Evidence for postsynaptic mediation of the hypothermic effect of 5‐HT1A receptor activation

Abstract

1 The 5-HT_1A ligand BMY 7378 (8-[2[4-(2-methoxyphenyl)-1-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-HT_1A receptors. 2 BMY 7378 (8 mg kg⁻¹, s.c.) and the 5-HT_1A 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-HT_1A receptors. Infusion of BMY 7378 (8–64 μg) 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-HT_1A 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-HT_1A agonists by postsynaptic sites is relevant to the interpretation of the effects on it of antidepressant treatments and depressive illness.