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 alpha7 receptors are very responsive to nornicotine (EC50 approximately 17 micromol/L I(max) 50%, compared with acetylcholine (ACh)). nAChRs containing the ligand-binding domain of the alpha6 subunits (in the form of an alpha6/alpha3 chimera) are also strongly responsive to nornicotine (EC50 approximately 4 micromol/L I(max) 50%, compared with ACh). Alpha7-type nAChRs have been suggested to be potential therapeutic targets for Alzheimer's disease, schizophrenia and possibly other pathologies. nAChRs containing alpha6 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.
Papke
Roger L
RL
Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, Florida 32610, USA. rlpapke@ufl.edu
Dwoskin
Linda P
LP
Crooks
Peter A
PA
D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D009538:Nicotine / Q000031:analogs & derivatives / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009865:Oocytes; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014029:Tobacco Use Disorder / Q000378:metabolism* / Q000503:physiopathology; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D011993:Recombinant Fusion Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; C104518:nicotinic receptor alpha6; D009538:Nicotine; C005311:nornicotine; D000109:Acetylcholine