Subunit-specific Regulation/Neuronal Nicotinic Receptors

描述（由申请人提供）：尼古丁成瘾必须作为尼古丁与其受体相互作用的下游结果而发展。因此，了解这一初始分子步骤如何产生中枢神经系统功能的长期变化，对于理解药物滥用行为是如何发展的至关重要。关于尼古丁诱导的分子变化，我们之前的研究表明，在异源表达系统中，尼古丁通过与高亲和力脱敏确认的受体特异性相互作用，导致质膜上尼古丁乙酰胆碱受体（nAChRs）数量明显增加。我们现在想将这些研究扩展到中枢神经系统中突触网络背景下的天然nachr。由于尼古丁存在于烟草使用者的脑脊液中，其浓度主要是在乙酰胆碱受体中脱敏，我们的观察结果导致了一般假设：慢性尼古丁改变突触功能的主要机制是乙酰胆碱受体的脱敏。我们将通过研究尼古丁诱导的alpha7*和alpha4beta2* nAChR脱敏如何调节海马中nAChR功能和突触传递来探索这一假设。

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.