FUNCTIONAL CORRELATES OF DOPAMINE D-3, RECEPTOR ACTIVATION IN THE RAT IN-VIVO AND THEIR MODULATION BY THE SELECTIVE ANTAGONIST, (+)-S-14297 .2. BOTH D-2 AND SILENT D-3 AUTORECEPTORS CONTROL SYNTHESIS AND RELEASE IN MESOLIMBIC, MESOCORTICAL AND NIGROSTRIATAL PATHWAYS

The preferential dopamine (DA) D-3 versus D-2 receptor agonist, (+)-7-OH-DPAT, dose-dependently decreased DA synthesis in the nucleus accumbens, olfactory tubercles, striatum and frontal cortex. This action was potently mimicked by several other high-potency D-3 agonists: CGS 15855A, (-)-quinpirole, quinelorane and N-0434. In contrast, piribedil, which displays a mild preference for D-2 sites, was less active. Across eight agonists, potency for inhibition of DA synthesis correlated more potently to affinity at D-3 (r = .82 +/- .04) than D-2 receptors (r = .60 +/- .06, P < .05). Correlations were also marked to potency for induction of a further D-3-mediated response, hypothermia (r = .93 +/- .02). The novel and selective D-3 versus D-2 antagonist, (+/-)-S 11556, attenuated the action of (+)-7-OH-DPAT in each structure. This action was shared by its active (+)-eutomer, (+)-S 14297, whereas its inactive (-)-distomer, (-)-S 17777, was ineffective. (+)-S 14297 similarly attenuated the inhibitory action of CGS 15855A and (-)-quinpirole upon DA synthesis, whereas it failed to modify inhibition of striatal DA synthesis by the alpha(2)-adrenergic receptor agonist, clonidine. As compared with the D-2/D-3, receptor antagonist, haloperidol, neither (+/-)-S 11566 nor (+)-S 14297 modified DA turnover upon administration alone. Furthermore, across (nine) antagonists, potency in facilitating DA synthesis more powerfully correlated to affinity at D-2 (r = .94 +/- .01) than D-3 (r = .73 +/- .01) sites (P < .01). Correlations were also marked to potency for induction of catalepsy (r = .91 +/- .01) and prolactin secretion (r = .89 +/- .01) but not for antagonism of (+)-7-OH-DPAT-induced hypothermia (r = .60 +/- .01). In freely moving rats, (+)-7-OH-DPAT dose-dependently reduced dialysate concentrations of DA in the nucleus accumbens and contralateral striatum: this action was potently mimicked by CGS 15855A, but only weakly so by piribedil. (+)-S 14297 markedly attenuated the action of (+)-7-OH-DPAT, whereas (-)-S 17777 was inactive. In contrast, haloperidol completely blocked the action of (+)-7-OH-DPAT. Finally, in distinction to haloperidol, upon administration alone, (+)-S 14297 did not significantly enhance the release of DA. In conclusion, these data suggest that D-3 (auto)receptors control synthesis and release of DA in dopaminergic pathways innervating the limbic system, cortex and striatum. D-3 (auto)receptors may, however, be ''silent'' under resting conditions, and the blockade of D-2 autoreceptors or the joint blockade of D-2 and D-3 sites may underlie acceleration of DA synthesis and release by antipsychotic drugs.