The role of dopamine D3 compared with D2 receptors in the control of locomotor activity:: a combined behavioural and neurochemical analysis with novel, selective antagonists in rats

Background. The role of dopamine D-3/D-2 receptors in the control of locomotion is poorly understood. Objectives. To examine the influence of selective antagonists at D-3 or D-2 receptors on locomotion in rats, alone and in interaction with the preferential D-3 versus D-2 receptor agonist, PD128,907. Methods. Affinities of ligands at rat D-2 and cloned, human hD(3), hD(2S), hD(2L) and hD(4) sites were determined by standard procedures. Locomotion was monitored automatically in rats pre-habituated for 30 min to an open-field environment. Extracellular levels of dopamine (DA) were determined by dialysis in the nucleus accumbens and striatum. Drugs were given acutely via the systemic route. Results. PD128,907, which preferentially recognised D-3 versus D-2 sites, biphasically reduced and enhanced locomotion at "low" (0.01-0.63 mg/kg) and "high" (2.5-10 mg/kg) doses, respectively. L741,626 and S23199, which behaved as preferential D-2 versus D-3 receptor antagonists, enhanced the reduction in locomotion evoked by the low dose of PD128,907, blocked the increase provoked by the high dose and suppressed spontaneous locomotion alone. Analogous findings were obtained with haloperidol and raclopride which showed equilibrated affinity at D-2 and D-3 receptors. UH232 and AJ76, which showed a mild preference for D-3 versus D-2 sites, did not modify the effect of a low dose of PD128,907, slightly enhanced the hyperlocomotion elicited by the high dose and exerted little influence on locomotion alone. S14297 and U99194, which acted as preferential D-3 versus D-2 receptor antagonists, abolished the reduction in locomotion elicited by a low dose of PD128,907, potentiated the induction of locomotion by a high dose, and failed to influence locomotion alone. The actions of S14297 were stereoselective inasmuch as they were mimicked by the racemic form, S11566, but not by the inactive enantiomer, S17777. In contrast to S14297, S11566 and U99194, however, S33084, SB269,652, GR218,231 and N-[-4-['-(1-naphtyl)piperazine-1-yl]butyl] anthracene-2-carboxamide ("NGB-1"), highly selective D-3 versus D-2 receptor antagonists, were inactive under all conditions. PD128,907 (0.01-10.0 mg/kg) suppressed dialysate levels of DA in the nucleus accumbens and striatum, actions blocked by L741,626 and haloperidol, yet unaffected by S14297 and S33084. Conclusions. The facilitatory influence of a "high" dose of PD128,907 upon locomotion is mediated by postsynaptic D-2 receptors and, possibly, countered by their D-3 counterparts. Correspondingly, selective blockade of D-2 but not of D-3 receptors alone suppresses motor function. The reduction in locomotion provoked by a "low" dose of PD128,907 may be mediated by D-2 autoreceptors, but a role of postsynaptic D-3 receptors cannot be excluded. Finally, mechanisms underlying the contrasting influence of chemically diverse D-3 receptor antagonists upon locomotion remain to be elucidated.