The broad goal of Project 2 is to establish roles played by nicotinic acetylcholine receptors (nAChR) in nicotinedependence and its treatment. As part of the integrated program of research proposed as an NCDDG-MD/NA, themore narrow goal of the project is to define profiles for functional interaction with diverse nAChR subtypes that arecritical to drug efficacy in treatment of nicotine dependence. The focus on nAChR subtypes, defined by their differentsubunit compositions, is justified because they play critical, broad, and diverse roles in synaptic and nervous systemfunction and are likley to be involved in nicotine dependence. Bupropion is a model substance for these studies, havingproven clinical efficacy as a smoking cessation aid, but also having activity as a functional nAChR antagonist. Theresearch program's central hypothesis is that agents effective in treatment of nicotine dependence will share withbupropion (and perhaps its metabolites) the ability to act with comparable potencies at multiple molecular targets. It ispostulated that drug interactions at selected nAChR subtypes and with dopamine and/or norepinephrine transportersintegrate to produce a neurochemical outcome that is an effective substitute for nervous system actions of chronicnicotine or tobacco product use. Project 2 will specifically test the hypothesis that potent drug action as an antagonistof the cx4132-nAChR subtype is a feature of drugs with high smoking cessation potential.To test this hypothesis, and to help elucidate sites and mechanisms of action involved, studies will be done to defineinteractions of bupropion, compounds of the 3-phenyltropane series, their analogs, and their possible metabolites withdiverse nAChR subtypes naturally or heterologously expressed by human clonal cell line models.
Specific Aim 1 is toefficiently establish acute functional antagonist potencies of drugs at o_4I_2-nAChR through a high throughput screeningprocess employing isotopic ion flux assays complemented and validated by results from whole cell current recording.
Specific Aim 2 is to provide a more detailed nAChR interaction profile for drugs meeting selection criteria from Aim 1and from the other projects in the research program. These studies will establish, for selected agents, acute effects on0_7-, c_3'- and other nAChR subtypes, effects of longer-term drug treatment on nAChR function, and whether selectedagents act as competitive or non-competitive antagonists. These studies will be repeated to define nAChR subtypeactivity for any new chemical entities developed in the research program.These studies are significant because they will delineate contributions, if any, of nAChR function in actions ofbupropion and other ligands with smoking cessation utility or potential. Definition of nAChR subtype interaction profilescorrelating with or predictive of drug utility in treatment of nicotine dependence also is expected and is anticipated tohave siqnificant druq discovery value. Mechanisms involved in nicotine dependence also will be clarified.
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