ROLE OF CHRNA5 IN MODULATING SENSITIVITY TO NICOTINE IN MICE

Bierut及其同事最近证明，编码阿尔法的基因中的多态性 亚基CHRNA 5与人类受试者的尼古丁依赖相关。此外，我们集团还 显示含有α S的nAChR参与调节nAChR功能，并且还证实了 编码小鼠α亚基ChrnaS的基因多态性与 对尼古丁高剂量效应的敏感性。尽管如此，烟碱乙酰胆碱受体的作用 （nAChR）α亚基在调节药物成瘾过程和脑功能中的作用知之甚少。在 根据COGEND计划项目的总体目标，即识别基因， 环境特征和生物机制，使个体易患或保护个体免受发病， 尼古丁依赖的持久性，我们计划进行一系列的实验，使用三种小鼠遗传 ChrnaS的模型，以解决ChmaS/alphaS可能有助于 尼古丁成瘾我们将使用的三种小鼠模型包括！）缺失ChrnaS的小鼠 （ChrnaS KO小鼠）; 2）其中天然存在的ChmaS等位基因变体已经交换的小鼠 在两个近交系小鼠品系（C3.D2Chma5和D2.C3Chma5）之间;和3）其中人非同义 已经引入SNP（ChmaS D398 N Kl）。有了这些小鼠模型，我们将1）定义 其功能由含有nAChR的α调节的脑区域和神经递质系统;以及 2)确定ChrnaS在调节行为中的作用，这些行为可以在被认为是 成瘾过程的组成部分，包括药物强化、药物厌恶、耐受性发展 和撤退。由于ChrnaS对药物滥用相关表型的影响可能发生在 在青春期和/或成年期，将评估两个年龄组的nAChR功能和行为。 与公共卫生的相关性：众所周知，基因在决定一个人是否 会成为一个吸烟者。在这项提议中，一种名为ChrnaS的特定基因的遗传差异的影响 将在老鼠身上进行研究，以确定这种基因如何影响个体对成瘾性药物的反应。 烟草中的物质尼古丁这项研究应该提供的信息，将提高我们的理解， 基因如何影响含尼古丁产品的使用。

Bierut and colleagues recently demonstrated that a polymorphism in the gene that encodes the alphas subunit, CHRNA5, is associated with nicotine dependence in human subjects. In addition, our group has shown that alphaS-containing nAChRs are involved in modulating nAChR function and also demonstrated that a polymorphism in the gene that encodes the mouse alphas subunit, ChrnaS, is associated with sensitivity to the high dose effects of nicotine. Nonetheless, the role of the nicotinic acetylcholine receptor (nAChR) alphas subunit in modulating the drug addiction process and brain function is poorly understood. In accordance with the overall goals of the COGEND Program Project, which are the identification of genes, environmental features, and biological mechanisms that predispose or protect individuals from the onset and persistence of nicotine dependence, we plan to conduct a series of experiments using three mouse genetic models of ChrnaS to address the basic mechanism(s) through which ChmaS/alphaS might contribute to nicotine addiction. The three mouse models we will utilize include!) Mice in which ChrnaS has been deleted (ChrnaS KO mice); 2) Mice in which naturally-occurring allelic variants of ChmaS have been exchanged between two inbred mouse strains (C3.D2Chma5 and D2.C3Chma5); and 3) Mice in which the human nonsynonymous SNP has been introduced (ChmaS D398N Kl). With these mouse models, we will 1) define the brain regions and neurotransmitter systems whose function is modulated by alphas containing nAChRs; and 2) determine the role of ChrnaS in regulating behaviors that can be modeled in mice that are thought to be components of the addiction process, including drug reinforcement, drug aversion, tolerance development and withdrawal. Because the influence of ChrnaS on drug abuse related phenotypes could occur in adolescence and/or adulthood, both age groups will be assessed for nAChR function and behavior. Relevance to public health: Genes are known to play a significant part in determining whether an individual will become a smoker. In this proposal, the influence of a genetic difference in a specific gene called ChrnaS will be studied in mice to determine how this gene might affect how an individual responds to the addictive substance in tobacco, nicotine. This study should provide information that will improve our understanding of how genes influence the use of nicotine-containing products.