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19 mai 2005
Pharmacol Biochem Behav
2000; 67, 161-168
Psychomotor activating effects mediated by dopamine D2 and D3 receptors in the nucleus accumbens
JJ Canales, SD Iversen
Department of Experimental Psychology, University of Oxford, UK


Introduction The mesolimbic and nigrostriatal dopamine systems and their target receptors play a significant role in the expression of a wide variety of motor behaviors. Two families of dopamine receptors have been differentiated; the D1class, which includes the D1 and D5 receptors, and the D2 class, which includes the D2, D3, and D4 receptors. Members of the family of D2 receptors share a high degree of sequence homology and similar pharmacological profile. Of these, one of the most studied in recent years has been the D3 receptor. Localization studies suggest that the expression of D3 receptors is prominent in limbic-based circuits that modulate affect and motivated behavior, including the islands of Calleja and the nucleus accumbens (Acb). Given that the expression of the dopamine D3 receptor in the limbic system is high, this receptor site has been postulated a a potential target for therapeutic intervention in schizophrenia and substance abuse.
Pharmacological evidence suggests that dopamine D3 receptors exert inhibitory actions on psychomotor functions. (+)-PD 128907, pramipexole, and 7-OH-DPAT, compounds with relative selectivity for dopamine D3 receptors. reduce locomotor activity and induce sedation and yawning over a wide dose range. Conversely, D3 receptor-preferring antagonists stimulate locomotor behavior, but while D2 receptor-preferring antagonists inhibit motor activity. However, pharmacological studies are not supported by behavioral studies on mice lacking D3 receptors. The behavioral effects induced by D3 receptor agonists, including decreased locomotor activity and hypothermia, are identical in wild-type and D3 receptor-mutant mice. At the functional level, therefore, studies on the functions of the D3 receptor have been inconclusive.
We have previously characterized the behavioral effects of quinpirole and (+)-PD 128907, drugs with some selectivity for the D3 receptor, following injections into the Acb and we have shown that the effects of these agonists critically depend on the level of activation of D1-class receptors. In the present experiments, we first admnistered the ergot compound bromocriptine into the Acb to compare its behavioral effects to those induced by microinjections of quinpirole and (+)-PD 128907. Second, we tested whether the behavioral effects of bromocriptine can he modified by concurrent administration of a D1 class receptor agonist. Third, we examined the relativ contributions of D2 and D3 receptors to the locomotor enhancing effects induced by coadministration of D1 class and D2 class receptor agonists into the Acb. In this case, we administered antagonist drugs with relative selectivity for D2 or D3 receptors prior to cocktail injections of D1 class and D2 class receptor agonists into the Acb. The results are discussed in terms of the relative contribution of D2 and D3 receptors to motor behavior. [...]
Typical and atypical behavioral profiles induced bv bromocriptine injections into the Acb: dependence on D2 class receptor activation
Bromocriptine exhibits the typical behavioral profile of a D2 class receptor agonist following systemic admnistration. Bromocriptine suppresses spontaneous locomotion at low doses, but it induces hypermotility and stereotyped behaviors at high doses. The expression of some bromocriptine induced behavioral effects depends on D1 class receptor activation. In rats exposed to a methyl-p-tyrosine plus reserpine, the locomotorenhancing effects of bromocriptine are not evident, but these can be reinstated by concurrent administration of behaviorally inactive doses of the dopamine D1 class receptor agonist SKF 38393 . Studies on the effects of bromocriptine following injections into the Acb have produced conflicting results. Bromocriptine decreased rat locomotor behavior in the open field and inhibited mouse spontaneous climbing behavior following direct injections into the Acb. In activity cages, however, bromocriptine induced no changes in locomotor activity. Using a similar measure of locomotor activity and a wider dose range, the present experiments confirm the findings of Jenkins and Jackson and extend their observations to other activityrelated measures, including sniffing and rearing. In this regard, considering the ability of quinpirole and (+) - PD 128907 to suppress locomotor activity following injections into the Acb, bromocriptine is an atypical D2 class receptor agonist.
Bromocriptine induces sedation and yawning responses following administration of low systemic doses. In the present experiments, however, bromocryptine injections into the Acb failed to elicit yawning or sedation at any of the doses tested. In addition, bromocriptyne produced only a weak tendency to increase oral activity. In this respect, bromocriptine also shows an atypical profile, because these behaviors are elicited by injections of quinpirole and (-I-)PD 128907 into the Acb. These atypical effects of bromocriptine could be due to its complex pharmacological profile. Binding studies have shown that bromocriptine has a high affinity for noradrenergic a1 and a2 receptors, and for, serotonin a receptors. Moreover, microdialysis studies have shown that bromocriptine increases 5-HT turnover, and reduces extracellular levels of acetylcholine and dopamine in the striatum. Thus, interactions with neurotransmitter systems other than the dopamine system may contribute to the atypical D2 class receptor agonist profile of bromocriptine following intracerebral injections.
Previous studies suggest that D1 class receptors may play a permissive role in the locomotor-stimulant effects of bromocriptine following systemic administration. In our study, the combination of SKF 38393 and bromocriptine enhanced locomotor activity and suppressed spontaneous yawning responses. These two effects are also observed following amphetamine treatment or coadministration of SU 38393 and quinpirole into the Acb. The present experiments indicate that activation of dopamine D1 class receptors at the level of Acb alters the effects of bromocriptine in a way such that the behavioral output clearly reflects class/D2 class receptor interactions. With regard to these interactions, bromocriptine behaves as a typical D2 class receptor agonist.
Studies with nafadotride and L-741626 suggest a contribution of D2 and D3 receptors in the Acb to the induction of enhanced locomotor behavior.
To study whether D2 and/or D3 receptors play a role in the enhanced locomotor stimulation induced by combinations of SKF 38393 and either bromocriptine ór (+)-PD 128907, the antagonist drugs L-741626 and nafadotride were administered before injections of the agonist drugs. The results showed that the locomotor response elicited by SKF 38393 plus (+)-PD 128907 was effectively blocked by nafadotride at doses that do not produce functional blockade of D2 receptors, while L-741626 was less effective. These results suggest that D3 receptors synergize with D1 -class receptors and contribute to the expression of behavioral hyperactivity. Nafadotride also attenuated the hyperactivity induced by SKF 38393 plus bromocriptine, although not significantly so. In the present experimental conditions, nafadotride was without effect on locomotor activity. Previously, however, stimulatory effects of nafadotride on locomotor activity have been observed in well-habituated rats, although this finding has not been replicated. In the present experiments, we did not detect any stimulatory effects of nafadotride on locomotor behavior.
At the doses tested, L-741 626 attenuated the responses to (+)-PD 128907 and bromocriptine following coadministration with SKF 38393, but the magnitude of this attenuation did not reach statistical significance. Considering the overall results obtained with the antagonist L-741626, it seems that slightly higher doses would have blocked the locomotor effects of both SKF 38393 plus bromocriptine and SKF 38393 plus (+)-PD 128907. In fact, previous studies have shown that some physiological effects of (+)-PD 128907 are readily blocked by L-741626 [6,9], suggesting that (+)-PD 128907 could lack selectivity for the D3 receptor in vivo. Moreover, (+)-PD 128907 elicits locomotor suppression and hypotherm both in wild-type and D3-mutant mice, but not in D2 knock-outs. This evidence should be carefully considered when reaching conclusions regarding the behavioral functions of the D3 receptor. In our study, low doses of nafadotride significantly attenuated the locomotor effects of the combination of SKF 38393 and (+) - PD 128907, suggesting that both D2 and D3 receptors in the Acb sergize with D1 class receptors for the induction of enhanced locomotor stimulation. This evidence, however, should be evaluated with a wider range of more potent and selective agonists and antagonists for D3, relative to D2, receptors.
The results of this study indicate that bromocriptine induces atypical D2-class receptor- mediated behavioral effects following administration into the Acb. However, in combination with a D1 class receptor agonist, bromocriptine displays the typical functional profile of a D2 class receptor agonist. The present observations further indicate that antagonists with relative selectivity for D2 or D3 receptors are able to attenuate the motor effects induced by coadministration of a D1 class receptor agonist and either bromocriptine or (+) - PD 128907 into the Acb. These results suggest that in the presence of sufficient D1 class receptor activation, wich critically modulates D2 class receptor-mediated behavioral responses at the level of the Acb, D2 and D3 receptors in the Acb may contribute in similar ways to the expression of heightened psychomotor arousal.
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-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 Synapse 2000; 36; 297-306
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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.