The long-term goal of this project is to establish whether and how chronic nicotine exposure alters nervous system function. The project is based on the central hypothesis that extended exposure to nicotine induces long-lasting changes in numbers and function of diverse nicotinic acetylcholine receptor (nAChR) subtypes. These effects have potential relevance for nicotine dependence, use of tobacco products, tobacco-related diseases, treatments to prevent, limit or cease tobacco use, and therapies for neurological and psychiatric disorders. Preliminary findings suggest our hypothesis that chronic nicotine exposure causes both (i) a persistent inactivation of nAChR function and (ii) an increase in numbers of nAChR via two causally- and mechanistically-distinct, posttranslational processes. Dose- and time-dependence of nicotine's effects are postulated to be nAChR subtype-specific, as are pharmacological profiles for other drugs acting to alter nAChR numbers and function. One principal aim of this multi-layered project is to establish effects of exposure to nicotine or related substances on function of diverse, human nAChR subtypes. The other principal aim is to determine effects of those agents on numbers of nAChR. For both aims, studies will involve alpha1 beta1 gamma delta- (muscle-type), (alpha3 alpha5 beta4- (autonomic), alpha4 beta2-(brain nicotine-binding), and alpha7- (autonomic or brain neurotoxin-binding) nAChR expressed naturally and/or heterologously by model cell lines. Time (onset of effects and recovery)- and dose-dependent effects of cell treatment with nicotine will be established. Time and dose profiles will also be obtained using other drugs alone or in combination with nicotine to assess whether they mimic or block nicotine's effects, nAChR functional activity will be quantified by electrophysiological recording and ion flux assays. Radioligand binding and immuno- assays will be used to quantitate nAChR and to assess their subcellular distribution and metabolism. Chemical reactivity of nAChR and mutational studies will be among those used to establish mechanisms involved in effects of nicotine and other drugs. These studies are significant because they will provide new perspectives on sites and mechanisms of chronic nicotine action in the modulation of nervous system function. Insights will also be provided into molecular bases of nicotine dependence. Specific nAChR subtypes that are affected most powerfully by chronic nicotine exposure will be identified. Insights will also be provided into the kinds of drugs that block or mimic nicotine's actions. Collectively, this knowledge will benefit development of strategies to treat mood, cognitive, and other nervous system disorders.
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