Nicotine-evoked [H-3]5-hydroxytryptamine release from rat striatal synaptosomes

The aim of this study was to characterize the pharmacology of presynaptic n icotinic cholinoceptors (nAChRs) that modulate release of 5-hydroxytryptami ne (5-HT) from superfused rat Grain synaptosomes preloaded with [H-3]5-KT. Nicotine increased 5-HT release from striatal synaptosomes (maximally by 15 -30%) but not from cerebral cortex or hippocampal synaptosomes. Release of striatal 5-HT was increased in a concentration-dependent manner by nicotine , epibatidine, cytisine, and ACh (with added esterase inhibitor and muscari nic antagonist). Respective EC50 values were: 0.5, 0.003, 0.1 and 0.7 mu M. The maximal effect of each agonist was virtually completely blocked by a h igh concentration of the insurmountable nicotinic antagonist mecamylamine; at a higher concentration of epibatidine (3 mu M), a mecamylamine-insensiti ve effect was revealed. Nicotine, ACh and epibatidine appeared equally effi cacious, whereas cytisine was of lower efficacy (60-70% of ACh). Release ev oked by a half-maximal concentration of nicotine was inhibited by the nicot inic antagonists dihydro-beta-erythroidine (IC50 0.04 mu M) and methyllycac onitine (IC50 0.06 mu M). Nicotine-evoked 5-HT release was not reduced by t etrodotoxin given in a concentration that blocked veratridine-evoked releas e. These findings provide functional evidence for a direct action of nicoti ne on 5-HT neurons in the brain. The presynaptic nAChRs that modulate stria tal 5-HT release appear to possess a novel pharmacological profile. (C) 200 0 Elsevier Science Ltd. All rights reserved.