The 5-HT(1) receptor agonist GR46611 (3-30 mg/kg s.c.) caused a dose-related decrease in rectal temperature in the adult guinea-pig. A lower dose (20 μg) administered directly into the lateral cerebral ventricle also caused a hypothermic response, suggesting that this effect is centrally mediated. GR46611-induced (10 mg/kg s.c.) hypothermia was not attenuated by WAY100135 (3-10 mg/kg s.c.), ritanserin (0.3-1 mg/kg s.c.), spiperone (0.1-0.3 mg/kg s.c.) and ondansetron (0.1-1 mg/kg s.c.), suggesting that 5-HT(1A), 5-HT(2A), 5-HT( 2C) and 5-HT(3) receptors are unlikely to be involved in this response. In contrast, the poorly selective 5-HT receptor antagonist, metergoline (1-10 mg/kg s.c.), and the potent 5-HT(1D) receptor antagonist, GR127935 (0.1-1 mg/kg p.o.), antagonized the effects of GR46611. The present data suggest that antagonism of GR46611-induced hypothermia may be useful for assessing the potency and duration of action of centrally-acting 5-HT( 1D) receptor antagonists in the guinea-pig.