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 repeate d nicotine administration. Nornicotine-evoked striatal dopamine release is Ca2+-dependent. stereoselective and sensitive to nicotinic receptor antagon ists, indicating nicotinic receptor-mediation. The present study determined if S-(-)-nornicotine desensitizes nicotinic receptors and if cross-de sens itization to S-( -)-nicotine occurs. S-( -)-Nicotine (10 and 100 nM) dimini shed [H-3]overflow from [H-3]dopamine-preloaded rat striatal slices followi ng subsequent superfusion with 10 muM S-(-)-nicotine (46% and 74%, respecti vely) or 10 muM S-(-)-nornicotine (59% and 81%, respectively). S-(-)-Nornic otine (1 and 10 muM) diminished the response to subsequent superfusion with 10 muM S-(-)-nornicotine (85% and 97%, respectively) or 10 muM S-(-)-nicot ine (82% and 88%, respectively). Thus, similar to S-(-)-nicotine, S-(-)-nor nicotine desensitizes nicotinic receptors, but with similar to 12-fold lowe r potency. Cross-desensitization suggests involvement of common nicotinic r eceptor subtypes. Therefore, S-(-)-nicotine metabolites, such as nornicotin e, have neuropharmacologically relevant effects. (C) 2001 Elsevier Science B.V. All rights reserved.