Role of Nicotinic Receptors in Effects of Alcohol

描述（由申请人提供）：经常使用酒精和尼古丁 一起酗酒者中有很大一部分是重度吸烟者， 对啮齿类动物的研究表明，小鼠和大鼠选择性地繁殖， 对乙醇的初始敏感性的差异也不同， 尼古丁。乙醇和尼古丁的药理学和行为学效应 都很复杂乙醇在大脑中有多个作用部位， 许多配体门控离子通道。尼古丁？大脑中的行为是由 多聚体离子烟碱胆碱能受体活化 由一个大的基因家族编码的通道。拟议研究的目标是 确定是否有任何烟碱受体亚单位参与 通过创建和测试缺失的无效突变体来研究酒精的特异性作用 在几个重要的烟碱受体基因中。研究将调查 在主要的、广泛表达的亚基中进行单基因操作， 其他亚基具有更有限但有趣的表达模式。广泛 将评估乙醇的一系列药理学和行为学作用 包括：最初的敏感性，几种形式的宽容，焦虑，学习 以及记忆力、注意力、酒精消耗和冲动。 具体目标是：（1）。为了检查含有α 4的大脑的作用， 尼古丁受体在酒精调节中的作用的影响，通过创造构成 和条件性α 4无效突变体以及含有位点特异性 α 4基因中的突变; 2.）为了确定α 7脑尼古丁 受体无效突变改变乙醇相关行为;和3.）审查 α 4和α 7受体无效突变对各种遗传学的影响 背景 这些研究的结果应能使人们更好地了解 潜在的相互作用和共同管理的机制 酒精与尼古丁

DESCRIPTION (provided by applicant): Alcohol and nicotine are frequently used together. An extremely large fraction of alcoholics are also heavy smokers and studies in rodents have demonstrated that mice and rats selectively bred for differences in initial sensitivity to ethanol also differ in response to nicotine. The pharmacological and behavioral effects of ethanol and nicotine are both complex. Ethanol has multiple sites of actions in the brain including many ligand-gated ion channels. Nicotine?s actions in the brain are produced by the activation of nicotinic cholinergic receptors that are multimeric ion channels encoded by a large gene family. The goal of the proposed studies is to determine whether any of the nicotinic receptor subunits are involved in specific actions of alcohol by creating and testing null mutants with deletions in several of the important nicotinic receptor genes. Studies will investigate single-gene manipulations in the major, widely expressed subunits as well as other subunits with more limited but interesting expression patterns. A wide range of pharmacological and behavioral actions of ethanol will be assessed including: initial sensitivity, several forms of tolerance, anxiety, learning and memory, attention, ethanol consumption and impulsivity. The specific aims are: 1.) To examine the role of alpha4 containing brain nicotinic receptors in mediation of alcohol?s effects by creating constitutive and conditional alpha4 null mutants as well as those containing a site specific mutation in the alpha4 gene; 2.) To determine whether an alpha7 brain nicotinic receptor null mutation alters ethanol-related behaviors; and 3.) To examine the effects of alpha4 and alpha7 receptor null mutations on various genetic backgrounds. The results of these studies should provide a better understanding of the potential interactions and mechanisms underlying the co-administration of ethanol with nicotine.