Involvement of GABA systems in acetylcholine release induced by 5-HT3 receptor blockade in slices from rat entorhinal cortex

The aim of the present study was to examine the role of 5-HT3 receptors in spontaneous and K+-evoked acetylcholine (ACh) release from rat entorhinal cortex and striatal slices. The 5-HT3 receptor antagonists ondansetron and granisetron (0.01-10 mu M) produced a concentration-dependent increase in both spontaneous and K+-evoked [H-3]ACh release in the two brain regions studied. The release of ACh was Ca2+-dependent and tetrodotoxin-sensitive. 5-HT3 receptor agonists, such as 2-methyl-5-HT and 1-phenylbiguanide, at concentrations up to 1 mu M, did not show any intrinsic effect on [H-3]ACh release in both rat brain regions. However, 2-methyl-5-HT, 1 mu M, fully blocked the ondansetron-induced enhancement in both basal and K+-evoked ACh release, suggesting that 5-HT, through 5-HT3 receptor activation, tonically inhibits ACh release. The possible implication of interposed inhibitory systems in ACh release after 5-HT3 receptor blockade was subsequently analyzed. While the effect of ondansetron was not modified by haloperidol or naloxone, the GABA(A) receptor antagonist bicuculline produced a marked potentiation of ACh release in the entorhinal cortex but not in the striatum. The results suggest that in this cortical area 5-HT activates 5-HT3 receptors located on GABAergic neurons which in turn inhibit cholinergic function.