In analogy to the dopamine D3 receptor agonist, (+)-7-OH-DPAT (7-hydroxy-2-(di-n-propylamino)tetralin) (0.01-0.63 mg/kg s.c.), clozapine dose-dependently (0.63-40.0 mg/kg s.c.) elicited hypothermia in rats. Haloperidol and raclopride, mixed dopamine D2/D3 receptor antagonists, failed, in contrast, to modify core temperature. Further, they dose-dependently inhibited the action of clozapine with inhibitory dose50 values (ID50) of 0.3 mg/kg s.c., in each case. The preferential dopamine D3 versus D2 receptor antagonist, (+)-AJ 76 (cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin) (ID50 = 2.8), and the selective dopamine D3 versus D2 receptor antagonist, (+/-)-S 11566 ((+/-)(-)[7-(N,N-dipropylamino)-5,6,7,8-tetrahydro-naphtho(2,3b) dihydro,2,3-furane]) (ID50 = 1.6) likewise blocked the action of clozapine without reducing core temperature alone. The action of (+/-)-S 11566 was stereospecific in that its active eutomer, (+)-S 14297 (ID50 = 1.0), also inhibited the action of clozapine whereas its inactive distomer, (-)-S 17777 (ID50 > 10.0), was not effective. Antagonist potency for blockade of clozapine-induced hypothermia correlated powerfully both with potency for blockade of (+)-7-OH-DPAT-induced hypothermia (r = 0.98) and with affinity at cloned human dopamine D3 receptors transfected into Chinese hamster ovary (CHO) cells (r = 0.92). In conclusion, these data suggest that dopamine D3 receptors may be involved in the induction of hypothermia by clozapine in the rat.