Serotonergic modulation of acetylcholine release from cortex of freely moving rats

The modulation of acetylcholine (ACh) release by 5-HT₃ receptor activation was studied using in vivo microdialysis. Spontaneous and K⁺- stimulated ACh release were measured in frontoparietal cortex and hippocampus of freely moving rats. Two consecutive exposures to high K⁺ produced ACh release of similar magnitude. In the cortex, serotonin (5-HT) failed to alter spontaneous ACh release, but caused a concentration-dependent decrease of K⁺-evoked ACh release. Phenylbiguanide (PBG) and m-chlorophenylbiguanide, two selective 5-HT₃ agonists, mimicked the 5-HT responses, but 8-hydroxy-2- (di-n-propylamino)tetralin, a selective 5-HT(1A) agonist, was without effect. However, PBG failed to modify K⁺-evoked ACh release from the hippocampus. Systemic and local administration of a highly selective 5-HT₃ antagonist, tropisetron ((3-α-tropanyl)1H-indole-carboxylic acid ester) blocked the effect of both 5-HT and PBG. The inhibition of ACh release by PBG was sensitive to tetrodotoxin. These observations provide direct evidence that, in rat cortex, 5-HT modulates in-vivo release of ACh through activation of 5- HT₃ receptors.