Subunit-specific Regulation/Neuronal Nicotinic Receptors

描述(申请人提供)：尼古丁成瘾必须发展为尼古丁与其受体相互作用的下游结果。因此，了解这一最初的分子步骤如何在中枢神经系统功能中产生长期变化，对于理解药物滥用行为是如何发展至关重要的。在尼古丁诱导的分子变化方面，我们先前的研究表明，在异源表达系统中，尼古丁通过与受体的高亲和力脱敏确认物发生特异性相互作用，导致质膜上烟碱型乙酰胆碱受体(NAChRs)数量明显增加。我们现在希望将这些研究扩展到突触网络背景下中枢神经系统中的天然nAChRs。由于尼古丁存在于吸烟者的脑脊液中，其浓度主要是使nAChRs脱敏，我们的观察结果导致了一个普遍的假设：nAChRs的脱敏是慢性尼古丁改变突触功能的主要机制。我们将通过研究尼古丁诱导的alpha7*和alpha4beta2*nAChRs如何调节nAChR功能和海马区的突触传递来探索这一假设。 有三个目标： 具体目标1：研究通过内源性突触传递的调节 激活nAChRs。 特定目的2：研究长时间尼古丁诱导对突触可塑性的调节 NAChRs的脱敏。 具体目标3：评估慢性暴露对nAChR数量和功能的调节 尼古丁。

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.