- Abstract :A series of experiments in
rats explored the possibility that D3/D2
dopamine receptors are involved in behaviors
that might be related to compulsion. A series of
D3/D2 agonists and antagonists were shown to
elicit yawning (D3-receptor mediated) and its
inhibition (D2- receptor mediated). In rats with
histories of cocaine exposure,
D3-agonist-elicited yawning was enhanced, and
quinpirole led to persistent operant responding
only if conditioned stimuli associated with
cocaine were presented for responding. Finally,
a more selective D3 partial agonist was reported
that had a novel profile of activity that could
have relevance to the suppression of
dopamine-related compulsions.
-
-
- Impulse control disorders involve behaviors
that occur excessively, seeming to be
disconnected from the feedback normally imposed
by the signaling, delivery, and consump- tion of
reinforcers. Thus, whereas normal eating stops
when the eater is sated, compulsive overeaters
are not limited by food satiation. A similar
lack of feedback restraint occurs with
hypersexual behavior. On the other hand,
compulsive behavior may continue even though the
previously positive or pleasurable results of
this behavior are no longer ob- tained.
Compulsive shoppers may have little interest in
the merchandise they seem unable to refrain from
purchasing, and compulsive gamblers and drug
abusers engage exces- sively in behaviors that
can destroy their social, economic, and personal
well-being, yet provide precious little apparent
enjoyment.
-
- A possible connection between the dopamine
receptors and impulse control disorders has been
given a fascinating measure of support from a
recently described clinical con- dition in
patients with Parkinson's disease (PD) who are
treated with dopamine agonists. As reviewed by
Voon and Fox (2007), approximately 6% of these
patients develop compulsive behaviors that
include hypersexuality, compul- sive gambling,
overeating, shopping, or medication use.
Although there is as yet no clear relation
between these particular behaviors and a
specific dopamine agonist ther- apy, and only
occasionally has a clear dose-effect correla-
tion been described in patients with PD, a
relation between dopamine agonists and these
aberrant behaviors in predis- posed individuals
seems clear.
-
- Two popular pharmacotherapies for PD that
are impli- cated in impulse control disorder are
pramipexole and ropi- nirole, used alone or in
combination with the dopamine precursor,
levodopa. Pramipexole and ropinirole are dopa-
mine agonists with preference for the D3
receptor over the D2 receptor, and with low
affinity for D1-like receptors (Piercey, 1998).
In the doses used for treatment, it is prob-
able that both D3 and the D2 receptors are
activated by these drugs, and the case studies
in which impulse control disorders are described
do not permit determination of whether action at
either or both of these sites is important
either for treating the symptoms of PD or for
producing impulse control disorders. In
addition, it is not known what the impact of the
neurochemical deficits produced by PD itself is
on dopamine-agonist induced compulsive behavior,
or why this effect is revealed in only a small
proportion of patients. Much remains to be
learned.
-
- This points to the need for preclinical
approaches to evaluation of the role of D2
and/or D3 receptor activation, and potential
setting conditions for the development of
compulsive behavior. Two major impediments have
re- stricted this research: one is the scarcity
of drugs, either agonists or antagonists, that
have the requisite selectivity for either the D3
or D2 receptor; the second is the lack of clear
criteria that define behavior as compulsive. We
have been evaluating the effects of
D3-preferring D3/D2 agonists on a variety of
behaviors in rats because of an interest in
iden- tifying D3-specific ligands. Our findings,
as well as the clinical and preclinical
literature, support the notion that compulsive
behavior may indeed be linked to activity at the
D3 receptor, and therefore potentially reduced
by selective D3 antagonists or partial
agonists.
-
- One of our most useful findings confirms the
suggestion (Levant, 1997) that dopamine
agonist-induced yawning in rats is specifically
mediated by D3 receptor activation (Col- lins et
al., 2007; Collins et al., 2005). Having a
selective assay for D3 activity is critical for
evaluation of effects of agonists and
antagonists at this site. Drugs that are D3-
preferring, with actions on D3 receptors at
small doses and on D3 and D2 receptors at larger
doses, produce an inverted U-shaped pattern of
activity in the yawning assay. Dose- dependent
increases in yawning are observed with small
doses of D3-preferring agonists including
pramipexole, quinpirole, PD-128,907, and
7-OH-DPAT, whereas dose- dependent decreases in
yawning are observed at higher doses. Correlated
with the decreasing limb of the yawning
dose-response curve is a decrease in body
temperature, an effect that appears to be
attributable to agonist activity at the D2
receptor (Figure 1A&endash;D). Antagonists
selective for D3 over D2 receptors inhibit the
induction of yawning pro- duced by small doses
of the agonists (Figure 1E) while having no
effect on the inhibition of yawning, or
induction of hypothermia produced by larger
doses. D2-selective an- tagonists, on the other
hand, do not affect the induction of yawning
following small agonist doses, but reverse the
inhibition of yawning (Figure 1F) and decrease
in body temperature observed at larger doses
(Collins et al., 2007, 2005). Analysis of these
dose-response functions not only permits the
characterization of agonists and antagonists
with activity at the D3 and D2 receptors, but
also allows for greater insight into the
receptor(s) involved in the mediation of other
behavioral effects of D3/D2 agonists and
antagonists.
-
- Following a finding by Nader and Mach
(1996), who reported that a D3-preferring D3/D2
agonist like quinpirole does not maintain
self-administration behavior in monkeys unless
the animals have a history of cocaine
self-adminis- tration, we evaluated the ability
of quinpirole to serve as a reinforcer in rats.
We replicated the findings of Nader and Mach
(1996), but also observed that even in rats with
a history of cocaine self-administration,
quinpirole failed to maintain responding if the
stimuli previously associated with cocaine were
not presented (Figure 2A). Furthermore,
responding maintained by the stimuli previously
paired with cocaine was observed if quinpirole
was simply adminis- tered, noncontingently,
prior to the session (Figure 2B). In the absence
of the cocaine-associated stimuli, quinpirole
pretreatment did not elicit responding (Figure
2C). In the absence of quinpirole, the stimuli
themselves did not main- tain responding (Figure
2C). What appeared to be quinpi- role-maintained
responding in cocaine-experienced rats ac-
tually was responding maintained by
cocaine-paired stimuli that seemed to become
salient in the presence of quinpirole.
-
- Other investigators have also noted unusual
effects of quinpirole administration. Amato,
Milella, Badiani, and Nencini (2006), for
example, have found that water-de- prived rats,
given quinpirole before daily sessions of water-
reinforced responding, initially showed
decreases in water- maintained responding, and
subsequently showed marked increases in
responding. However, the rats did not consume
the reinforcers they earned, and in fact,
continued to re- spond and receive water
presentations even when water was freely
available in their operant chambers.
-
- The requirement that quinpirole be given for
several days before a disconnection was observed
between responding and consumption of the water
reinforcer is not incidental. Neither was the
requirement of several days of exposure to
cocaine before quinpirole induced lever pressing
for co- caine-paired stimuli, nor the daily
administration of levo- dopa to patients with PD
long before compulsive behavior developed.
Chronic administration of dopamine agonists or
dopamine-releasing compounds appears to be
required to set the stage for the development of
D3/D2-induced com- pulsive responding. The
sensitized response involves, but is not
necessarily limited to the D3 receptor, as
indicated by our finding (Truong and Collins,
unpublished raw data) that pramipexole becomes
more effective and potent in its capacity to
elicit yawning in rats that have been exposed to
a sensitizing regimen of cocaine injections (2
days of 15 mg/kg/day followed by 5 days of 30
mg/kg cocaine). Co- caine, itself, does not
induce yawning, and this exposure to cocaine did
not result in an immediate increase in the
potency or effectiveness of pramipexole, but
rather the sensitization increased gradually
over a period of more than a week (see Figure
3), suggesting that an incubation period may be
a necessary component for the development of
impulse control disorders.
-
- These and other studies have led us to
define compulsive behavior in terms of the
setting conditions that appear to evoke it and
the conditions that appear to maintain it. The
setting conditions for compulsive behavior
includes the presence of agonist actions on D3
and/or D2 receptors and a past history of
exposure to these drugs or other dopamine
agonists or dopamine releasing drugs. Once the
setting conditions of previous dopamine exposure
and current pres- ence of D3 or D2 agonists are
met, the compulsive behavior will appear as
excessive (if the opportunity for excessive
behavior is present) or as behavior that occurs
regardless of whether that behavior is
reinforced (i.e., in extinction) or the organism
is sated. All that appears to be required is
that the behavior generates stimuli that were
previously paired with a "potent
reinforcer."
- If it is the case that the D3 receptor is
especially critical to the development, either
of the sensitization necessary for compulsive
behavior, or for the expression of compulsive
behavior, or both, it is possible that a
selective D3 antagonist or partial agonists
would be effective in reducing compulsive
behavior as modeled in animals or in impulse
control disorders in humans. On- going efforts
to synthesize ever more selective D3 li- gands
has had some recent positive results, and
evalua- tion of the compounds in animal tests of
stimulus-bound compulsive disorder has been
positive (Di Ciano, Under- wood, Hagan, &
Everitt, 2003; Spiller et al., 2008).
-
- We have, in collaboration with Drs. Shaomeng
Wang, Jianyong Chen, and Beth Levant synthesized
and evalu- ated a selective D3 partial agonist,
CJ-1037 (Chen et al., 2008). Unlike full
agonists, such as pramipexole, or antagonists,
such as PG01037, at the D3 receptor, which
either produce significant increases in yawning
with an inverted U-shaped dose-response curve,
or do not induce yawning, respectively, CJ-1037
displays a distinct behav- ioral profile with
low levels of yawning observed over a wide range
of doses resulting in a relatively flat dose-
response curve (Chen et al., 2008). Moreover,
the effects of CJ-1037 on pramipexole-induced
yawning are easily distinguished from those of
selective D3 (PG01037) or D2 (L-741,626)
antagonists (Figure 1E&endash;F). As shown in
Figure 4, CJ-1037 differentially affects the
ascending limb of the yawning dose-response
curve, enhancing the low levels of yawning
observed with small doses, and inhibiting the
high levels of yawning observed at peak doses of
pramipexole. Important to note, these effects
are observed at doses that do not affect the
D2-mediated inhibition of yawning or induction
of hypothermia, which occur with larger doses of
pramipexole, suggesting that CJ-1037 possesses a
selective partial agonist activity at the D3
receptor.
-
- It is important to point out some caveats in
this pre- sentation. Our definition of
compulsive behavior ac- counts nicely for the
experimental models described, and also for
patients with PD whose long treatment with
levodopa may set the stage for D3/D2
agonist-induced compulsive responding that
produces stimuli associated with gambling, sex,
purchasing, food, or medication. It may also
account for compulsive drug abuse, because drug
abusers also have a history of exposure to drug-
induced dopamine release, and then engage in
excessive behavior related to obtaining the
stimuli associated with drug taking. This
conceptual framework does not neces- sarily
surround all forms or aspects of compulsive be-
havior, however. Most individuals who engage
exces- sively in some behaviors do not have PD
and are not taking dopamine agonists. A very
detailed history would be necessary to determine
whether any previous exposure to increased
levels of central dopamine can be docu- mented
in, otherwise normal, compulsive gamblers,
shoppers, or eaters. It is possible that these
individuals have idiosyncratically enhanced
sensitivity to endoge- nous dopamine, and
appropriate brain imaging might show this, but
there is no certainty that this would be the
case. This framework also does not account for
the ability of antagonist treatments to treat
drug abuse. The admin- istration of a
long-acting opioid antagonist reduces her- oin
abuse through the process of extinction, and
this can be quite effective treatment in some
circumstances (Comer, Sullivan, & Hulse,
2007). In our notion, com- pulsive behavior is
very difficult to extinguish by simply removing
the reinforcer unless the stimuli related to
drug taking are also removed, or
pharmacologically blunted. Again, careful
evaluation of the behaviors and the stim- ulus
conditions that exist during and following
extinction might permit a more thorough
evaluation of how this type of successful
extinction is managed. We certainly have much to
learn about how compulsive behaviors develop and
how they might be treated, but some significant
inroads have been made recently that offer
considerable hope for future understanding and
treatment of some of these conditions.
-
- -Collins
C, Truccone A et al. Pro-erectile Effects of
Dopamine D2-like Agonists are Mediated by the D3
Receptor in Rats and Mice. J J Pharmacol Exp
Ther 2009
- -Canales JJ,
Iversen SD Psychomotor activating effects
mediated by dopamine D2 and D3 receptors in the
nucleus accumbens Pharmacol Biochem Behav 2000;
67;161-168
- -Canales
JJ, Iversen SD Dynamic dopamine receptor
interactions in the core and shell of nucleus
accumbens differentially coordinate the
expression of unconditioned motor behaviors
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- -Collins GT, JM
Witkin et al Dopamine agonist-induced
yawning in rats: a dopamine d3 receptor mediated
behavior. J Pharmacol Exp Ther
2005;314(1):310-319
- -Collins GT, Newman
AH,Woods JH et al.Yawning and hypothermia in
rats: effects of dopamine D3 and D2 agonists and
antagonists. Psychopharmacology
(Berl).
2007;193(2):159-170
- -Collins GT. et
al. Food restriction alters
pramipexole-induced yawning, hypothermia, and
locomotor activity in rats: Evidence for
sensitization of dopamine D2 receptor-mediated
effects. JEPT 2008;325:691-697
- -Collins
GT et al. Narrowing in on compulsions:
dopamine receptor functions Exp Clin
Psychopharmacol 2008,16(4):498,502
- -Chen J, Gregory T.
Collins, et al. Design, Synthesis, and
Evaluation of Potent and Selective Ligands for
the Dopamine 3 (D3) Receptor with a Novel in
Vivo Behavioral Profile. J Med. Chem.,
2008;51(19):5905&endash;5908
- -Collins GT,
Truong YN, et al. Behavioral sensitization
to cocaine in rats: evidence for temporal
differences in dopamine D(3) and D (2) receptor
sensitivity. Psychopharmacology (Berl).
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- Li SM,
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-
- Distribution
of dopamine D3 receptor expressing neurons in
the human forebrain:
- comparison
with D2 receptor expressing
neurons
- Gurevich EV, Joyce JN.
- Neuropsychopharmacology
1999;20(1):60-80
- Based on studies in the
rat, Sokoloff et al. have made the valuable
suggestion that the D3 receptor is a
particularly important target for antipsychotics
in the mesolimbic DA system. These study in the
human demonstrates that the distribution of D3
receptors and D3 mRNA-bearing neurons is
consistent with relative segregation of the D3
subtype to the limbic striatum as well as it
primary and secondary targets and many sources
of its afferents.
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