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26 mai 2005
Dynamic dopamine receptor interactions in the core and shell of nucleus accumbens differentially coordinate the expression of unconditioned motor behaviors
Canales JJ, Iversen SD
Department of Experimental Psychology, University of Oxford, England


The nucleus accumbens (Acb) of the ventral striatum is a prominent structure of the basal forebrain. Several lines of evidence support the distinction in the Acb between a medial portion, the shell, and a lateral sector, the core. The shell of the Acb is connected with the lateral hypothalamus and the neurotensin-rich ventromedial and ventrolateral portions of the ventral pallidum, which are regarded as transitional areas between the basal ganglia and the "extended amygdala". In turn, thecore of Acb is affiliated with the motor centers of the basal ganglia, including the dorsolateral part of the ventral pallidum, the substantia nigra, and the pedunculopontine nucleus. Functional and behavioral evidence suggests that the core of Acb is involved in motor integrative functions typical of the basal ganglia, while the shell of Acb mediates various aspects of incentivedriven behavior, including feeding and stimulant-induced reinforcement . These functions are believed to be mediated in part by the mesolimbic dopamine system that projects to the core and the shell of Acb.
Dopamine exerts physiological effects in the brain through actions on multiple dopamine receptors. These have been grouped into two families, the dopamine D1-class, which includes Dl and D5 receptors and the D2-class, which includes D2, D3, and D4 receptors. Many behavioral effects mediated by dopamine D2-class receptor agonists, including hyperlocomotion and stereotypies, are dependent on simultaneous dopamine D1class receptor activation. The striatum is a critical site for the functional interaction between dopamine D1-class and D2-class receptors. For example, the coadministration of dopamine D1-class and D2-class receptor agonists into the Acb induces a synergistic increase in locomotor activity. Moreover, this treatment, but not each agonist treatment given alone, induces stereotyped oral behavior following injections into the ventrolateral striatum. These findings are consistent with the classical view, according to which the postsynaptic effects of D2-class receptor agonists require D1-class receptor enabling.
We previously characterized the effects elicited by infusions of the dopamine D2-class receptor agonist quinpirole and the indirect dopamine agonist d-amphetamine on unconditioned motor behaviors following microinjections into the striatum. The effects of quinpirole infusions into the striatum, but not those elicited by d-amphetamine, including sedation, oral dyskinesia, and motor inhibition, showed a marked homogeneity across distinct striatal sectors. These findings prompted us to examine whether the behavioral effects of D2-class receptor agonists are homogenous within the Acb, and whether the expression of specific D2-class receptor-mediated effects following administration into the core and the shell of Acb depends on the level of activation of Dlclass receptors. As a D2-class receptor agonist we selected (+)-PD 128907, which displays some selectivity for the dopamine D3 receptor in binding studies and functional tests. As a D1-class receptor agonist we chose SKF 38393, which induces potent D1-class receptor-mediated effects in vivo despite its partial agonist profile. These experiments were designed to characterize the unconditioned motor effects evoked by microinjections of (+)-PD 128907 into the core and the shell of Acb, and to determine whether these effects, and those previously reported for quinpirol, can be modified by concurrent activation of the dopamine D1-class receptor.
SKF 38393 switches the pattern of responses induced by quinpirole
The dose of SKF 38393 selected in Experiment 1 was behaviorally inert, producing only marginal effects on locomotion and oral behaviors. Administration of this dose of SIT 38393 followed by quinpirole into the Acb induced a striking "behavioral switch." We have shown that animals treated with quinpirole into the Acb display a syndrome of hypoactivity, sedation, and oral dyskinesia. SIT 38393 virtually eliminated all behavioral signs associated with the quinpirole syndrome. Moreover, animals receiving SKF 38393 followed by quinpirole into the Acb were hyperactive. Interactions between dopamine Dlclass and D2-class receptors have been demonstrated previously for the induction of locomotor activity and motor stereotypies following systemic drug administration and intracerebral microinjection into the Acb. We further characterized these interactions. SKF 38393 followed by quinpirole reduced spontaneous grooming and yawning responses, effects typically observed following amphetamine infusions into the Acb. Further, SIT 38393 canceled the increase in oral dyskinesia typically induced by quinpirole injections into the Acb. This finding suggests that abnormal orofacial movements may result from an imbalance in the activity of dopamine D1-class and D2-class receptor-mediated neuronal output pathways.
(+)-PD 128907 induces a quinpirole-like pattern of behavioral responses
Microinjections of (+)-PD 128907 into the core or the shell of Acb produced a strong suppression of rearing, locomotor activity, and grooming behavior, together with an increase in oral dyskinesia, yawning, and sedation. This behavioral profile is remarkably similar to that observed after quinpirole injections into the Acb (Canales and Iversen, 1998). (+ )-PD 128907 was equipotent at these two anatomical sites. These results indicate that dopamine D2-class receptors in the shell and core of Acb have inhibitory effects on exploratory activity, including rearing and locomotor behavior. Systemic administration of (+)-PD 128907 and of other agonists with limited selectivity for dopamine D3 receptors reduces locomotor activity in a dose-dependent fashion. Moreover, in this study, injections of (+)-PD 128907 into the core or shell of Acb induced intense bouts of oral dyskinesia. Anatomical and behavioral studies support an involvement of both core and shell sectors of Acb in oral behaviors. While the shell of Acb is mainly associated with the lateral hypothalamus and the extended amygdala, the core of Acb maintains strong links with the substantia nigra. The accumbens-hypothalamic pathway is known to be critical for the control of ingestive behavior, whereas the substantia nigra is implicated in the expression of oral stereotypies and oral dyskinesias. (+)-PD 128907 also induced yawning and sedation in a dose-dependent manner. At low systemic doses, dopamine D2-class receptor agonists, e.g., apomorphine, quinpirole, and (+)-PD 128907, are known to elicit sedation and yawning behavior. Taken together, our results indicate the core and the shell of Acb are homogeneous for the expression of D2-class receptor-mediated behavioral responses such as exploratory behavior, oral dyskinesia, sedation, and yawning.
SKF 38393 switches the pattern of responses induced by (+)-PD 128907
Coadministration of SIT 38393 and (+)-PD 128907 into the core or the shell of Acb revealed striking differences between these two sites at the functional level. SKF 38393 almost completely abolished the syndrome elicited by (+ )-PD 128907 following administration into the core, but not into the shell, of Acb. Following treatment with SKF 38393 and (+)-PD 128907 into the shell of Acb, oral dyskinesia, yawning, and sedation were significantly increased relative to controls, while animals injected into the core of Acb did not differ from controls in these measures. Furthermore, a specific synergistic interaction was observed between SKF 38393 and (+)-PD 128907 for the induction of locomotor activity. The coadministration of SKF 38393 and (+ )-PD 128907 into the core of Acb significantly increased locomotor activity, while levels were significantly depressed following administration into the shell of Acb, compared to control levels. Thus, the cooperative interaction between dopamine receptors to evoke hypermotility was specific to the core of Acb. Taken together, these results indicate that the functional coupling between dopamine D1-class and D2class receptors is not homogenous within the Acb.
These results suggest that doses of quinpirole and of (+ )-PD 128907 that elicit behavioral effects classically associated with dopamine autoreceptor activation, such as locomotor depression and yawning, possess "latent" postsynaptic activity at dopamine D2-class receptors, readily uncovered by SKF 38393. A similar profile was previously described for other D2-class receptor agonists following systemic drug administration. The results further suggest that, at the behavioral level, the postsynaptic effects of quinpirole and of (+ )-PD 128907 in the Acb depend critically on the level of activation of dopamine Dlclass receptors. We show that there are two aspects to the postsynaptic effects of D2-class receptor agonists: I behavioral suppression and sedation following removal of D1-class receptor tone, and behavioral arousal and j hyperactivity following D1-class receptor activation. Thus, dopamine D1-class receptors in the Acb not simply enable certain dopamine D2-class receptor-mediated behavioral responses, but in fact regulate the switch between states of sedation and motor inhibition to states of strong behavioral stimulation.
A major finding in this study was that the effects of coadministration of SKF 38393 and (+)-PD 128907 into distinct sectors of the Acb showed marked anatomical selectivity, suggesting a differential sensitivity of the ( core and shell of Acb with regards to the functional interaction between dopamine receptors. Morphological evidence indicated that tyrosine-hydroxylase-contaming fibers contact the dendrites of spiny projections neurons of the core of Acb more frequently than those of the shell region, and that neurons of the core sector branch more often, have more spines and a larger area available for synaptic interactions. Anatomical evidence indicates that the core of Acb preferentially interacts with motor output structures of the basal ganglia. At the behavioral level, the present results suggest that there is clear functional segregation within the ventral striaturn such that the core of Acb exerts predominant control over the expression of dopamine receptor mediated unconditioned motor behaviors.
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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.