5‐Hydroxytryptamine‐mediated effects of nicotine on endogenous GABA efflux from guinea‐pig cortical slices

Abstract
1 The effect of nicotine on endogenous basal GABA outflow was studied in guinea-pig cerebral cortex slices. 2 Nicotine 1.86-18.6 μmol 1−1 significantly decreased the basal, tetrodotoxin-sensitive GABA efflux, whereas at higher concentrations (186–620 μmol 1−1) nicotine increased it. The inhibition was prevented by mecamylamine while the facilitation was blocked by mecamylamine, (+)-tubocurarine and tetrodotoxin. 3 The effect of nicotine was due to an indirect 5-hydroxytryptaminergic action. In fact, MDL 72222 (1 μmol 1−1) completely prevented the alkaloid inhibition and methysergide (1 μmol 11) reversed the facilitation into inhibition; concomitant treatment with methysergide and MDL 72222 antagonized the effect of nicotine at 186 μmol 1−1 4 Lower concentrations of 5-HT (3–10 μmol 1−1) decreased, whereas higher concentrations (30–100 μmol 1−1) increased, spontaneous GABA outflow. The inhibition of GABA efflux was prevented by MDL 72222 whereas the facilitation was reversed by methysergide (1 μmol 1−1) into inhibition, and prevented by MDL 72222 1 μmol 1−11. 5 These results suggest that, by activating nicotinic receptors present on 5-hydroxytryptaminergic terminals, nicotine releases 5-HT which, in turn, inhibits or increases the secretory activity of cortical GABA interneurones via 5-HT3 and methysergide-sensitive receptors, respectively.