Although nicotine produces diverse pharmacological effects in the central nervous system, relatively little is known regarding subtypes of nicotinic receptors responsible for mediating the different actions of nicotine. The broad goal of this proposal is to understand the function of neuronal nicotinic receptors and establish the role of various nicotinic receptors subunits in the pharmacological effects of nicotine in the CNS using both in vivo and in vitro approaches. We propose to continue our structure- activity relationship studies which are providing intriguing results and expand our current series of analogs as well as proceed with several new initiatives. Analogs will be evaluated in several in vivo (antinociception and hypomotility in mice and drug discrimination in rats) and in vitro (3(H)-nicotine and 125I-alpha-BGTX binding) assays for nicotine-like effects. Interesting analogs will be evaluated in frog oocytes expressing different nicotinic receptor subunits to corroborate in vivo and in vitro findings. This approach should provide us with novel compounds with greater selectivity and unique profiles to be used for distinguishing receptor subtypes responsible for mediating the different actions of nicotine. We plan to test the hypothesis that spinal nicotinic receptors differ from those in ganglia and brain by studying the SAR for nicotinic receptor activation after intrathecal (i.t.) and i.c.v. administration. In addition, we will determine the effectiveness of selective nicotinic antagonists to block these agonists after i.t. and i.c.v. administration. Furthermore, we will determine some of the mechanisms underlying desensitization and tolerance using both in vitro and in vivo approaches. A comparison between in vitro receptor desensitization and the 'desensitization' process observed in vivo will be performed. The rate and extent of desensitization associated with different nicotinic agonists on neuronal nicotinic acetylcholine receptor subunit combinations expressed in Xenopus laevis oocytes will be compared with the in vivo """"""""desensitization"""""""" obtained with different nicotinic agonists administered in animals. Finally, we will investigate the importance of intrinsic activity of nicotinic receptors in producing tolerance to the antinociceptive effect after chronic infusion of several nicotinic agonists with a wide spectrum of affinity for [(3)H]-nicotine binding sites. These studies will help to understand the function of neuronal nicotinic receptors and establish the role of various nicotinic receptors subunits in the pharmacological effects of nicotine.
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