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 microM S-(-)-nicotine (46% and 74%, respectively) or 10 microM S-(-)-nornicotine (59% and 81%, respectively). S-(-)-Nornicotine (1 and 10 microM) diminished the response to subsequent superfusion with 10 microM S-(-)-nornicotine (85% and 97%, respectively) or 10 microM S-(-)-nicotine (82% and 88%, respectively). Thus, similar to S-(-)-nicotine, S-(-)-nornicotine desensitizes nicotinic receptors. but with approximately 12-fold lower potency. Cross-desensitization suggests involvement of common nicotinic receptor subtypes. Therefore, S-(-)-nicotine metabolites, such as nornicotine, have neuropharmacologically relevant effects.
Dwoskin
L P
LP
College of Pharmacy and Graduate Center for Toxicology, University of Kentucky, Lexington 40536-0082, USA. LDWOSKIN@POP.UKY.EDU
Teng
L H
LH
Crooks
P A
PA
D000818:Animals; D002021:Buffers; D004298:Dopamine / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism; D014026:Nicotiana / Q000737:chemistry
D002021:Buffers; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D009538:Nicotine; C005311:nornicotine; D004298:Dopamine