ROLE OF CHRNA5 IN MODULATING SENSITIVITY TO NICOTINE IN MICE

CHRNA5 在调节小鼠尼古丁敏感性中的作用

• 批准号: 7874635
• 负责人: JERRY A STITZEL
• 金额: $ 34.32万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7874635
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; Age; Alleles; Animals; Anxiety; Autonomic ganglion; Behavior; Behavioral; Biological; Biological Assay; Biological Models; Blood Pressure; Brain; Brain region; Cholinergic Receptors; Chronic; Congenic Mice; Congenic Strain; Consumption; Data; Development; Disinhibition; Dopamine; Dose; Drug Addiction; Drug abuse; Exhibits; Exposure to; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Heart Rate; Human; Impairment; Inbred Strains Mice; Individual; Individual Differences; Intravenous infusion procedures; Ions; Knock-in Mouse; Knock-out; Learning; Measurable; Measurement; Measures; Methods; Modeling; Mouse Strains; Mus; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Nucleus Accumbens; Oral; Pharmaceutical Preparations; Phenotype; Plasma; Play; Population Decreases; Positioning Attribute; Principal Investigator; Process; Program Research Project Grants; Property; Public Health; Publishing; Radio; Research; Rodent; Role; Series; Smoker; Synaptosomes; System; Taste Perception; Temperature; Testing; Tobacco; Variant; Withdrawal; addiction; age group; behavior measurement; conditioned fear; dopaminergic neuron; drinking; drug of abuse; drug reinforcement; gamma-Aminobutyric Acid; human data; human subject; improved; mouse model; mutant; neurobiological mechanism; osmotic minipump; preference; programs; receptor; receptor function; research study; response

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.

Bierut及其同事最近证明了编码alpha的基因中的多态性 亚基ChRNA5与人类受试者的尼古丁依赖性有关。此外，我们的小组有 表明含有alpha的NACHR参与调节NACHR功能，并且也证明了 编码小鼠alphas亚基ChRNA的基因中的多态性与 对尼古丁的高剂量作用的敏感性。但是，烟碱乙酰胆碱受体的作用 （NACHR）在调节药物成瘾过程和大脑功能方面的Alpha子单位知之甚少。在 根据Cogend计划项目的整体目标，这是基因的识别， 环境特征和生物学机制，可易受或保护个体免受发作的影响 尼古丁依赖性的持久性，我们计划使用三种小鼠遗传进行一系列实验 CHRNA模型以解决Chmas/Alpha可能有助于的基本机制 尼古丁成瘾。我们将使用的三种鼠标模型包括！）删除了ChRNA的小鼠 （chrnas ko小鼠）； 2）已交换了Chmas的自然等位基因变体的小鼠 在两个近交小鼠菌株（C3.D2CHMA5和D2.C3CHMA5）之间； 3）人类非同义词的老鼠 SNP已被引入（CHMAS D398N kl）。使用这些鼠标模型，我们将1）定义 大脑区域和神经递质系统的功能由含有nACHR的alpha调节；和 2）确定CHRNA在调节可以在被认为是的小鼠中建模的行为中的作用 成瘾过程的组成部分，包括药物加强，药物厌恶，耐受性发展 和退出。因为CHRNA对药物滥用相关的表型的影响可能发生在 青春期和/或成年期，将评估两个年龄组的NACHR功能和行为。 与公共卫生相关：众所周知，基因在确定个人是否发挥着重要作用 将成为吸烟者。在此提案中，遗传差异在称为ChRNA的特定基因中的影响 将在小鼠中研究以确定该基因如何影响个人如何应对上瘾 烟草中的物质。这项研究应提供的信息将提高我们对 基因如何影响含尼古丁产物的使用。