Genetic influences on the use of tobacco products in humans and on the acute response in animals to a challenge dose of nicotine have been well documented. Similarly, genetic factors seem to influence the development of tolerance to nicotine. The intent of the proposed studies is to explore the hypothesis that differences in the number of brain nicotinic receptors, measured by the binding of L-(3H)nicotine and Alpha-(125I)bungarotoxin, underlie these genetically determined differences in response to nicotine. Several laboratories have been studying the brain (3H)nicotine binding site and some investigators suggest that this site is noncholinergic. Experiments are designed in this proposal that should resolve whether the (3H)nicotine binding site is or is not cholinergic. Previous studies in our laboratory have demonstrated that nicotine-induced seizures may be regulated in the mouse by a single gene that also regulates the number of hippocampal nicotinic receptors. Studies are proposed that should increase our understanding of this relationship. We have also demonstrated that chronic nicotine treatment results in a dose- and time-dependent increase in the number of brain nicotinic receptors. This increase parallels the development of tolerance to nicotine. Experiments to explore more fully the relationship between the increase in receptor numbers and tolerance development are planned. These studies will include autoradiographic analyses that should allow a determination as to whether all, or only some, of the nicotinic receptors increase following chronic nicotine treatment. Only some of the acute sensitivity differences and tolerance can be explained by differences in receptor number. Therefore, studies of nicotine-induced ion flux and densitization of the receptor are included. In order to carry out the desensitization studies, an enrichment of the brain nicotinic receptors must be achieved. Lastly, studies designed to measure the nicotine withdrawal syndrome in the mouse are described. Taken together these experiments may prove to be valuable in understanding the genetic regulation of acute sensitivity to nicotine, tolerance to nicotine, and the underlying neurochemical processes that control these behaviors. Such knowledge can be instrumental in designing rational therapies that would aid smokers in terminating tobacco use.
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