Role of Nicotinic Receptors in Effects of Alcohol

描述(申请人提供)：经常使用酒精和尼古丁 在一起。极大一部分酗酒者也是烟瘾很大的人 对啮齿动物的研究表明，小鼠和大鼠选择性地繁殖是为了 乙醇初始敏感性的差异也因反应不同而不同 尼古丁。乙醇和尼古丁的药理和行为效应 都很复杂。乙醇在大脑中有多个作用部位，包括 许多配基门控离子通道。尼古丁？S在大脑中的活动是由 多聚离子烟碱能受体的激活 由一个大的基因家族编码的频道。拟议研究的目标是 确定是否有任何尼古丁受体亚基参与 通过创建和测试带有缺失的无效突变体来实现酒精的特定作用 在几个重要的尼古丁受体基因中。研究将调查 在主要的、广泛表达的亚基以及 其他具有更有限但有趣的表达模式的亚基。宽阔的 将评估乙醇的药理和行为作用的范围。 包括：最初的敏感、几种形式的容忍、焦虑、学习 还有记忆力、注意力、饮酒和冲动。 具体目标是：1.研究含有Alpha4的脑的作用 烟碱受体在酒精调节中的作用--S通过构造性产生的效应 和条件性alpha4零突变体以及那些包含特定位点的突变体 α4基因突变；2.以确定阿尔法7脑尼古丁是否 受体零突变改变与酒精相关的行为；要检查 α4和α7受体零突变对多种基因的影响 背景。 这些研究的结果应该会让我们更好地理解 潜在的相互作用和潜在的共同管理机制 酒精和尼古丁。

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.