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（应用程序提供）：全基因组关联研究确定了编码为5烟碱受体（NACHR）亚基的CHRNA5基因中的非同义SNP（RS16969968）。该SNP产生的大量吸烟风险增加了两倍，并增加了患肺癌的风险。与人类遗传学一致，我们的初步研究表明，nachr对于表达尼古丁戒断综合征是必不可少的。 �5NACHR还调节对尼古丁诱导的行为敏感，并以高剂量控制尼古丁自我给药。在这些拟议的研究中，我们将研究�5对中脑多巴胺（DA）系统的机械作用，以增强奖励和其他行为。我们将研究RS16969968 SNP对中脑中其源的DA信号传导的作用，包括纹状体中的主要靶标，包括Accumbens（NAC）（NAC），这对于处理奖励很重要。我们的体内多四个录音表明，尼古丁增加了DA神经元的阶段性爆发，我们的环状伏安法和体内微透析数据表明，尼古丁诱导的DA神经元触发的变化在包括NAC核心（包括NAC核心）的区域中以目标特异性的方式翻译，包括NAC核心。然而，关于�5亚基或RS16969968 SNP的作用以及�5-subunit在重新计算目标中DA神经元射击与DA释放之间关系中的作用的作用知之甚少。我们的工作假设是，尼古丁通过�5-NACHR亚基起作用，以调节源（即中脑中的DA神经元）和靶标（包括NAC和背侧纹状体）调节DA信号。目的检验了以下假设：尼古丁诱导的DA系统在慢性尼古丁暴露期间和戒断期间的变化。该研究的意义源于这些尼古丁诱导的活动和DA系统变化的期望，这导致了从最初的尼古丁使用到成瘾的过渡。烟草使用仍然是美国可预防死亡的主要原因，这些研究为尼古丁成瘾和开发疗法提供了帮助戒烟的机械基础。