Differential interaction between 5-HT3 receptors and GABAergic neurons inhibiting acetylcholine release in rat entorhinal cortex slices

The 5-HT3 receptor antagonists, ondansetron, MDL 72222 and granisetron (0.01-1 microM), produced a concentration-dependent increase of K+-evoked [3H]ACh efflux in slices from rat entorhinal cortex preloaded with [3H]choline. Bicuculline and flumazenil, antagonists at different sites of the GABAA receptor, also enhanced [3H]ACh efflux. While the ACh releasing effect of ondansetron was markedly potentiated, in a TTX-sensitive manner, by bicuculline, the effects of MDL 72222 and granisetron were not significantly modified. A qualitatively identical interaction was found by using flumazenil, a GABAA antagonist at the benzodiazepine recognition site, in combination with the 5-HT3 receptor antagonists. The potentiation by the GABAA antagonists of [3H]ACh efflux was also observed in a superfusion medium deficient in Cl-. The nonspecific K+-channel blockers TEA and Ba2+ also increased K+-evoked [3H]ACh efflux in this preparation but the releasing effect was not modified by bicuculline. The results support the functional interaction of ondansetron with GABAergic interneurons in the rat entorhinal cortex, GABA-independent mechanisms may however be involved in the regulation of cortical cholinergic function by other 5-HT3 receptor antagonists.