Contribution of CNS nicotine metabolites to the neuropharmacological effects of nicotine and tobacco smoking

Peter A. Crooks, Linda P. Dwoskin

Research output: Contribution to journalComment/debate

110 Scopus citations


Nicotine, the principal alkaloid in tobacco products, is generally accepted to be the active pharmacological agent responsible for CNS effects resulting from tobacco use. Arguments are presented in this commentary which take issue with this popular dogma, by providing evidence that nicotine metabolites may also be responsible for the CNS effects commonly attributed to nicotine. CNS effects attributed to nicotine include reinforcing effects, mood elevation, arousal, locomotor stimulant effects, and learning and memory enhancement. The reinforcing and locomotor stimulant effects of nicotine have been suggested to be the result of activation of CNS dopaminergic systems, and nicotine-induced modulation 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 native nicotinic receptors and the functional significance of the receptor subtype diversity are currently unknown. This nicotinic subtype diversity increases the complexity of the potential mechanisms of action of nicotine and its metabolites. Although peripheral metabolism of nicotine has been studied extensively, metabolism in the CNS has not been investigated to any great extent. Recently, studies from our laboratory have demonstrated that several nicotine metabolites are present in the CNS after acute nicotine administration. Moreover, nicotine metabolites are pharmacologically active in neurochemical and behavioral assays. Thus, CNS effects resulting from nicotine exposure may not be due solely to nicotine, but may result, at least in part, from the actions of nicotine metabolites.

Original languageEnglish
Pages (from-to)743-753
Number of pages11
JournalBiochemical Pharmacology
Issue number7
StatePublished - Oct 1 1997

Bibliographical note

Funding Information:
The work of the authors discussedi n this commentary was supported by a grant from the Tobaccoa nd Health ReseurchIn stitute,L exington, KY. The authors would also like to thank Dr. .John Lit&ton for his insightfucl ommentsre garding this commentary.


  • Behavioral and neurochemical assays
  • CNS metabolism
  • Cotinine
  • Dopamine
  • Nicotine
  • Nicotinic receptor
  • Norcotinine
  • Nornicotine

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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