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28 décembre 2008
Experimental Clini Psychopharmacol
Narrowing in on Compulsions:
Dopamine Receptor Functions
Gregory T. Collins and James H. Woods
University of Michigan


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.
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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
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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.