EVIDENCE FOR POSTSYNAPTIC MEDIATION OF THE HYPOTHERMIC EFFECT OF 5-HT1A RECEPTOR ACTIVATION

1 The 5-HT1A ligand BMY 7378 (8-[2[4-(2-methoxyphenyl)-l-piperazinyl]ethyl]8-azaspirol [4,5]-decane-7,9-dione dihydrochloride, 0.032-2 mg kg-1, s.c.) caused hyperphagia, a response to the activation of presynaptic 5-HT1A receptors. 2 BMY 7378 (8 mg kg-1, s.c.) and the 5-HT1A agonist (8-hydroxy-2-(di-n-propylamino) tetralin(8-OH-DPAT), 0.10 and 0.25 mg kg-1 s.c.) also caused hypothermia. This was inhibited by (-)-pindolol (1 mg kg-1, i.p.) and not prevented by pretreatments with p-chlorophenylalanine which grossly depleted 5-hydroxytryptamine (5-HT) from terminal regions. The hypothermic effects are explicable by activation of postsynaptic 5-HT1A receptors. Infusion of BMY 7378 (8-64-mu-g) into the dorsal raphe was without convincing hypothermic effect. 3 BMY 7378 (8 mg kg-1, s.c.) inhibited another effect of activation of postsynaptic 5-HT1A receptors, i.e., the induction of components of the 5-HT syndrome by 8-OH-DPAT (0. 5, 1.0 mg kg-1, s.c.) which suggests that BMY 7378 has antagonistic as well as agonistic effects at these sites. 4 Partial agonist properties of BMY 7378 at postsynaptic sites were also indicated by doses for hypothermia being much greater than those for hyperphagia i.e., ED50 (hypothermia) > 2 mg kg-1, ED50 (hyperphagia) = 0.010 mg kg-1. This contrasts with the similar ED50 values for both the hypothermic (ED50=0.08-0.10 mg kg-1) and hyperphagic (ED50=0.06-0.10 mg kg-1) effects of 8-OH-DPAT. 5 The evidence obtained for mediation of the hypothermic response to 5-HT1A agonists by postsynaptic sites is relevant to the interpretation of the effects on it of antidepressant treatments and depressive illness.