Nicotine produces diverse pharmacological effects after acute administration, and we have shown recently that profound dependence occurs after repetitive exposure. Pharmacological evidence, coupled with molecular biology, has revealed multiple neuronal nicotinic receptor subtypes in brain, and the definitive functional role for these receptor subtypes is slowing emerging. In order to continue establishing the functional role of these receptor subtypes, we will continue to pursue our structure-activity relationship studies that are providing intriguing leads for developing more receptor selective agonists and antagonists. Moreover, these probes are providing a means for assessing structural requirements for activation of the receptor. Analogs will be evaluate for receptor selectivity and efficacy using receptor binding, a battery of in vivo pharmacological effects, and in vitro functional assays. The synthetic analogs that we will be examining have sufficient structural diversity to allow redefinition of the pharmacophore for nicotine receptors. In addition to understanding nicotine's acute actions, we propose to investigate the mechanism by which nicotine produces dependence. We recently developed a dependence model using chronic nicotine infusion in mice. This model will allow us to determine which receptor subtypes are involved in dependence. These studies will consist of substituting receptor selective agonists for nicotine as well as participating withdrawal with receptor selective antagonists. Chronic infusion in nicotine in receptor knock-out mice will confirm the involvement of specific receptor subtypes in nicotine dependence. Moreover, we propose to distinguish between the contributions of peripheral and central nicotine receptors in the development of dependence. Finally, our observations that bupropion has both nicotine agonist and antagonist properties represents an important lead for further exploration of the mechanisms underlying the pharmacological effects of nicotine and the development of dependence. To further investigate the antagonistic effect of bupropion, a number of bupropion analogs as well as its metabolites will be evaluated for antagonism of nicotine effects. Finally, bupropion will be evaluated in mice chronically infused with nicotine to determine whether it alleviates or exacerbates withdrawal.
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