MOLECULAR PHARMACOLOGY AND PHYSIOLOGY OF NICOTINE

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DESCRIPTION: (Applicant's Abstract) The long term objective of this research is to understand the molecular basis of nicotine addiction, associated with the usage of tobacco. Nicotinic acetylcholine receptors (nAChRs) are ligand gated ion channels that are the primary central target of nicotine. A diverse family of nAChRs is expressed in the central nervous system, where their pharmacology and physiological roles are only partially understood. The availability of recombinant neuronal nAChRs subunits now makes it possible to characterize the interaction of nicotine and acetylcholine with specific nicotinic receptor subtypes. Nicotine has a dual agonist-antagonist action because it can desensitize its receptor. Preliminary data show that central nAChRs receptor subunits vary dramatically in their desensitization properties and pharmacology. In this project we will characterize the pharmacology and physiology of five recombinant nAChRs expressed in Xenopus oocytes. Receptors will be functionally characterized using whole cell voltage clamp and single channel patch clamp techniques. Special attention will be given to the antagonist mecamylamine (MECA), which facilitates smoking abstinence in nicotine patch therapy. The specific aims of this project are: (i) to define the pharmacological profiles of the specific recombinant receptors, (ii) to determine the potency of nicotine as an agonist, during prolonged drug application, (iii) to characterize the role of subunits in desensitization by acetylcholine and nicotine, and (iv) to characterize the physiological interaction of acetylcholine, nicotine and mecamylamine. These experiments will establish a molecular basis for the pharmacology and physiology of specific neuronal nAChRs. The role of individual subunits in determining the dual pharmaco-logical action of nicotine will be defined. The results will be important for understanding both the development of tobacco dependence during smoking, as well as its reversion during smoking cessation therapy.