Alpha 5 nAChR is a Risk Factor within the Dopamine System for Nicotine Addiction

Alpha 5 nAChR 是多巴胺系统内尼古丁成瘾的危险因素

• 批准号: 9428198
• 负责人: John A. Dani
• 金额: $ 10.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9428198
• 关键词: Acute; Addictive Behavior; Area; Behavior Control; Behavioral; Cessation of life; Chronic; Corpus striatum structure; Data; Dopamine; Dorsal; Dose; Drosophila acetylcholine receptor alpha-subunit; Event; Experimental Designs; Exposure to; Genes; Human Genetics; In Vitro; Knockout Mice; Link; Malignant neoplasm of lung; Measures; Mediating; Methodology; Microdialysis; Midbrain structure; Modeling; Mus; Mutant Strains Mice; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Nucleus Accumbens; Organism; Periodicity; Phase; Physiology; Preparation; Process; Psychological reinforcement; Research; Rewards; Risk; Risk Factors; Rodent; Role; Scanning; Self Administration; Signal Transduction; Single Nucleotide Polymorphism; Smoker; Smoking; Source; Substance Withdrawal Syndrome; Synapses; System; Time; Tobacco; Tobacco Dependence; Tobacco use; Translating; United States; Ventral Tegmental Area; Wild Type Mouse; Withdrawal; addiction; base; dopamine system; dopaminergic neuron; drinking water; expectation; experience; genome wide association study; high risk; in vivo; neuroadaptation; premature; public health relevance; response; reward processing; smoking cessation; therapy development

DESCRIPTION (provided by applicant): Genome-wide association studies identified a nonsynonymous SNP (rs16969968) within the CHRNA5 gene that encodes for the �5 nicotinic receptor (nAChR) subunit. This SNP produces a twofold higher risk for heavy smoking and increases the risk for lung cancer. Consistent with the human genetics, our preliminary studies showed that the �5 nAChR is necessary for the expression of the nicotine withdrawal syndrome. The �5 nAChR also regulates sensitive to nicotine-induced behaviors and controls nicotine self-administration at high doses. In these proposed studies, we will investigate �5's mechanistic action on the midbrain dopamine (DA) systems that reinforce rewarding and addictive behaviors. We will examine the effect of the rs16969968 SNP on DA signaling from its source in the midbrain to its main targets in the striatum, including the nucleus accumbens (NAc) which is important for processing reward. Our in vivo multi-tetrode recordings show that nicotine increases the phasic burst firing of DA neurons, and our cyclic voltammetry and in vivo microdialysis data show that nicotine-induced changes in DA neuron firing are translated in a target-specific manner in areas that process reinforcement and reward, including the NAc core and shell. However, little is known about the role of the �5 subunit or the rs16969968 SNP and about the role of the �5-subunit in regulating the relationship between DA neuron firing and DA release in targets. Our working hypothesis is that nicotine acts via the �5-nAChR subunit to modulate DA signaling both at the source (i.e., DA neurons in the midbrain) and at the targets (including the NAc and the dorsal striatum). The aims examine the hypothesis that nicotine-induced changes in the DA system evolve during chronic nicotine exposure and during the withdrawal period. The significance of the study originates from the expectation that these nicotine-induced activities and changes in the DA system contribute to the transition from initial nicotine use to addiction. Tobacco use remains the leading cause of preventable death in the United States, and these studies provide a mechanistic basis for nicotine addiction and for developing therapies to aid smoking cessation.

描述（由申请人提供）：全基因组关联研究发现 CHRNA5 基因中存在一个非同义 SNP (rs16969968)，该基因编码 5 烟碱受体 (nAChR) 亚基。该 SNP 使重度吸烟的风险增加两倍。与人类遗传学一致，我们的初步研究表明 5 nAChR 对于肺癌的表达是必需的。尼古丁戒断综合征。5 nAChR 还调节对尼古丁诱导的行为的敏感性，并控制高剂量的尼古丁自我施用。在这些拟议的研究中，我们将研究 5 对中脑多巴胺 (DA) 系统的机制作用，以增强奖励和奖励。我们将研究 rs16969968 SNP 对从中脑来源到纹状体主要目标的 DA 信号的影响。伏隔核（NAc）对奖赏处理很重要，我们的体内多四极记录表明尼古丁增加了 DA 神经元的相爆发放电，我们的循环伏安法和体内微透析数据表明尼古丁诱导的 DA 神经元放电发生变化。在处理强化和奖励的区域（包括 NAc 核心和外壳）以特定目标的方式进行翻译。然而，人们对 5 亚基或 5 亚基的作用知之甚少。 rs16969968 SNP 以及 5-亚基在调节靶标中 DA 神经元放电和 DA 释放之间关系中的作用我们的工作假设是尼古丁通过 5-nAChR 亚基在源头（即，中脑的 DA 神经元）和目标（包括 NAc 和背侧纹状体）的目标检验尼古丁引起的变化的假设。 DA 系统在长期接触尼古丁期间和戒断期间发生变化，这项研究的意义在于预期这些尼古丁诱导的活动和 DA 系统的变化有助于从最初的尼古丁使用到烟草使用的转变。在美国，尼古丁是可预防死亡的主要原因，这些研究为尼古丁成瘾和开发帮助戒烟的疗法提供了机制基础。