FUNCTIONAL CORRELATES OF DOPAMINE D-3 RECEPTOR ACTIVATION IN THE RAT IN-VIVO AND THEIR MODULATION BY THE SELECTIVE ANTAGONIST, (-S-14297 .1. ACTIVATION OF POSTSYNAPTIC D-3, RECEPTORS MEDIATES HYPOTHERMIA, WHEREAS BLOCKADE OF D-2 RECEPTORS ELICITS PROLACTIN SECRETION AND CATALEPSY())

Using [I-125]-iodosulpride as a radioligand, the novel naphthofurane, (+/-)-S 11566 6,7,8-tetrahydro-naphtho(2,3b)dihydro,2,3-furane]} showe d a marked preference for human, recombinant D-3 as compared with D-2 receptors stably transfected into Chinese hamster ovary cells (K(i)s = 24/529 nM). This activity resided in its (+)-eutomer, (+)-S 14297 (13 /297 nM) as compared with its (-)-distomer, (-)-S 17777 (406/3544 nM). In contrast, (+)-AJ 76 manifested only a mild 2-fold preference for D -3 sites (70/154 nM), whereas haloperidol and six additional antagonis ts showed a mild (2-7-fold) preference for D-2 sites. As concerns agon ists, (+)-7-OH-DPAT, (+/-)-CGS 15855A, quinerolane, (-)-quinpirole and N-0434 displayed a preference (6-40-fold) for D-3 receptors, whereas piribedil showed a slight, 2-fold, preference for D-2 sites (243/126 n M). (+)-S 14297 showed low (> 1.0 mu M) affinity at rat D-1 and D-2 si tes and at cloned, human D-4 and D-5 receptors and only low affinity ( 145 to > 10,000 nM) at all other sites examined. In vivo, administered s.c., (+)-7-OH-DPAT, CGS 15855A, quinelorane, (-)-quinpirole and N-04 34 potently evoked hypothermia. Across all (8) agonists tested, potenc y correlated significantly with affinity at D-3 sites (r = .84, P < .0 01) but not D-2 sites (r = .50, P > .05). (+)-S 14297 (0.16-1.25 mg/kg , s.c.) blocked the induction of hypothermia by (+)-7-OH-DPAT, CGS 158 55A and (-)-quinpirole, but not by the alpha(2)-adrenergic agonist, cl onidine, without influencing core temperature alone. In contrast, (-)- S 17777 (10.0 mg/kg, s.c.) was only partially active. Across all (9) a ntagonists, potency for inhibition of (+)-7-OH-DPAT-induced hypothermi a correlated more strongly with affinity at D-3 (r = .96, P < .001) th an D-2 (r = .75, P < .02) sites. Whereas haloperidol and the other ant agonists provoked prolactin secretion and elicited catalepsy, (+)-S 14 297 and (+/-)-S 11566 at doses of up to 10.0 and 40.0 mg/kg, s.c., res pectively, were not significantly effective (P > .05). Across all anta gonists, potency for eliciting prolactin secretion and catalepsy corre lated better with affinity at D-2 (r = .95 and .96) than D-3 (r = .76 and .91) sites. In conclusion, these data demonstrate that the novel n aphtofurane, (+)-S 14297, is a selective ligand (antagonist) at dopami ne D-3 receptors and suggest that their activation mediates hypothermi a in the rat. in distinction, (+)-S 14297 elicits neither prolactin se cretion nor catalepsy, actions that appear to reflect blockade of dopa mine D-2 receptors.