Functional correlates of dopamine D3 receptor activation in the rat in vivo and their modulation by the selective antagonist, (+)-S 14297: II. Both D2 and "silent" D3 autoreceptors control synthesis and release in mesolimbic, mesocortical and nigrostriatal pathways.

The preferential dopamine (DA) D3 versus D2 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 D3 agonists: CGS 15855A, (-)-quinpirole, quinelorane and N-0434. In contrast, piribedil, which displays a mild preference for D2 sites, was less active. Across eight agonists, potency for inhibition of DA synthesis correlated more potently to affinity at D3 (r = .82 +/- .04) than D2 receptors (r = .60 +/- .06, P < .05). Correlations were also marked to potency for induction of a further D3-mediated response, hypothermia (r = .93 +/- .02). The novel and selective D3 versus D2 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 D2/D3 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 D2 (r = .94 +/- .01) than D3 (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 D3 (auto)receptors control synthesis and release of DA in dopaminergic pathways innervating the limbic system, cortex and striatum.(ABSTRACT TRUNCATED AT 400 WORDS)