The pharmacological activity of nicotine and nornicotine on nAChRs subtypes: Relevance to nicotine dependence and drug discovery

Cigarette smoking and other forms of tobacco use deliver an array of pharmacologically active alkaloids, including nicotine and ultimately various metabolites of these substances. While nornicotine is a significant component in tobacco as well as a minor systemic metabolite of nicotine, nornicotine appears to be N-demethylated locally in the brain where it accumulates at relatively high levels after chronic nicotine administration. We have now examined the effects of nornicotine on specific combinations of neuronal nicotinic acetylcholine receptor (nAChR) subunits expressed in Xenopus oocytes and compared these responses to those evoked by acetylcholine and nicotine. Of the nAChR subtypes studied, we have found that α7 receptors are very responsive to nornicotine (EC₅₀ ≈ 17 μmol/LI_max 50%, compared with acetylcholine (ACh)). nAChRs containing the ligand-binding domain of the α6 subunits (in the form of an α6/α3 chimera) are also strongly responsive to nornicotine (EC₅₀≈ 4 μmol/L I _max 50%, compared with ACh). α7-type nAChRs have been suggested to be potential therapeutic targets for Alzheimer's disease, schizophrenia and possibly other pathologies. nAChRs containing α6 subunits have been suggested to have a role in nicotine-evoked dopamine release. Thus, understanding the actions of nornicotine in the brain may have significance for both emerging therapeutics and the management of nicotine dependence.