期刊
JOURNAL OF NEUROCHEMISTRY
卷 101, 期 1, 页码 160-167出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2006.04355.x
关键词
dopamine release; nicotine metabolism; voltage clamp; Xenopus oocytes
资金
- NIDA NIH HHS [DA 017548, DA 05274] Funding Source: Medline
- NIGMS NIH HHS [GM57481-01A2] Funding Source: Medline
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 alpha 7 receptors are very responsive to nornicotine (EC50 approximate to 17 mu mol/LImax 50%, compared with acetylcholine (ACh)). nAChRs containing the ligand-binding domain of the alpha 6 subunits (in the form of an alpha 6/alpha 3 chimera) are also strongly responsive to nornicotine (EC50 approximate to 4 mu mol/L I-max 50%, compared with ACh). alpha 7-type nAChRs have been suggested to be potential therapeutic targets for Alzheimer's disease, schizophrenia and possibly other pathologies. nAChRs containing alpha 6 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.
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