Use of rodent self-administration models to develop pharmacotherapies for cocaine abuse

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National Institute on Drug Abuse
RESEARCH
MONOGRAPH SERIES
Neurobilolgical
Models for
Evaluating
Mechanisms
Underlying Cocaine
Addiction
1
4
5
U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health

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
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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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in the public domain and may be used or reproduced without permission
from the Institute or the authors. Citation of the source is appreciated.
Opinions expressed in this volume are those of the authors and do not
necessarily reflect the opinions or official policy of the National Institute on
Drug Abuse or any other part of the U.S. Department of Health and Human
Services.
The 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.
ii

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 . . . . . . . . . . . . . . 40
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 neuropharmaco-
logical 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 self-
administered 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 micro-
injections 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 norepinephrine-
sparing 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 self-
administers 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 self-
administration 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
123
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 self-
administration.
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-adminis-
tration (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 sedative-
hypnotics. 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 respond-
ing in rats self-
administering 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 Newman-
Keuls test.
Taken with permission
from Koob et al.
(1987
b)
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
1991
a
). 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 with-
drawal 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 self-
administering 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 trig-
gered 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 self-
administration 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 self-
administration (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 meso-
corticolimbic 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 psycho-
pathology 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 threshold-
lowering 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 self-
biting 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-d-
aspartate (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 threshold-
lowering 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 self-
administration 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 schedule-
dependent. 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 self-
stimulation 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 dose-
dependently 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-hydroxy-
tryptophan (5-HTP) was reported to reduce cocaine-evoked hyper-
locomotion 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
hyperactivity
17
’
18
5-HTP
5-HT
1A
agonists
hyperactivity
14,17,19
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-HT
1F
], 5-HT
2
[5-HT
2A
, 5-HT
2B
, 5-HT
2C
], 5-HT
3
, 5-HT
4
, 5-HT
5
[5-HT
5A
,
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-(di-
n-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 cocaine-
induced 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-HT
1A
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 cocaine-
induced 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 cocaine-
induced 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-HT
1A
agonists
8-OHDPAT
Gepirone
Other 5-HT agonists
LSD (5-HT
2A/2C
)
Mescaline (5-HT2A/2C)
MCPP (5-HT
1B/2C
)
MK 212 (5-HT
1B/2C
)
TFMPP (5-HT
1B/2C
)
5-HT
3
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 enhance-
ment ENHANCES) is defined as a significant increase in
the percentage of cocaine-lever responses upon coadmini-
stration of the compound with cocaine. A complete
and partial antagonism are defined as < 30 percent and
31-60 percent cocaine-lever responses following the combi-
nation of the 5-HT compound and cocaine. An X and ?
indicate that the drug had no effect or was not tested, respect-
ively. 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
1Baker et al. (1993)
2
Berman et al. (1982)
3
Callahan and Cunningham (1993b)
4Colpaert 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 dose-
dependently 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 two-
lever, 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.
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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
1Stern et al. (1982)
2Rickels et al. (1982)
3Bianchine (1980)
4Chait 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.
IC
50
values for drugs as inhibitors of [
3
H]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
1Hamilton et al. (1983); Miller and Griffith (1983); Parrott et al.
(1982); Peck and Hamilton (1983); Shekim et al. (1989); Yakabow et
3
al. (1984)
2Bianchine (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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rhesus monkeys given a choice between cocaine and food. Drug Alcohol
Depend 8:69-78, 1981.
Woolverton, W.L.; Goldberg, L.I.; and Ginos, J.Z. Intravenous
self-administration of dopamine receptor agonists by rhesus monkeys.
J Pharmacol Exp Ther 230:678-683, 1984.
Woolverton, W.L., and Virus, R.M. The effects of a D1 and D2 antagonist on
behavior maintained by cocaine or food. Pharmacol Biochem Behav
32:691-698, 1989.
Yakabow, A.L.; Hardman, S.; and Nash, R.J. An overview of side effects
and long-term experience with nomifensine from United States clinical
trials. J Clin Psychiatry 45:96-101, 1984.
Yokel, R.A., and Wise, R.A. Amphetamine-type reinforcement by
dopaminergic agonists in the rat. Psychopharmacology (Berl) 58:289-296,
1978.
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
87

Use of Rodent Self-Administration
Models to Develop Pharmaco-
therapies 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 drug-
maintained 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 drug-
taking 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 self-
administration 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 self-
administration 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 self-
administration (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 self-
administered 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
91

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 self-
administration (at least in rats) are consistent over several hours and do
not indicate an increasing direct effect of the drug as more drug is self-
administered.
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
92

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 self-
administer 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
93

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 self-
administration of the lower doses and the increase in the self-
94

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 self-
administration 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 self-
administration 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 self-
administration (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, 1992
c
; 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
96

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 self-
administration. 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 self-
administration (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 food-
maintained 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 self-
administration and food-maintained responding. However, decreases in
cocaine self-administration occurred at a dose that did not alter food-
maintained responding. These results demonstrate the ability to
investigate the effects of potential treatment compounds for cocaine
abuse.
101

FIGURE 8. Cumulative records of the effects of PIT on food-
maintained 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.
103

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 self-
administration
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 delay-
correlated 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 self-
administration 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 self-
administration. 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 self-
administered 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. 1990
a
), 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 self-
administration 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. 1990
c
). 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 self-
administration. 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 self-
administration. 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-methyl-
D-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 dose-
related 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 self-
administration 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 self-
administration in squirrel monkeys. In these experiments, squirrel
monkeys responded for consequent injections of cocaine under a second-
order 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 D
1
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 schedule-
controlled 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 D
1
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 self-
administration. 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 drug-
maintained 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.
141

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
142

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 low-
quality 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 require-
ment 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, 1983
a
, 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 1991
a
; 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 1991
a
; 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): After-
session 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 self-
administration. 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.
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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 incentive-
motivational 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 incentive-
motivational 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 incentive-
motivational 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 pharmaco-
therapeutics, 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 D
1
and D
2
antagonists on cocaine-
conditioned 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. (1993
a
)
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. (1993
a
) 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 incentive-
motivational 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 cocaine-
induced 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 cocaine-
induced 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 self-
administration 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 monoamine-
containing 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, phenoxy-
benzamine, 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 self-
administration (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 1985
a
, 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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RESEARCH FINDINGS ON SMOKING OF ABUSED
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CARDIOVASCULAR TOXICITY OF COCAINE:
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LONGITUDINAL STUDIES OF HIV INFECTION IN
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MOLECULAR APPROACHES TO DRUG ABUSE RESEARCH:
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EMERGING TECHNOLOGIES AND NEW DIRECTIONS IN
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ECONOMIC COSTS, COST EFFECTIVENESS, FINANCING,
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METHODOLOGICAL ISSUES IN CONTROLLED STUDIES
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MOLECULAR APPROACHES TO DRUG ABUSE RESEARCH
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PROGRESS AND ISSUES IN CASE MANAGEMENT. Rebecca
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INHALANT ABUSE: A VOLATILE RESEARCH AGENDA.
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IMPACT OF PRESCRIPTION DRUG DIVERSION CONTROL
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PROBLEMS OF DRUG DEPENDENCE, 1992: PROCEEDINGS
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BEHAVIORAL TREATMENTS FOR DRUG ABUSE AND
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SCIENTIFIC METHODS FOR PREVENTION INTERVENTION
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NCADI #M141
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THE CONTEXT OF HIV RISK AMONG DRUG USERS AND
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NIH Publication No. 94-3600
Printed 1994