CONTRIBUTION OF CNS NICOTINE METABOLITES TO THE NEUROPHARMACOLOGICAL EFFECTS OF NICOTINE AND TOBACCO SMOKING

Nicotine, the principal alkaloid in tobacco products, is generally acc epted to be the active pharmacological agent responsible for CNS effec ts resulting from tobacco use. Arguments are presented in this comment ary which take issue with this popular dogma, by providing evidence th at nicotine metabolites may also be responsible for the CNS effects co mmonly attributed to nicotine. CNS effects attributed to nicotine incl ude reinforcing effects,, mood elevation, arousal, locomotor stimulant effects, and learning and memory enhancement. The reinforcing and loc omotor stimulant effects of nicotine have been suggested to be the res ult of activation of CNS dopaminergic systems, and nicotine-induced mo dulation of dopaminergic neurotransmission has been studied in detail. Nicotine acts at a family of nicotinic receptor subtypes composed of multiple subunits; however, the exact composition of the subunits in n ative nicotinic receptors and the functional significance oi the recep tor subtype diversity are currently unknown. This nicotinic subtype di versity increases the complexity of the potential mechanisms oi action oi nicotine and its metabolites. Although peripheral metabolism of ni cotine has been studied extensively, metabolism in the CNS has not bee n investigated to any great extent. Recently, studies from our laborat ory have demonstrated that several nicotine metabolites are present in the CNS after acute nicotine administration. Moreover, nicotine metab olites are pharmacologically active in neurochemical and behavioral as says. Thus, CNS effects resulting from nicotine exposure may not be du e solely to nicotine, bur. may result, at least in parr, ti-om the act ions oi nicotine metabolites. (C) 1997 Elsevier Science Inc.