5-HT₃ receptors mediate inhibition of acetylcholine release in cortical tissue

THE release of cerebral acetylcholine from terminals in the cerebral cortex has been shown to be regulated by 5-hydroxytryptamine (5-HT)^1-6 but it is not known which subtype of the 5-HT receptor is involved. 5-HT receptor agonists increase acetylcholine levels in vivo^{l, 2} indicating a reduced turnover, and reduce release of acetylcholine from striatal slices in vitro^3-5. Depleting 5-HT by inhibiting synthesis or by destroying the neurons containing 5-HT potentiates acetylcholine release⁵, and increases acetylcholine turnover in the cerebral cortex and hippocampus⁶. Selective antagonists for the 5-HT₃ receptor subtypes which seem to have effects on mood and activity^7-10 may exert their effect through the regulation of acetylcholine release in the cortex and limbic system. Radioligand binding studies show a high density of 5-HT₃ receptors in the cholinergic-rich entorhinal cortex^{11, 12} and we provide evidence that a reduction in cortical cholinergic function can be effected in vitro by 5-HT₃ receptors.