Nornicotine, a nicotine metabolite and tobacco alkaloid: Desensitization of nicotinic receptor-stimulated dopamine release from rat striatum

Nornicotine, a major tobacco alkaloid and nicotine metabolite, accumulates in rat brain in pharmacologically relevant concentrations following repeated nicotine administration. Nornicotine-evoked striatal dopamine release is Ca²⁺-dependent, stereoselective and sensitive to nicotinic receptor antagonists, indicating nicotinic receptor-mediation. The present study determined if S-(-)-nornicotine desensitizes nicotinic receptors and if cross-desensitization to S-(-)-nicotine occurs. S-(-)-Nicotine (10 and 100 nM) diminished [³H]overflow from [³H]dopamine-preloaded rat striatal slices following subsequent superfusion with 10 μM S-(-)-nicotine (46% and 74%, respectively) or 10 μM S-(-)-nornicotine (59% and 81%, respectively). S-(-)-Nornicotine (1 and 10 μM) diminished the response to subsequent superfusion with 10 μM S-(-)-nornicotine (85% and 97%, respectively) or 10 μM S-(-)-nicotine (82% and 88%, respectively). Thus, similar to S-(-)-nicotine, S-(-)-nornicotine desensitizes nicotinic receptors, but with ∼12-fold lower potency. Cross-desensitization suggests involvement of common nicotinic receptor subtypes. Therefore, S-(-)-nicotine metabolites, such as nornicotine, have neuropharmacologically relevant effects.