EPIBATIDINE - A NICOTINIC ACETYLCHOLINE-RECEPTOR AGONIST RELEASES MONOAMINERGIC NEUROTRANSMITTERS - IN-VITRO AND IN-VIVO EVIDENCE IN RATS

The effect of the neuronal acetylcholine-gated ion channel receptor ag onist (+/-)-epibatidine was studied on neurotransmitter release in vit ro and motor behavior in vivo. (+/-)-Epibatidine (3-300 nM) caused a c oncentration- and calcium-dependent release of [H-3]-dopamine from str iatal slices and [H-3]-norepinephrine release from hippocampal and tha lamic slices. (+/-)-Epibatidine-induced neurotransmitter release was i nhibited in all three regions by mecamylamine (3 mu M). In contrast, D -tubocurarine (10-100 mu M) inhibited only (+/-)-epibatidine-induced [ H-3]-norepinephrine release from the hippocampus and the thalamus. Con versely, dihydro beta-erythroidine (3-100 mu M) inhibited (+/-)-epibat idine-induced [H-3]-dopamine release in the striatum without significa ntly altering [H-3]-norepinephrine release from either the hippocampus or the thalamus. This is consistent with the observation that differe nt nAChRs modulate dopamine release as compared with norepinephrine re lease. The effect of (+/-)-epibatidine on both [H-3]-dopamine and [H-3 ]-norepinephrine release was tetrodotoxin-sensitive, suggesting the in volvement of sodium channels. (+/-)-Epibalidine (1-3 mu g/kg s.c.) pro duced ipsilateral turning in the unilaterally [6(OH)-DA]-lesioned rat. This effect was mimicked by (-)-nicotine (0.35 mg/kg s.c.). Both (+/- )-epibatidine- and (-)-nicotine-induced turning were significantly inh ibited by mecamylamine (3 mg/kg s.c.), indicating that the turning res ponse was mediated by nAChRs. (+/-)-Epibatidine also increased locomot or activity in a dose-dependent manner, (+/-)-Epibatidine-induced hype ractivity was blocked by D1 and D2 receptor antagonists, SCM 23390 and eticlopride, respectively, suggesting that both dopamine receptor sub types might be required for the locomotor effect of (+/-)-epibatidine. These results demonstrate that (+/-)-epibatidine displays nAChR agoni st activity in the rat CNS and that certain effects are mediated via n AChR-stimulated catecholamine release and subsequent activation of cor responding receptors.