Characterizing Alpha5* Nicotinic Receptors in Alcohol and Nicotine Co-Dependence

酒精和尼古丁相互依赖性中 Alpha5* 烟碱受体的特征

• 批准号: 7855783
• 负责人: Selena E. Bartlett
• 金额: $ 101.04万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7855783
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcohols; Alleles; Animal Model; Behavior; Behavioral; Biochemical; Brain; Brain region; Cessation of life; Cigarette; Clinical Research; Consumption; Dependence; Development; Disease; Double-Blind Method; Drosophila acetylcholine receptor alpha-subunit; Effectiveness; Electrophysiology (science); Ethanol; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Grant; Heavy Drinking; Human; Human Genetics; Kinetics; Knock-in Mouse; Link; Measures; Mediating; Medical; Minor; Modeling; Molecular; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Outpatients; Pathway interactions; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Pharmacotherapy; Placebos; Play; Primary Care Physician; Process; Property; Randomized; Relapse; Research; Role; Saccharin; Single Nucleotide Polymorphism; Smoke; Smoker; Substance Use Disorder; Synapses; Techniques; Tobacco use; United States; Ventral Tegmental Area; addiction; alcohol abstinence; alcohol abuse therapy; alcohol effect; alcohol measurement; alcohol response; alcohol use disorder; base; cohort; desensitization; disability; dopaminergic neuron; drinking; drinking behavior; effective therapy; effectiveness measure; follow-up; genetic analysis; genetic association; genetic variant; hazardous drinking; improved; innovation; interdisciplinary approach; multidisciplinary; placebo controlled study; programs; public health relevance; research study; response; standard care; trafficking; treatment duration; treatment program; treatment response; treatment strategy; varenicline

DESCRIPTION (provided by applicant): Tobacco use is the leading cause of preventable disease, disability, and death. Excessive alcohol consumption is the number-three cause of preventable death in the United States. Despite the fact that addiction represents more than 40% of brain-related illnesses, there is a dearth of innovative treatments. Alcohol and nicotine addiction are often treated as separate disorders even though most people with alcohol use disorders also smoke, and continued tobacco use during abstinence from alcohol leads to significantly higher relapse rates. These findings suggest that alcohol and nicotine addictions may develop, and depend on, common pathways. Recently, a large number of human genetic association studies have implicated the neuronal nicotinic receptors (nAChRs), such as the a5 nAChR subunit as playing a critical role in developing alcohol and nicotine dependence processes and recent molecular studies indicate that the a5 nAChR subunit changes the activity of a4b2* nAChRs. Our main objective is to apply a multidisciplinary approach that integrates basic and clinical research to define the molecular basis of the role of nAChRs in ethanol and nicotine consumption and substance use disorders with the goal of generating medications and treatment strategies. In the first part of the project, we will combine behavior and electrophysiology studies and there are two objectives: 1) to characterize the role of the a5* nAChRs in the behavioral effects of ethanol and nicotine and varenicline and 2) to measure the expression and synaptic properties of a4b2* nAChRs responses in dopamine neurons in the ventral tegmental area, a brain region that plays a key role in the reinforcing properties of nicotine and ethanol. These studies have been greatly facilitated by an innovative drinking model we developed that enables ethanol and nicotine to be consumed together without the need for saccharin. In the second part of the project, we will combine clinical studies and genetics to determine whether genetic variants in nAChRs correlate with response to varenicline in a cohort clinically characterized for nicotine dependence and hazardous alcohol use. There are two major objectives: 1) to measure the effectiveness of varenicline, as a treatment for hazardous alcohol use and 2) to genotype the subjects and assess whether polymorphisms in the genes encoding for nAChRs moderate the effect of varenicline to reduce heavy drinking. The linking of genetic analyses with human responses to varenicline will provide a means by which we can measure both the efficacy of varenicline for diminishing alcohol use disorders and to determine whether there are underlying genetic differences in responses to varenicline. Our overall goal is to accelerate the development of more effective medications, and to improve and personalize treatment strategies for substance use disorders. PUBLIC HEALTH RELEVANCE: We have developed a multidisciplinary collaborative research program focused on defining the molecular basis of the role of neuronal nicotinic receptors (nAChRs) in ethanol and nicotine consumption and substance use disorders with the goal of generating medications and treatment strategies. We propose to combine behavior and electrophysiology to define the molecular basis of the role of a5* nAChRs in ethanol and nicotine consumption and determine whether genetic variants in nAChRs correlate with response to varenicline in a cohort clinically characterized for nicotine dependence and hazardous alcohol use. The research garnered from this proposal will facilitate the development of medications that target nAChRs for the treatment of alcohol and substance use disorders.

描述（由申请人提供）：烟草使用是可预防疾病、残疾和死亡的主要原因。在美国，过度饮酒是可预防死亡的第三大原因。尽管事实上成瘾占了40%以上的脑相关疾病，但缺乏创新的治疗方法。酒精和尼古丁成瘾通常被视为不同的疾病，尽管大多数有酒精使用障碍的人也吸烟，并且在戒酒期间继续使用烟草会导致复发率显著提高。这些发现表明，酒精和尼古丁成瘾可能会形成，并依赖于共同的途径。近年来，大量的人类遗传关联研究表明，神经元尼古丁受体（nAChR），如a5 nAChR亚基，在酒精和尼古丁依赖过程中起着关键作用，最近的分子研究表明，a5 nAChR亚基改变a4b2* nAChR的活性。我们的主要目标是应用多学科方法，整合基础和临床研究，以确定nachr在乙醇和尼古丁消耗和物质使用障碍中的作用的分子基础，目标是产生药物和治疗策略。在项目的第一部分，我们将结合行为学和电生理学研究，有两个目标：1)表征a5* nAChRs在乙醇、尼古丁和伐尼克兰的行为效应中的作用；2)测量a4b2* nAChRs在腹侧被皮层多巴胺神经元中的表达和突触特性，腹侧被皮层在尼古丁和乙醇的强化特性中起关键作用。我们开发的一种创新的饮酒模式极大地促进了这些研究，这种模式使乙醇和尼古丁可以一起饮用，而不需要糖精。在该项目的第二部分，我们将结合临床研究和遗传学来确定nachr的遗传变异是否与临床特征为尼古丁依赖和危险酒精使用的队列中对伐尼克兰的反应相关。有两个主要目的：1)测量伐尼克兰作为治疗危险酒精使用的有效性；2)对受试者进行基因分型，评估编码nachr基因的多态性是否会调节伐尼克兰减少大量饮酒的效果。将基因分析与人类对伐尼克兰的反应联系起来，将为我们提供一种方法，通过这种方法，我们既可以测量伐尼克兰减少酒精使用障碍的功效，也可以确定对伐尼克兰的反应是否存在潜在的遗传差异。我们的总体目标是加速开发更有效的药物，并改进和个性化药物使用障碍的治疗策略。