Nicotinic-receptor mediation of S(-)nornicotine-evoked [³H]overflow from rat striatal slices preloaded with [³H]dopamine

Previous results from our laboratory demonstrated that S(-)nornicotine, a major tobacco alkaloid and an active nicotine metabolite present in the CNS, increases dopamine release from rat striatal slices in a concentration- dependent and calcium-dependent manner. The present study determined if S(- )nornicotine-evoked dopamine release was the result of nicotinic receptor stimulation. Stereoselectivity and the ability of classical noncompetitive and competitive nicotinic receptor antagonists (mecamylamine (MEC) and dihydro-β-erythroidine (DHβE), respectively) to inhibit S(-)nornicotine- evoked [³H]overflow from [³H]dopamine-preloaded rat striatal slices were investigated. Nornicotine increased [³H]overflow n a stereoselective manner at concentrations from 1 to 100 μM. MEC (0.01-100 μM) or DHβE (0.01-10 μM) alone did not evoke [³H]overflow. However, 100 μM DHβE evoked [³H]overflow, and therefore, was not used in experiments investigating antagonism of S(-)nornicotine's effect. MEC and DHβE inhibited S(- )nicotine- (10 μM) evoked [³H]overflow in a concentration-dependent manner. Concentrations of MEC (100 μM) and DHβE (10 μM) which maximally inhibited S(-)nicotine's effect were chosen for subsequent experiments determining inhibition of the effect of S(-)nornicotine (0.1 μM-3 mM). MEC and DHβE significantly inhibited the effect of low concentrations (<100 βM) of S(- )nornicotine; however, higher concentrations (>100 μM) of S(-)nornicotine were not inhibited by either nicotinic antagonist. Taken together, the results suggest that low concentrations of S(-)nornicotine stimulate nicotinic receptors to evoke the release of dopamine from dopaminergic presynaptic terminals. Thus, nornicotine, which acts as an agonist at neuronal nicotinic receptors, may contribute to the neuropharmacological effects of nicotine and tobacco use.