8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents

Studies using selective drugs and knockout mice have demonstrated that the 5-HT7 receptor plays an instrumental role in serotonin-induced hypothermia. There is also evidence supporting an involvement of the 5-HT1A receptor, although mainly from studies using 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A/7 receptor agonist. Here we studied the effects of 8-OH-DPAT and selective antagonists for the 5-HT1A and 5-HT7 receptors on body temperature in rats, wild-type (5-HT7+/+) mice and knockout (5-HT7-/-) mice. At lower doses (0.3-0.6 mg/kg, i.p.), 8-OH-DPAT decreased body temperature in 5-HT7+/+ mice but not in 5-HT7-/- mice. At a higher dose (I mg/kg, i.p.) 8-OH-DPAT induced hypothermia in both 5-HT7-/- and 5-HT7+/+ mice. The 5-HT1A receptor antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide (WAY-100135) (10 mg/kg, i.p.) inhibited the effect of 8-OH-DPAT at all doses in rats and mice. In 5-HT7+/+ mice the selective 5-HT7 receptor antagonist (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-l-sulfonyl)phenol (SB-269970) (10 mg/kg, i.p.) fully inhibited the hypothermia induced by 0.3 mg/kg 8-OH-DPAT, but not that of higher doses. In rats, SB-269970 caused a 60% inhibition of the hypothermia induced by 0.3 mg/kg 8-OH-DPAT. Thus, both 5-HT7 and 5-HT1A receptors are involved in a complex manner in thermoregulation, with the 5-HT7 receptor being more important at lower, possibly more physiological, concentrations. (C) 2004 Elsevier B.V. All rights reserved.