5‐HT1A agonists increase and 5‐HT3 agonists decrease acetylcholine efflux from the cerebral cortex of freely‐moving guinea‐pigs

Abstract

1 The influence of 5-hydroxytryptamine_1A (5-HT_1A), 5-HT₂ and 5-HT₃ agonists and antagonists on acetylcholine (ACh) release from the cerebral cortex was studied in freely moving guinea-pigs. 2 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.01–1 mg kg⁻¹, s.c.) caused the 5-HT syndrome and dose-dependently increased ACh release. Ru 24969 (1–10 mg kg⁻¹, s.c.) shared the same effects, but it was less potent. (−)-Propranolol (5 mg kg⁻¹) and metitepine (2 mg kg⁻¹) prevented these behavioural and neurochemical responses. 3 (±)-1(4-Iodo-2,5-dimethoxyphenyl)2-aminopropane (DOI) up to 2 mg kg⁻¹ did not modify ACh release and ketanserin (0.5 mg kg⁻¹) was ineffective on 5-HT-induced changes of ACh outflow. 4 2-Methyl-5-HT (500 μg, i.c.v.) and 5-HT (500 μg, i.c.v.) plus metitepine (2 mg kg⁻¹, s.c.) inhibited the gross behaviour and ACh release. ICS 205–930 (0.5 mg kg⁻¹) prevented these responses. 5 2-Methyl-5-HT, up to 10 μmoll⁻¹, and 8-OH-DPAT, up to 0.1 μmoll⁻¹, (like 5-HT) did not change [³H]-choline efflux from cerebral cortex slices. 6 These results suggest that exogenous 5-HT and related selective agonists modulate guinea-pig cortical cholinergic structures through 5-HT_1A and 5-HT₃ receptors. The stimulation of 5-HT_1A autoreceptors may lead to disinhibition of the cholinergic cells, tonically inhibited by the tryptaminergic control. Conversely, the stimulation of 5-HT₃ receptors inhibits ACh release, possibly through an interneurone. No direct 5-HT modulation of the cholinergic nerve endings was found.