Role of Nicotinic Receptors in Effects of Alcohol

烟碱受体在酒精作用中的作用

• 批准号: 6477753
• 负责人: JEANNE M WEHNER
• 金额: $ 45.82万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6477753
• 关键词: anxiety; attention; drug interactions; drug tolerance; ethanol; gene targeting; genetically modified animals; impulsive behavior; laboratory mouse; learning; nicotine; nicotinic receptors; pharmacogenetics; point mutation; receptor expression; substance abuse related behavior

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.

描述（由申请人提供）：经常使用酒精和尼古丁 一起。很大一部分酗酒者同时也是重度吸烟者 对啮齿类动物的研究表明，小鼠和大鼠经过选择性繁殖 对乙醇的初始敏感性差异也因反应而异 尼古丁。乙醇和尼古丁的药理和行为影响 两者都很复杂。乙醇在大脑中具有多个作用位点，包括 许多配体门控离子通道。尼古丁在大脑中的作用是由 多聚离子烟碱胆碱能受体的激活 由一个大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基参与 通过创建和测试具有缺失的无效突变体来发挥酒精的特定作用 存在于几个重要的烟碱受体基因中。研究将调查 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 将评估乙醇的药理和行为作用范围 包括：最初的敏感性、几种形式的耐受性、焦虑、学习 以及记忆力、注意力、乙醇消耗和冲动。 具体目标是： 1.) 检查含α4的大脑的作用 烟碱受体通过产生组成型介导酒精的作用 和条件 alpha4 无效突变体以及含有位点特异性的突变体 α4基因突变； 2.) 确定α7大脑是否具有烟碱样 受体无效突变改变乙醇相关行为； 3.) 检查 α4和α7受体无效突变对各种遗传的影响 背景。 这些研究的结果应该可以让人们更好地理解 共同管理的潜在相互作用和机制 乙醇与尼古丁。