Subunit-specific Regulation/Neuronal Nicotinic Receptors

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DESCRIPTION (provided by applicant): Nicotine addiction must develop as a down-stream consequence of the interaction of nicotine with its receptors. Thus, knowledge of how this initial molecular step produces long-term changes in CNS function will be critical to understanding how drug abuse behavior develops. With respect to nicotine-induced molecular changes our previous research has shown that in heterologous expression systems nicotine causes an apparent increase in the number of nicotinic acetylcholne receptors (nAChRs) on the plasma membrane through a specific interaction with high affinity desensitized confirmations of the receptor. We now want to extend these studies to native nAChRs in the CNS in the context of a synaptic network. Because nicotine is present in the CSF of tobacco users a t c oncentrations t hat primarily desensitize n AChRs, our observations Iead t o t he general hypothesis that: Desensitization of nAChRs is the primary mechanism through which chronic nicotine modifies synaptic function. We will explore this hypothesis by examining how nicotine-induced desensitization of alpha7* and alpha4beta2* nAChRs regulates both nAChR function and synaptic transmission in the hippocampus. There are three aims: Specific Aim 1: Examine the regulation of synaptic transmission via the endogenous activation of nAChRs. Specific Aim 2: Study the regulation of synaptic plasticity by prolonged nicotine-induced desensitization of nAChRs. Specific Aim 3: Assess the regulation of nAChR number and function by chronic exposure to nicotine.