of cocaine because it is most often taken that

way on the street.

It is clear that self-reports do not substitute for measuring actual

drug-taking behavior. For example, on the basis of subjects’ verbal

reports alone, one would predict that desipramine-maintained subjects

who showed reduced cocaine craving would not self-administer cocaine.

This prediction would have been strengthened by the decreases in the

magnitude of verbal reports of stimulant effects and increases in the

magnitude of dysphoric drug effects during desipramine maintenance.

However, reductions in cocaine self-administration during desipramine

maintenance were not observed.

Based on the preliminary data presented here, fluoxetine had minimal

effects on cocaine choice and may have enhanced the subjective effects of

lower doses. This suggests that fluoxetine, by itself, may have minimal

efficacy as a treatment drug for cocaine abuse.

158
CONCLUSION

In conclusion, it is only by evaluating drug-taking behavior within a

behavioral context that one can fully understand and predict the

likelihood that a potential treatment drug will be effective in reducing

cocaine-taking behavior. In addition, by combining choice procedures

with other behavioral measures, including subjective and cardiovascular

effects, it is possible to characterize the behavioral mechanism of action

of potential treatment drugs for cocaine abuse.

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ACKNOWLEDGMENTS

This research was supported by grant nos. DA-03818 and DA-06234

from the National Institute on Drug Abuse, and was approved by the

Johns Hopkins Medical School Joint Committee on Clinical

Investigation. Subjects resided on the Johns Hopkins Clinical Research

Unit supported by grant no. MOI-RR-00035 from the National Institutes

of Health.

AUTHORS

Richard W. Foltin, Ph.D.

Associate Professor of Behavioral Biology

Marian W. Fischman, Ph.D.

Professor of Behavioral Biology

Department of Psychiatry

College of Physicians and Surgeons

Columbia University

722 West 168th Street, Unit #66

New York, NY 10032

162
Neurobiological Mechanisms

Underlying the Acquisition and

Expression of Incentive

Motivation by Cocaine-Associated

Stimuli: Relationship to Craving

Agu Pert

INTRODUCTION

The development of pharmacotherapeutics for treatment of cocaine

addiction has focused primarily on designing drugs that are effective

cocaine antagonists at the dopamine transporter. While this strategy may

ultimately yield effective pharmacotherapeutics, greater emphasis should

be placed on the development of drugs that prevent or attenuate craving,

the process that compels an individual to seek cocaine and is also

responsible for recidivism following abstinence. The success of such a

program, however, rests on the development of appropriate and simple

animal models, as well as on a greater understanding regarding the

neurobiological processes involved.

MOTIVATIONAL SUBSTRATES UNDERLYING CRAVING

Craving, unfortunately, is a rather maligned and misunderstood

hypothetical construct. Some have, in fact, suggested that craving is not

an appropriate construct for scientific inquiry (World Health Organization

Committees on Mental Health and on Alcohol 1955). Others have

viewed craving as a useful concept and have conceptualized it in a variety

of ways. Some, for example, have suggested that craving and other

physical symptoms constitute physical dependence (Jellinek 1960), while

others have proposed that craving is instead the result of physical

symptoms (Eddy 1973; Marlatt 1978). Other, more cognitive models

have suggested that craving is a result of cognitive processes modified by

both internal and external cues (Ludwig and Stark 1974). More recently,

incentive motivational concepts have gained prominence as underlying

substrates of craving (Markou et al. 1993; Marlatt 1987; Robinson and

163
Berridge 1993; Wise 1988). Whatever the underlying neurobiological

mechanisms are, it is clear that craving has strong motivational

components.

Two motivational processes have been postulated by motivational

theorists to energize and direct behavior-drive and incentive motivation

(Bindra 1968; Bolles 1967). There are several important distinctions

between these two constructs. First, drives are innate or determined

through perturbations to innate biological mechanisms, while incentive

motivation has to be acquired by learning. Second, drives are thought to

be elicited by imbalances in homeostatic mechanisms, while incentive

motivation is elicited by environmental or external stimuli. The concept

of drive arises from the notion that there exist conditions within an

organism that compel it to action. The concept of incentive motivation is

derived from the notion that there are objects in the environment to which

an organism is attracted. In this sense, drives are thought to “push”

behavior while incentives “pull” (Bolles 1967).

Two categories of contemporary neurobiological theories have evolved to

account for craving within the constraints of these two motivational

constructs. Some have viewed craving to be the direct result of a deficit

or aversive state produced by prolonged exposure to drugs of abuse.

Koob and Bloom (1988), for example, have proposed that the " . . .

‘negative reinforcing’ effects (for example, malaise, dysphoria, and

anhedonia) are a major etiological and motivational factor in maintaining

drug dependence.” Others have also viewed the motivational forces

underlying cocaine addiction, for example, to be the result of either

withdrawal symptomatology (Gawin 1991) or deficit states (e.g.,

dopamine [DA] depletion) induced by chronic exposure to the drug

(Dackis and Gold 1985).

These types of theories assert that drug (e.g., cocaine) use is maintained

because the drugs alleviate some type of deficit or aversive state and, for

this reason, have been termed “negative-reinforcement theories” (Koob

and Bloom 1988; Robinson and Berridge 1993; Wise 1955). The basic

motivational process behind these formulations is drive reduction. They

have arisen essentially from the study of opiate addiction, where

withdrawal symptoms are clearly and readily defined. Whether they have

applicability for understanding the addiction to cocaine and other drugs

for which withdrawal effects are not very prominent remains to be

determined. Robinson and Berridge (1993) have recently provided a

concise review of the many problems faced by theories of this nature, the

164
chief being that they have great difficulty accounting adequately for

craving and recidivism following prolonged abstinence.

Other theorists in drug addiction research have emphasized the

importance of incentive-motivational mechanisms in the addiction

process (Markou et al. 1993; Marlatt 1987; Robinson and Berridge 1993;

Stewart et al. 1984; Wise 1988). As noted above, incentive motivation is

acquired through learning. Stimuli that are repeatedly associated with a

primary reinforcer such as food or drugs are thought to acquire, through

classical conditioning, two properties. The first is secondary

reinforcement and the second is incentive motivation (Bindra 1968). The

secondary reinforcing properties of such stimuli, when they follow a

specific behavior, enable them to facilitate and augment performance of

the behavior. Secondary reinforcing properties of stimuli associated with

drugs of abuse have been demonstrated by several investigators (Davis

and Smith 1976; Schuster and Woods 1968). When such stimuli appear

prior to a particular behavior, their incentive-motivational properties

appear to energize and facilitate initiation of the behavior. Drugs such as

cocaine can be thought of as positive incentives similar to food, water, or

a sexual partner. Incentive-motivational properties are not established,

however, until the pharmacological effect is experienced. Such

properties are then conferred to stimuli associated with the drug (white

powder, paraphernalia, or environment).

The energizing function of incentive-motivational stimuli has been

known for some time. It has been well established, for example, that

stimuli repeatedly associated with positive reinforcers such as food can

increase general motor activity or energize behavior when presented

alone (Bindra and Palfi 1967; Bolles 1963; Sheffield and Campbell

1954). Bindra and Palfi (1967) have suggested that such incentivemotivational activity is characterized by anticipatory excitement often

seen during classical appetitive conditioning and appears to be

investigatory and goal directed in nature. Bindra (1969) has also

proposed that conditioned incentive-motivational stimuli established by

pairing with a positive reinforcer such as food acquire similar appetitive

properties and come to energize the appetitive-motivational system as a

whole and produce a positive incentive-motivational state.

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THE ENERGIZING COMPONENT OF INCENTIVE MOTIVATION

AS A DETERMINANT OF CRAVING

Figure 1 illustrates findings from a recent study in which the energizing

function of stimuli paired with feeding was measured by subsequently

assessing their ability to alter locomotor activity. In this study, three

groups of rats were employed. The first group was deprived of food for

23 hours and then allowed to consume all of their daily food during 1

hour in a photocell locomotor activity chamber scented with peppermint

extract to enhance the saliency of the environmental cues. The second

group was deprived of food for 21 hours and then placed in the same

locomotor chambers for 1 hour with no food available. These animals

were allowed to consume all their daily food in a 60-minute session 1

hour following return to their home cages. The third group had ad lib

access to food in their home cages. These animals were also exposed to

the locomotor activity chamber for 1 hour.

Training described above was carried out for 3 consecutive days. On day

4, all three groups were returned to the activity chamber for 1 hour. The

first two groups were both run under 23-hour deprivation conditions. It

was apparent that environmental stimuli paired with feeding enhanced

horizontal locomotor activity when they were subsequently presented

alone. Such effects were most apparent during the first lo-minute period

and then dissipated rapidly thereafter. It is proposed that the increases in

motor activity seen in this study reflect the energizing function of

incentive motivation.

As noted above, incentive-motivational processes have also been

postulated by a number of researchers to underlie and determine craving

in drug addicts. Marlatt (1987), for example, has suggested that

". . . craving could be considered to be a conditioned appetitive response

much like the conditioned salivary response in anticipation of food

observed in Pavlov’s dogs. Craving in this sense is viewed as

anticipatory in nature, an appetitive motivational state associated with a

strong desire for one expected outcome.” Several recent reviews of

animal studies have also emphasized the importance of incentive

motivation as a determinant of drug craving (Markou et al. 1993; Stewart

and de Wit 1987; Wise 1988). In addition, Robinson and Berridge

(1993) have proposed a rather intriguing model in which incentivemotivational mechanisms are thought to sensitize through neuronal

adaptations in response to repetitive drug exposure.

166
ACTIVITY BY STIMULI ASSOCIATED WITH

FEEDlNG

10 Minute intervals

FIGURE 1. Conditioned locomotor activity by

environmental stimuli associated

with feeding. (Top): Locomotor

activity of the three groups of rats

on three training days. (Bottom):

Locomotor activity of the three

groups over the course of 60 min

on day 3. The PAIRED group had

activity levels that were

significantly higher than the

UNPAIRED or CONTROL groups

during the first 10-min interval.

167
In the context of incentive motivation, it is of interest to note that a

number of clinical studies have revealed that cocaine users report craving

cocaine in response to presentation of stimuli previously associated with

the drug. Such stimuli also precipitate a host of physiological arousal

signs, such as reductions in peripheral skin temperature, decreases in skin

resistance, and increases in heart rate (Childress et al. 1990; Ehrman et al.

1992).

Approximately six decades ago, Tatum and Seevers (1929) as well as

Down and Eddy (1932) reported that dogs develop increased activity,

excitement, and eagerness in the presence of situational cues that had

been associated with cocaine. Both of these early studies appeared to

suggest that stimuli paired with cocaine injections acquire incentivemotivational properties. More contemporary studies with rodents using

the place-performance methodology (Hoffman 1989) also have reported

the development of such properties by stimuli associated with

psychomotor stimulations and other drugs of abuse. Conditioned

increases in general locomotor activity (Barr et al. 1983; Bridger et al.

1982; Hinson and Poulos 1981; Pert et al. 1990; Pickens and Crowder

1967; Pickens and Dougherty 1971; Post et al. 1981; Schiff 1982;

Stewart and Vezina 1988) and stereotypy (Barr et al. 1983; Schiff 1982)

have also been observed following the administration of psychomotor

stimulants in the presence of previously neutral stimuli. It is proposed

that such increases in motoric output reflect the energizing functions of

incentive-motivational processes elicited by stimuli associated previously

with the drugs, similar to that seen with other reinforcers, such as food

(see above).

NEUROBIOLOGICAL PROCESSES UNDERLYING THE

ACQUISITION OF COCAINE-INDUCED CONDITIONED

INCREASES IN MOTOR ACTIVITY

Although the behavioral variables regulating the conditioning of drug

effects have been extensively studied (Pert et al. 1990), considerably less

focus has been directed at the underlying neurobiological processes.

Understanding such processes and principles might provide greater

insights for designing new pharmacological agents to alleviate craving or

for formulating strategies to extinguish it. In work described in this

chapter, the author and colleagues at the National Institute of Mental

Health utilized a relatively simple and efficient paradigm to study the

168
processes and neural mechanisms underlying the acquisition, expression,

and extinction of cocaine-induced conditioned increase in motor activity.

Similar to the food-conditioning study described above, three groups of

rats were employed. On day 1, the first group (PAIRED) was injected

with a high dose of cocaine HCl (40 mg/kg) intraperitoneally and placed

in locomotor activity chambers for 30 minutes. One hour following

return to their home cages, these rats were injected with saline. The

record group (UNPAIRED) was treated in a similar fashion but received

saline prior to placement in the locomotor activity chambers and then

cocaine (40 mg/kg) in the home cage. The third group (CONTROL)

received saline in both environments. On day 2, all animals were

challenged with 10 mg/kg of cocaine immediately prior to placement in

the locomotor activity chambers. Figure 2 illustrates the behavioral

effects seen on both days. On day 1, the PAIRED group, of course,

exhibited a dramatic increase in motor activity in response to 40 mg/kg of

cocaine compared to the UNPAIRED and CONTROL groups, which

were exposed to the apparatus following saline injections. On day 2,

when all groups were reexposed to the activity chambers following

injections of 10 mg/kg of cocaine, the PAIRED group exhibited

considerably higher activity levels than the other two groups. Since the

PAIRED and UNPAIRED groups received the same exposure to cocaine

on day 1, the difference in locomotor behavior between them must be

related to the context in which the drug was experienced (i.e.,

conditioning). It has been found that the establishment of such

conditioned increase in motor activity depends on associative learning

processes (Rothman and Pert, in press) and follows the principles of

classical conditioning. For example, the magnitude of the conditioned

response appears to be related to the intensity of the unconditioned

stimulus (i.e., dose of drug). In addition, the conditioned response decays

with time and is subject to extinction, and the conditioned stimulus

follows the principle of stimulus generalization (Barr et al. 1983; Hayashi

et al. 1980; Hinson and Poulos 1981; A. Pert, unpublished observations;

Pickens and Crowder 1967; Tilson and Rech 1973; Weiss et al. 1989).

It should be noted that the conditioning paradigm in these studies was

somewhat unconventional in that the unconditioned stimulus was present

during the test day, although at a lower intensity (dose). Conditioned

increases in locomotor activity in other studies have generally been

assessed in the conditioning chamber following injections of saline or the

drug vehicle. This may not always be appropriate or adequate to reveal

conditioned drug effects in all circumstances, especially when rather

169
DAY 1

CONDITIONING SESSION

DAY 2 TEST FOR CONDITIONING:

ALL ANIMALS CHALLENGED WITH

10 mg/kg COCAINE

FIGURE 2. Conditioned increased in locomotor activity

following 1 day of training with cocaine.

(Top): Horizontal locomotor activity during

the training day. The PAIRED rats were

injected during the training day. The PAIRED

rats were injected with 40 mg/kg of cocaine

prior to a 30-min training session. (Bottom):

Horizontal locomotor activity during the test

day (day 2) when all three groups were tested

with 10 mg/kg of cocaine.

170
subtle conditioned responses are expected, as in the paradigm discussed

above that utilizes a single 30-minute conditioning session. The

pharmacological actions of cocaine on the training day produce two

critical effects that determine conditioning. First, cocaine has

motivationally significant consequences that probably serve as the basis

for its ability to act as an unconditioned stimulus (Mackintosh 1974). It

has been suggested, in fact, that the locomotor stimulatory effects of

drugs like cocaine are related to their appetitive-motivational or

rewarding properties (Stewart et al. 1984; Wise and Bozarth 1987).

Second, cocaine also produces a variety of interoceptive cues (e.g.,

alterations in heart rate or blood pressure) through peripheral sympathetic

activation, that have the potential of contributing to the total stimulus

complex that comes to serve as the conditioned stimulus. It has been

shown, for example, that leg flexion reactions in dogs can be conditioned

to interoceptive cues produced by peripherally administered epinephrine,

norepinephrine, and acetylcholine (Cook et al. 1960). It is likely that the

excitatory (appetitive-motivational) effects of cocaine (determined

through the central nervous system are conditioned to a stimulus complex

consisting of environmental as well as drug-produced interoceptive cues.

If this is the case, the most robust conditioned response would be

expected to be elicited in the presence of cues that are most similar to

those present during the conditioning process (i.e., both interoceptive as

well as environmental).

An additional reason to test in the presence of a lower dose of cocaine is

to amplify the rather subtle conditioned effects that are likely following a

30-minute conditioning session. There is considerable evidence, for

example, to indicate that psychomotor stimulants enhance conditioned

responses in other learning paradigms (Robbins 1975, 1978; Robbins and

Koob 1978; Robbins et al. 1983, 1989). Using a conditioning paradigm

similar to the one described, it was found recently that the rather modest

conditioned effects normally seen following a saline challenge on day 2

are accentuated considerably by 10 mg/kg of cocaine (A. Pert,

unpublished observations). The strength and persistence of conditioning

also appears to depend on the degree of training. The conditioned effects

after 1 day of conditioning dissipate rather rapidly and are generally no

longer present three days after training. One week of training, on the

other hand, produces conditioned effects that are still present up to at least

60 days later. When needed (especially in studies aimed at evaluating

mechanisms involved in the expression of cocaine-conditioned

behaviors), a more prolonged training regime (3-7 days) has been used.

171
Since DA is involved in mediating the stimulatory and appetitive

properties of psychomotor stimulants, it is not surprising that disruptions

in the actions of this brain amine would alter the acquisition of

conditioning. For example, neuroleptics, co-administered with either

amphetamine (Beninger and Hahn 1983) or cocaine (Beninger and Herz

1986; Weiss et al. 1989) have been found to prevent the development of

conditioned locomotor behaviors. More recently, Fontana et al. (19933)

found that D1 or D2 DA receptor antagonists are equally effective in

preventing the formation of cocaine-induced conditioning (figure 3).

Likewise, conditioning in the l-day design was found only following

administration of a combination of D1 and D2 agonists during training and

not when either was administered separately (figure 4). This would

suggest that concurrent D1 and D2 DA receptor occupation is necessary

for conditioning to occur.

There are a variety of mechanisms by which DA antagonists could

disrupt the acquisition of cocaine-induced conditioning (Fontana et al.

19933). It is most likely, however, that the ability of these drugs to

decrease or prevent conditioning to psychomotor stimulants is related to

their ability to attenuate the unconditioned effects of the drugs, which are

critical in forming the conditioned association. It is proposed that the

ability of DA blockers to prevent conditioning is related to their ability to

decrease the motivational significance of the unconditioned stimulus

(e.g., cocaine). It is well established that the strength of conditioning is

directly related to the intensity of the unconditioned stimulus in other

conditioning paradigms (Kamin and Brimer 1963; Ost and Lauer 1965;

Wagner et al. 1961). Both D1 and D2 blockers have been known to be

effective in decreasing the reinforcing efficacy of cocaine (Hubner and

Moreton 1991), indicating that both receptor subtypes participate in

determining the motivational properties of the drug. It is not surprising,

therefore, that both D1 and D2 DA antagonists are effective in preventing

the development of cocaine-induced conditioning.

The critical role of dopamine in the conditioned effects of cocaine is also

supported by lesion studies. DA-depleting 6-OHDA lesions of the

nucleus accumbens have been found to prevent the conditioned effects of

cocaine (Pert et al. 1990) and amphetamine (Gold et al. 1988). Similar

lesions to the amygdala also produced modest disruptions to conditioning

(Pert et al. 1990) that can be overcome by more extensive training. It is

possible that two different components of the conditioning process are

mediated through these two structures innervated by the mesolimbic DA

system. It is of interest to note that 6-hydroxydopamine (6-OHDA)

172
DA ANTAGONISTS PREVENT THE ACQUISITION OF

COCAINE-INDUCED CONDITIONING

DAY 2 TEST FOR CONDlTlONING:

ALL ANIMALS CHALLENGE0 WITH 10 mg/kg

COCAINE

FIGURE 3. Blockade of cocaine-induced conditioning by D1 and D2

antagonist pretreatment. (Top): PAIRED and

UNPAIRED rats were pretreated with saline,

haloperidol, SCH 23390, raclopride, or sulpiride prior

to injections of either 40 mg/kg of cocaine or saline.

(Bottom): On day 2, all rats were injected with 10

mg/kg of cocaine prior to a 30-min test session.

SOURCE: Fontana et al. (19933)

173
DAY 1 AGONIST CONDlTlONING

DAY 2 TEST FOR CONDITIONING:

AU ANIMALS CHALLENGED WITH 10mg/kg cocaine

FIGURE 4. The ability of D1 and D2 agonists to induce

conditioning. (Top): PAIRED animals were injected

with various D1 agonists prior to placement in

locomotor activity chambers on day 1. While the

UNPAIRED rats were injected with the respective D1 or

D2 agonists 1 hour following their return to the home

cages, the PAIRED rats received saline. A control

group (CONTROL) that received saline in both

environments was included for purposes of comparison.

(Bottom): Horizontal activity in all groups on day 2

following injections of IO mg/kg of cocaine. * p < 0.05

for comparisons of the PAIRED groups with their

respective controls. Vertical lines indicate the S.E.M.

SOURCE: Fontana et al. (19936)

174
lesions of the striatum or frontal cortex were ineffective as were

serotonin-depleting lesions of the dorsal and median raphe nuclei or

norepinephrine depleting lesions of the locus coeruleus. The author and

colleagues have also failed to disrupt cocaine-induced conditioning with

radio-frequency lesions of the ventral and dorsal hippocampus or

cerebellum. Such findings, along with the ability of DA antagonists to

prevent cocaine conditioning strongly suggest that intact DA function in

the nucleus accumbens and, to a lesser degree, in the amygdala is

necessary for the formation of incentive-motivational properties by

stimuli associated with cocaine.

NEUROBIOLOGICAL PROCESSES INVOLVED IN THE

EXPRESSION OF COCAINE-INDUCED CONDITIONED

INCREASES IN MOTOR ACTIVITY

While of theoretical interest, understanding the processes involved in the

formation of conditioned and incentive-motivational properties of drugs

of abuse will probably have little utility for the design of pharmacotherapeutics, unless the mechanisms involved in the acquisition and

expression are similar. Relatively little is known regarding the neural

processes involved in the expression of cocaine-conditioned increases in

motor activity.

Although mixed D1/D2 and selective D1 and D2 antagonists have been

found to prevent the establishment of conditioning to cues associated

with cocaine, they have been reported to be relatively ineffective in

preventing expression once established. Early studies by Beninger and

Hahn (1983) and Beninger and Herz (1986) found that pimozide did not

eliminate the differential in behaviors between the conditioned and

nonconditioned groups when either amphetamine or cocaine was used as

the unconditioned stimulus. Weiss and colleagues (1989) have also

found that haloperidol is ineffective in eliminating the behavioral

differential between cocaine-conditioned animals and their controls.

Fontana and colleagues (19933) have extended these findings by

demonstrating that neither D1 nor D2 antagonists are effective in altering

the differential in performance between the conditioned and

unconditioned rats during the test phase (figure 5). Carey (1990) has also

found that neither SCH 23390 nor haloperidol is effective in blocking the

expression of conditioned rotational behaviors induced by pairing

175
apomorphine injections with the test environment in rats with unilateral

6-OHDA lesions of the nigrostriatal DA pathways.

On the surface, these findings, together with the ability of DA antagonists

to block the acquisition of conditioned behaviors, appear to suggest that,

while intact DA function is critical for the development of conditioning to

cocaine-associated cues, it is not necessary for the expression of the

conditioned response once established. It is possible that

nondopaminergic pathways acquire the ability to elicit such conditioned

reactions. The second alternative is that DA is involved in the expression

of the conditioned behavior and that the differential in activity seen

between the conditioned and nonconditioned groups is determined and

maintained by increased activity of mesolimbic DA pathways in the

former group despite similar partial blockade of DA receptors in all

experimental groups. Using a paradigm similar to that described above, a

significant elevation has been noticed on day 2 of DA in the nucleus

accumbens, measured by in vivo microdialysis (Fontana et al. 1993a) in

the PAIRED rats, relative to the two control groups (figure 6). Similar

increases have not been found in the amygdala or striatum (A. Pert and D.

N. Thomas, unpublished observations). Kalivas and Duffy (1990) also

have reported increases in mesolimbic DA elicited by stimuli associated

with cocaine. Thus, there appears to be a difference in mesoaccumbens

DA output between the conditioned and nonconditioned rats during

second reexposure to the apparatus.

In order to conclude definitively that DA is not involved critically in the

expression of the conditioned response on the basis of the inability of the

DA antagonists studies cited above, it must be assumed that the

antagonists have achieved total blockade of DA function (an unlikely

event considering the doses used). In the presence of partial blockade,

the unbound receptors in the conditioned rats are still exposed to higher

extracellular levels of DA than those in the control animals, thus

providing a neuropharmacological basis for the behavioral differences

seen between the groups.

It should also be noted that under some circumstances the conditioned

effects of psychomotor stimulants can be antagonized by DA blockers.

Drew and Glick (1987) were able to block the expression of

amphetamine-conditioned rotational behavior in unlesioned rats with

haloperidol, and they concluded that both the unconditioned as well as

conditioned effects of amphetamine are mediated by DA. In a

176
DA ANTAGONISTS DO NOT PREVENT THE EXPRESSION

OF COCAINE-INDUCED CONDITIONING

FIGURE 5. The effects of D1

 and D2 antagonists on cocaineconditioned effects when administered prior to the 10

mg/kg cocaine challenge on day 2. (Top): Horizontal

activity in PAIRED, UNPAIRED, and CONTROL rats

on day I. (Bottom): The effects of raclopride and SCH

23390 on the conditioned effects of cocaine on day 2.

* p < 0.05 for comparisons of the PAIRED group with

its respective UNPAIRED control. Vertical lines

indicate the S.E.M.

SOURCE: Fontana et al. (1993b)

177
LOCOMOTOR ACTIVITY

N. ACCUMBENS DA OVERFLOW

Cocaine 10 mg/kg

TIME (minutes)

FIGURE 6. Effects of day 1 treatments on day 2 locomotor activity

and nucleus accumbens DA overflow when all groups

were challenged with IO mg/kg of cocaine prior to

placement in the locomotor chambers. For locomotor

activity and DA overflow, * p < 0.05 for PAIRED

versus UNPAIRED; + p < 0.05 for PAIRED versus

CONTROL with the Scheffe test.

SOURCE: Fontana et al. (1993a)

178
subsequent study, the same investigators (Drew and Glick 1990) reported

that both the D1 (SCH 23390) and the D2 (metaclopramide) antagonists

attenuated conditioned rotational behaviors established with

amphetamine. Conditioned stereotypy established with apomorphine also

has been reported to be antagonized with pimozide (Hiroi and White

1989), although similar behaviors conditioned with amphetamine were

only partially blocked by the same antagonist. Poncelet and colleagues

(1987) also have reported blockade of amphetamine-conditioned

locomotor activity and stereotypy with sulpiride and haloperidol but not

pimozide. Further support for a role of mesolimbic DA immediating

conditioned behaviors comes from lesion studies. Gold and colleagues

(1988) for example, found that DA-depleting 6-OHDA lesions of the

nucleus accumbens made following amphetamine-induced conditioning

of locomotor behavior were able to block the expression of the

conditioned response. A similar ability of 6-OHDA nucleus accumbens

lesions to prevent the expression of cocaine-induced conditioned

behaviors has recently been found (A. Pert, unpublished observations)

(figure 7).

Not all investigators agree, however, that stimuli associated with

psychomotor stimulants enhance mesolimbic DA function. Brown and

Fibiger (1992), for example, failed to find increases in extracellular DA

in the nucleus accumbens following presentation of stimuli previously

associated with cocaine, while Brown and colleagues (1992) did not

observe increases in c-fos expression in the nucleus accumbens. In the

latter study, significant increases in c-fos expression were, however, seen

in the cingulate cortex, claustrum, lateral septal nucleus, paraventricular

nucleus of the thalamus, lateral habenula, and amygdala, suggesting the

participation of these regions (but not the nucleus accumbens) in the

expression of cocaine-conditioned behaviors. The reasons for the

disparity between the findings of Brown and Fibiger (1992) and those of

Fontana et al. (1993a) and Kalivas and Duffy (1990) are not readily

apparent but may rest with methodological issues (Fontana et al. 1993a) .

The importance of understanding the precise neural substrates underlying

the conditioned effects of cocaine and other drugs of abuse is readily

apparent if these conditioned effects indeed reflect craving. The design

of pharmacotherapeutics to alleviate craving would depend on which

neurochemical system or systems participate in mediating the incentivemotivational properties of drugs of abuse. If mesoaccumbens DA is

involved, DA blockers would be expected to aid in attenuating craving.

179
DAY 1-7: TRAINING

DAY 18: TEST WITH SALINE

SHAM LESIONED

FIGURE 7. Effects of 6-OHDA lesions of the nucleus accumbens on

the expression of cocaine conditioned behaviors. (Top):

PAIRED and UNPAIRED rats were trained for 7 days

as described in text with 30 mg/kg of cocaine. On day

8, half of the rats in each group were lesioned in the

nucleus accumbens with 6-OHDA. On day 15, all rats

were tested in the activity chambers following injections

of saline. (Bottom): Locomotor activity of all groups

on day 15. * p < 0.05 for comparisons between

PAIRED and UNPAIRED groups.

180
If other systems are responsible, it will be necessary to define their coding

so that appropriate pharmacotherapeutics can be designed more

rationally.

If mesolimbic DA is involved in mediating the expression of cocaineinduced conditioning, it is not working in isolation. Sensory information

from conditioned stimuli, for example, needs to gain access to

mesoaccumbens DA neurons. Likewise, these neurons need to ultimately

activate motor pathways either directly or indirectly. It may be possible

to disrupt the expression of cocaine-induced conditioned increases in

locomotor behavior by altering the functional activity at any link of this

circuit.

As noted, sensory information from conditioned stimuli needs to gain

access to mesoaccumbens DA neurons. Although neither the nucleus

accumbens (DA terminals) nor the ventral tegmental area (DA perikarya)

receive input from primary sensory cortical regions, DA activity in the

system could be influenced indirectly through other structures such as the

amygdala or frontal cortex. The amygdala, for example, receives

polysensory information from cortical sensory association areas and

projects in turn to the nucleus accumbens. Since corticofugal neurons are

predominately glutamatergic in nature, it should be possible to disrupt

both the acquisition and expression of cocaine-conditioned behaviors

with excitatory amino acid (EAA) blockers. Figure 8 illustrates findings

from a recent study in which pretreatment of rats with various doses of

MK-801, a noncompetitive NMDA antagonist, on day 1 prevented the

acquisition of cocaine-induced conditioned increases in locomotor

activity when tested on day 2. Similar findings have been reported by

Kalivas and Alesdatter (1993) using a somewhat analogous design. It

would be especially important to determine the role of EAAs in the

expression of the conditioned response.

If craving is established predominantly by learning, extinction should be

the most effective strategy for attenuating this component of the addictive

process. Extinction procedures have been utilized with some degree of

success in clinical settings. O’Brien and his colleagues (Childress et al.

1987; O’Brien et al. 1988, 1992) gradually exposed cocaine addicts to

drug-associated cues without allowing consumption. Interestingly,

craving for cocaine was the most intense as well as the most frequently

reported subjective response during the extinction sessions. It was found

to decrease gradually in response to drug-related stimuli over the course

181
EFFECT OF MK-801 ON THE ACQUISITION OF

COCAINE INDUCED CONDITIONING

DAY 1

COCAINE

PRETREAMENT: SALINE 0.25 MK-801 0.5 MK-801 1.0 MK-801

DAY 2

COCAINE

PRETREATMENT: SALINE 0.25 MK-801 0.5 MK-801 1.0 MK-801

FIGURE 6. Effects of MK-801 on the acquisition of cocaineinduced conditioning. (Top): PAIRED and

UNPAIRED rats pretreated with either saline or

various doses (.25, .5, or 1.0 mg/kg i.p.) of MK-801

prior to 40 mg/kg of cocaine. (Bottom): Locomotor

activity in all groups after injections of 10 mg/kg of

cocaine. MK-801 was not administered on the test

day. * p < 0.05 for comparisons between PAIRED and

UNPAIRED groups.

182
of 15 extinction sessions. Alterations in skin temperature and galvanic

skin response were also found to decrease over the extinction procedure.

Almost nothing is known regarding the neurobiological mechanisms

underlying extinction. Figure 9 illustrates findings from a recent study in

which the extinction of cocaine-conditioned increases in locomotor

behavior in rats was examined. Three groups of rats (PAIRED,

UNPAIRED, and CONTROL), previously described, were trained for 7

days. On days 8-14, animals in all three groups were injected with saline

and placed in the locomotor activity chambers for 30 minutes as before.

On day 15, all rats were injected with a low dose of cocaine (10 mg/kg)

prior to placement in the activity monitors for 30 minutes. Relatively

robust conditioning was observed on day 1, as evidenced by enhanced

activity in the PAIRED group relative to the UNPAIRED and

CONTROL groups. The conditioned response persisted for 4 days. On

the seventh session, extinction was apparently complete since there

appeared to be no differences in locomotor activity among the three

groups. Surprisingly, however, administration of a low dose of cocaine

on day 15 reinstated in full the conditioned response in the PAIRED

group. These findings suggest that, while apparently extinguished, the

incentive-motivational processes elicited by cocaine-associated cues can

be fully reinstated with reexposure to the drug. Such reinstatement is

very reminiscent of the priming effect, which refers to the ability of small

priming doses of opiate agonists or cocaine needed to reinstate selfadministration behavior in animals extinguished for this behavior (de Wit

and Stewart 1981; Stewart and Wise 1992).

One interesting strategy for developing effective pharmacotherapeutics

for treating drug addiction might be to screen for compounds that

enhance the extinction of conditioned drug effects. At any rate,

increasing understanding of the neural mechanisms underlying this

process should provide a more rational basis for drug design.

183
CONDITIONING SESSIONS

FlGURE 9. Extinction of cocaine-conditioned behavior.

(Top): Locomotor activity of PAIRED,

UNPAIRED, and CONTROL groups during

7 consecutive days of training with 30

mg/kg of cocaine or saline. (Top):

Performance of all these groups during

extinction in which all animals were

injected with saline prior to testing.

(Middle): Performance of these groups on

day 15, when all animals were tested in the

activity chambers following injections of 10

mg/kg cocaine. (Bottom): * i.p. < .05 for

comparisons between PAIRED and

UNPAIRED groups.

184
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AUTHOR

Agu Pert, Ph.D.

National Institute of Mental Health

9000 Rockville Pike

Bethesda, MD 20892

190
Cocaine Reward and Cocaine

Craving: The Role of Dopamine

in Perspective

Roy A. Wise

INTRODUCTION

It is now well established that the habit-forming properties of cocaine

derive primarily from its ability to block neurotransmitter reuptake-and

thus enhance neurotransmitter action-in the mesocorticolimbic

dopamine (DA) system (Koob and Bloom 1988; Wise 1978; Wise and

Bozarth 1987; Wise and Rompré 1989). Cocaine also blocks

noradrenaline and serotonin reuptake, but these actions and cocaine’s

well-known local anesthetic effects appear to contribute little, if anything,

to the rewarding effects of cocaine. Because the nondopaminergic

actions of cocaine do not appear to contribute to the drug’s habit-forming

properties, and because DA is known to play an important role in the

rewarding effects of food, water, and direct electrical stimulation of the

brain (Wise and Rompré 1989), attempts to find pharmacological

treatments for cocaine abuse have focused largely on drug actions that

influence dopaminergic function.

There has been particular interest in the potential of DA agonists as aids

in the treatment of cocaine craving. The fact should not be overlooked,

however, that other transmitter systems play important roles in cocaine

reinforcement and may offer useful targets for pharmacological treatment

regimens. This chapter offers a brief overview of the evidence

implicating DA in the habit-forming effects of cocaine, an assessment of

the potential of DA agonists in the treatment of cocaine craving, and a

discussion of nondopaminergic circuitry that appears to interact with the

mesolimbic DA system and may thus be capable of modulating or

contributing to the habit-forming actions of cocaine.

191
THE ROLE OF DOPAMINE IN THE HABIT-FORMING ACTIONS

OF COCAINE

It has long been known that cocaine and amphetamine are indirect

monoaminergic agonists. Amphetamine causes impulse-independent

(Carboni et al. 1989) release of norepinephrine, DA, and serotonin from

brain stem cells that project widely to the diencephalon and

telencephalon. Amphetamine also blocks the uptake mechanism that

normally clears these transmitters from extracellular spaces (Heikkila

et al. 1975). Cocaine does not cause monoamine release; indeed, since it

decreases dopaminergic impulse flow (Henry et al. 1989), cocaine is an

indirect inhibitor of DA release per se. However, cocaine blocks

monoamine uptake mechanisms (Heikkila et al. 1975) and thus, like

amphetamine, causes accumulation of monoamines near monoaminecontaining nerve terminals (Carboni et al. 1989; Kalivas and Duffy 1990)

and dendrites (Kalivas and Duffy 1988).

The first studies that confirmed an essential role for monoamines in the

habit-forming actions of cocaine and amphetamine were studies in which

the habit-forming actions of these drugs were blocked with monoamine

antagonists. Like amphetamine and cocaine themselves, the early

antagonists were not selective for specific monoamine receptor types.

The first indication that the habit-forming properties of amphetamine and

cocaine involved the catecholamines came from the fact that

chlorpromazine increased self-administration of amphetamine and

cocaine, suggesting a reduction in their rewarding effectiveness (Wilson

and Schuster 1972). Since chlorpromazine blocks both noradrenergic and

dopaminergic receptors, it was important to challenge amphetamine and

cocaine self-administration with more selective antagonists in order to

determine which catecholamine was involved.

It soon became clear that it was the dopaminergic, and not the

noradrenergic, actions of cocaine and amphetamine that made them habit

forming. Selective dopamine blockers, including pimozide (deWit and

Wise 1977; Risner and Jones 1976; Yokel and Wise 1975, 1976);

haloperidol (Davis and Smith 1975); butaclamol (Yokel and Wise 1976);

alpha flupenthixol (Ettenberg et al. 1982); and SCH 23390 (Koob et al.

1987) attenuated the rewarding properties of amphetamine and cocaine

(deWit and Wise 1977; Ettenberg et al. 1982; Risner and Jones 1980),

while selective noradrenergic blockers like propranolol, phenoxybenzamine, and phentolamine did not (deWit and Wise 1977; Risner and

Jones 1976; Yokel and Wise 1975, 1976). Moreover, rats were shown to

192
readily self-administer the selective DA agonists apomorphine (Baxter et

al. 1974, 1976; Davis and Smith 1977; Wise et al. 1976; Woolverton et

al. 1984; Yokel and Wise 1978); piribedil (Woolverton et al. 1984; Yokel

and Wise 1978); and bromocriptine (Wise et al. 1990; Woolverton et al.

1984), whereas the selective noradrenergic agonists methoxamine (Risner

and Jones 1976) and clonidine (Yokel and Wise 1978) were not

self-administered, except at a narrow range of doses (Davis and Smith

1977; Woolverton et al. 1982) that were perhaps more relevant to

autoreceptor inhibition of noradrenergic systems than to postsynaptic

actions on their efferents.

Thus it was well established in the 1970s that one or more of the DA

systems was the main substrate of cocaine’s abuse liability; the same

conclusion would be reached a decade and a half later on the grounds of

.

correlational evidence (Ritz et al. 1987).

While good serotonergic agonists and antagonists had not yet been

developed, early studies suggested that lesions and antagonism of the

serotonergic projections to the forebrain increased rather than decreased

the abuse liability of cocaine and amphetamine (Lyness and Moore 1983;

Lyness et al. 1981). More convincing recent studies appear to confirm

this initial impression (Loh and Roberts 1990). However, recently

developed drugs that act on newly identified subtypes of serotonin

receptor may prove to modulate the rewarding effectiveness of cocaine

and amphetamine, possibly through serotonin-DA interactions.

The identification of habit-forming actions of cocaine with the

mesolimbic and mesocortical subdivisions of the DA system derived

from studies involving selective lesions, local injections of antagonists,

and studies of direct intracranial drug self-administration. Selective

damage to forebrain DA projections reduced or blocked the rewarding

properties of cocaine (Roberts and Koob 1982; Roberts et al. 1977, 1980)

and amphetamine (Lyness et al. 1979), while damage to noradrenergic

systems had no effect (Roberts et al. 1977). These lesions do not

discriminate the contributions of nucleus accumbens (NACC) and frontal

cortex DA projections, as lesions of the former can damage axons

projecting to the latter. However, microinjections of DA antagonists

(Phillips et al. 1983) and excitotoxin lesions to the NACC (Zito et al.

1985), each of which spares the mesocortical DA projections, also reduce

the rewarding effects of cocaine. These data point clearly to a major role

for the NACC in cocaine reinforcement.

193
In addition, rats have been trained to lever press for injections of

amphetamine (Hoebel et al. 1983) and DA (Guerin et al. 1984), but not

cocaine (Goeders and Smith 1983), directly into the NACC.

Amphetamine injections into the NACC are rewarding, as reflected in the

conditioned place preference paradigm (Carr and White 1983, 1986).

Thus a role in psychomotor stimulant reinforcement seems clearly

established for the NACC.

A role for frontal cortex in the rewarding action of cocaine has also been

suggested. Goeders and Smith (1983, 1986) and Goeders and colleagues

(1986) were successful in training rats to self-administer cocaine into the

frontal cortex but unsuccessful in training them to self-administer cocaine

into the NACC. This finding is troublesome because these same

researchers have reported that DA itself is rewarding when injected into

the NACC (Guerin et al. 1984). It is clear that cocaine binds to DA

uptake carriers in the NACC (Boja and Kuhar 1989) and causes elevation

of NACC DA (Di Chiara and Imperato 1988); cocaine has such actions

even when given by local injection into the NACC proper (Hernandez

et al. 1991; Nomikos et al. 1990). Moreover, lesions of frontal cortex do

not have a significant influence on intravenous cocaine selfadministration (Martin-Iverson et al. 1986). While frontal cortex lesions

do seem to alter acquisition of cocaine self-administration habits (Schenk

et al. 1991), this may well be explained by effects of frontal cortex DA

manipulations on NACC DA turnover (Louilot et al. 1989). Thus, the

role of frontal cortex actions in cocaine reward remains unclear on

present evidence.

DA AGONlSTS IN TREATMENT OF CRAVING

Two pharmacotherapies for opiate addiction have each had some degree

of success; they involve the opiate methadone and the noradrenergic

agonist clonidine. Each is used in an attempt to reduce drug craving by

reducing drug withdrawal symptoms. Methadone maintenance therapy

(Dole and Nyswander 1965, 1967) is based on the fact that methadone

produces less euphoria than heroin, as well as on the belief that, while it

produces physiological dependence in its own right, the cravings

associated with methadone withdrawal symptoms are weaker than those

associated with heroin. The fact that methadone penetrates the brain

more slowly and is more slowly metabolized appears to make methadone

a less compulsively self-administered drug than heroin. The fact that it is

less compulsively self-administered and the fact that it reduces heroin

194
craving (essentially by partially satisfying it) makes methadone

maintenance among the more successful approaches to the management

of heroin addiction.

Clonidine also alleviates opiate withdrawal symptoms (Gold and Kleber

1981; Gold et al. 1978); in addition, it is reported to reduce nicotine and

ethanol cravings (Glassman et al. 1984; Walinder et al. 1981). Clonidine

is a noradrenergic agonist and is thought to alleviate opiate and other

withdrawal symptoms (Gold and Kleber 1981; Gold et al. 1978) by

inhibiting the noradrenergic cells of locus coeruleus (Aghajanian

1978)-the primary source of noradrenergic innervation of the forebrain.

Opiates also inhibit the cells of the locus coeruleus; opiate withdrawal

symptoms include hyperactivity of the locus coeruleus, which is a

rebound after effect of chronic inhibition by dependence-producing

regimens of opiate administration (Aghajanian 1978).

The possibility that DA agonists might be used to treat cocaine craving

(Dackis and Gold 1985a, 1985b) was suggested on the basis of the

evidence that a DA system, rather than a noradrenaline system, plays a

role in cocaine self-administration. The first suggestion came from Gold,

who had participated (Gold et al. 1978) in the development of clonidine

for the treatment of opiate addiction, and the hypothesis seemed to have

been based on an attempt to find a clonidine-like drug that would work in

the DA system.

Cocaine inhibits the firing of dopaminergic neurons (Henry et al. 1989),

though not in quite the same way that morphine inhibits the firing of

noradrenergic cells. Moreover, the primary parallel ends there. There is

no evidence that hyperactivity of the DA system is a consequence of

cocaine withdrawal. Indeed, DA has been suggested to be depleted

during cocaine withdrawal and craving (Dackis and Gold 1985b), and

recent microdialysis studies indicate that hypoactivity of the DA system

is a correlate of cocaine withdrawal (Imperato et al. 1992; Parsons et al.

1991; Robertson et al. 1991; Rossetti et al. 1991). Moreover, direct DA

agonists are self-administered by laboratory animals (Baxter et al. 1974,

1976; Davis and Smith 1977; Wise et al. 1976, 1990; Woolverton et al.

1984; Yokel and Wise 1978). Clonidine is self-administered only at low

doses that appear to be preferential for autoreceptor inhibition of

noradrenergic function (Davis and Smith 1977; Risner and Jones 1976;

Yokel and Wise 1978). Thus, while DA agonists have been suggested to

alleviate cocaine craving, they do so in a way that differs significantly

195
from the alleviation of heroin craving by the noradrenergic agonist

clonidine.

The DA agonists alleviate cocaine craving for a reason more analogous to

the reason that heroin craving is alleviated by methadone; these drugs

stimulate the same brain mechanism that is stimulated by the abused drug

itself. Thus DA agonists like methadone (but unlike clonidine) may have

abuse potential of their own. Indeed, bromocriptine, an agonist that has

been used in attempts to treat human cocaine users, is not only

self-administered by laboratory animals (Wise et al. 1990; Woolverton

et al. 1982, 1984); it also precipitates relapse to extinguished habits that

were trained under either cocaine or heroin (Wise et al. 1990). This

relapse would appear to be due to similarity between the stimulus

properties of bromocriptine and cocaine; bromocriptine causes rats to

behave as if they have been given a taste of cocaine.

However, while bromocriptine apparently reduces cocaine craving

temporarily by satisfying it, and while bromocriptine is self-administered

by lower animals, it appears on present evidence to have little abuse

liability in humans. The most likely reason is that DA agonists have

aversive properties in the brain stem of higher primates. Indeed,

apomorphine is used in aversion therapy in humans, despite the fact that

it is readily self-administered by rodents. The aversive side effects of

bromocriptine and apomorphine appear to keep these drugs from being

used compulsively or even recreationally by humans. Nonetheless, recent

clinical trials have been disappointing; bromocriptine has not been shown

to be effective in permanently eliminating cocaine self-administration

habits (Teller and Devenyi 1988).

NONDOPAMINERGIC CONTRIBUTIONS TO REWARD

CIRCUITRY

The first indication that the rewarding effects of amphetamine (Davis and

Smith 1975; Yokel and Wise 1975) and cocaine (deWit and Wise 1977)

depend on a dopaminergic substrate emerged along with evidence that the

rewarding effects of hypothalamic brain stimulation also depend on a

dopaminergic substrate (Fouriezos and Wise 1976; Fouriezos et al. 1978).

The same neuroleptics that block the rewarding effects of amphetamine

and cocaine also block the rewarding effects of hypothalamic stimulation

(Gallistel and Davis 1983). This finding and the fact that reward sites in

the ventral tegmental area (VTA) have the same anatomical dispersion as

196
the DA cells themselves (Corbett and Wise 1980; Wise 1981) suggests

that the first-stage reward neurons of the medial forebrain bundle (MFB)

were the DA-containing neurons themselves.

Several findings now rule out the possibility that direct depolarization of

dopaminergic fibers by the stimulating current itself plays a major role in

the rewarding effects of hypothalamic stimulation-at least when

traditional stimulation parameters are used. The dopaminergic fibers are

small and unmyelinated, and their thresholds appear to be too high for

them to be significantly activated in traditional brain stimulation reward

(BSR) experiments. Rather, parametric studies involving paired pulse

stimulation implicate fast myelinated fibers (Gallistel et al. 1981; Wise

and Rompré 1989) that may, in turn, synapse on the DA cells (Wise

1980) or on their afferents. To date, neither the origin nor the transmitter

of the descending reward neurons is known; however, once the

descending component of the BSR circuitry is identified, it is likely to

offer a nondopaminergic candidate for pharmacological modulation of

basal DA activity. Since cocaine is a DA uptake inhibitor, its ability to

increase synaptic DA concentrations depends on DA release; thus, drugs

that affect dopaminergic impulse flow may well have significant impact

on the rewarding effects of cocaine. For this reason, the identification of

the descending MFB reward neurons is of potential significance for the

development of addiction treatment.

The activity of the dopaminergic cells of the VTA is modulated by a

number of neurotransmitters at the level of the cell bodies. Opiate actions

in the VTA are strongly habit forming (Bozarth and Wise 1981; Phillips

and LePiane 1980; van Ree and de Wied 1980; Welzl et al. 1989). Fibers

containing enkephalin and dynorphin each project to this area; indeed,

while it is not clear that they are functional, enkephalin-containing axons

appear to make direct synaptic contact with dopaminergic dendrites

(Sesack and Pickel 1992). Dopaminergic cell bodies do not appear to

have opiate receptors (Johnson and North 1992; Lacey et al. 1989),

although the possibility should perhaps not be ruled out that such

receptors could be localized too distal on the dopaminergic dendrites to

respond to iontophoretically administered opiates.

Dopaminergic cells do appear to have gamma aminobutyric acid (GABA)

receptors (Lacey et al. 1988), and the firing of dopaminergic cells is

inversely related to the firing of local GABAergic neurons. The

GABAergic cells have mu opiate receptors, and it appears that the local

action of opiates on dopaminergic cell firing involves disinhibition of

197
dopaminergic cells due to inhibition of GABAergic interneurons

(Johnson and North 1992); mu opioids are self-administered into the

VTA (Devine and Wise 1990).

Ventral tegmental DA neurons may also receive an excitatory cholinergic

input (Lacey et al. 1990) relevant to reward function. Cholinergic

blockade eliminates the contribution of the fastest of the MFB reward

fibers (Gratton and Wise 1985), and cholinergic antagonists injected

directly into the VTA attenuate the rewarding effects of MFB stimulation

(Yeomans et al. 1985). In addition, it should be noted that the VTA

appears to receive noradrenergic input from the locus coeruleus (Simon

et al. 1979) and serotonergic input from the raphe nuclei (Moore et al.

1978; Parent et al. 1981). Since each of these inputs should be influenced

by cocaine, each provides a potential modulation of dopaminergic reward

signals.

There are several neurotransmitter systems not yet theoretically linked to

reward function but nonetheless capable of interacting with the

mesolimbic DA system. Cholecystokinin is colocahzed and released by

dopaminergic neurons and is known to be capable of modulating

dopaminergic function (Phillips et al. 1989). Neurotensin (Kalivas et al.

1983) and substance P (Elliot et al. 1986) are released from nerve

terminals in the VTA, and each can modulate DA cell firing.

Finally, drugs could modulate the reward system at some stage efferent to

the dopaminergic link in that system. The mesolimbic DA system

appears to synapse on GABAergic cells and perhaps cholinergic cells in

the NACC, and the GABAergic cells project-through a GABAergic

cascade involving synapses in the pallidum, substantia nigra, and superior

colliculus-to the pedunculo-pontine nucleus in the mesencephalic

locomotor region. This nucleus appears to have reward-relevant

functions and may be part of a common final path of reward signals from

the forebrain (Bechara and van der Kooy 1992).

CONCLUSION

The afferents to and efferents from the mesolimbic DA system offer

multiple targets for pharmacological interventions designed to reduce

cocaine reinforcement or craving. Basic studies of the synaptic links in

reward circuitry (Phillips 1984; Wise and Bozarth 1984) would appear to

198
offer the most direct and immediate way to identify additional candidates

for pharmacological treatment approaches.

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AUTHOR

Roy A. Wise, Ph.D.

Department of Psychology

Concordia University

1455 de Maisonneuve Blvd., West

Montreal, P.Q., Canada H3G 1M8

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NEEDLE SHARING AMONG INTRAVENOUS DRUG

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PHARMACOLOGY AND TOXICOLOGY OF AMPHETAMINE

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RESEARCH FINDINGS ON SMOKING OF ABUSED

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102 ANABOLIC STEROID ABUSE. Geraline C. Lin, Ph.D., and

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107 DRUG ABUSE PREVENTION INTERVENTION RESEARCH:

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109 LONGITUDINAL STUDIES OF HIV INFECTION IN

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111 MOLECULAR APPROACHES TO DRUG ABUSE RESEARCH:

RECEPTOR CLONING, NEUROTRANSMITTER

EXPRESSION, AND MOLECULAR GENETICS: VOLUME I.

Theresa N.H. Lee, Ph.D., ed.

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112 EMERGING TECHNOLOGIES AND NEW DIRECTIONS IN

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113 ECONOMIC COSTS, COST EFFECTIVENESS, FINANCING,

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METHODOLOGICAL ISSUES IN CONTROLLED STUDIES

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METHODOLOGICAL ISSUES IN EPIDEMIOLOGY,

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126 MOLECULAR APPROACHES TO DRUG ABUSE RESEARCH

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Theresa N.H. Lee, Ph.D., ed.

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127 PROGRESS AND ISSUES IN CASE MANAGEMENT. Rebecca

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128 STATISTICAL ISSUES IN CLINICAL TRIALS FOR

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129 INHALANT ABUSE: A VOLATILE RESEARCH AGENDA.

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131 IMPACT OF PRESCRIPTION DRUG DIVERSION CONTROL

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137 BEHAVIORAL TREATMENTS FOR DRUG ABUSE AND

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IMAGING TECHNIQUES IN MEDICATIONS

DEVELOPMENT: CLINICAL AND PRECLINICAL ASPECTS.

Heinz Sorer, Ph.D., and Rao S. Rapaka, Ph.D., eds.

NCADI #M138

SCIENTIFIC METHODS FOR PREVENTION INTERVENTION

RESEARCH. Arturo Cazares, M.D., M.P.H., and Lula A. Beatty,

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NCADI #M139

PROBLEMS OF DRUG DEPENDENCE, 1993: PROCEEDINGS

OF THE 55TH ANNUAL SCIENTIFIC MEETING, THE

COLLEGE ON PROBLEMS OF DRUG DEPENDENCE, INC.

VOLUME I: PLENARY SESSION SYMPOSIA AND ANNUAL

REPORTS. Louis S. Harris, Ph.D., ed.

NCADI #M140

PROBLEMS OF DRUG DEPENDENCE, 1993: PROCEEDINGS

OF THE 55TH ANNUAL SCIENTIFIC MEETING, THE

COLLEGE ON PROBLEMS OF DRUG DEPENDENCE, INC.

VOLUME II: ABSTRACTS. Louis S. Harris, Ph.D., ed.

NCADI #M141

ADVANCES IN DATA ANALYSIS FOR PREVENTION

INTERVENTION RESEARCH. Linda M. Collins, Ph.D., and

Larry A. Seitz, Ph.D., eds.

THE CONTEXT OF HIV RISK AMONG DRUG USERS AND

THEIR SEXUAL PARTNERS. Robert J. Battjes, D.S.W.; Zili

Sloboda, Sc.D.; and William C. Grace, Ph.D., eds.

THERAPEUTIC COMMUNITY: ADVANCES IN RESEARCH

AND APPLICATION. Frank M. Tims, Ph.D.; George De Leon,

Ph.D.; and Nancy Jainchill, Ph.D., eds.

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