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: 7944068
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944068
• 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。过量饮酒是美国可预防死亡的第三大原因。尽管成瘾占大脑相关疾病的 40% 以上，但仍缺乏创新的治疗方法。酒精和尼古丁成瘾通常被视为单独的疾病，尽管大多数患有酒精使用障碍的人也吸烟，并且在戒酒期间继续吸烟会导致明显更高的复发率。这些发现表明，酒精和尼古丁成瘾可能会发展并依赖于共同的途径。最近，大量人类遗传关联研究表明神经元烟碱受体 (nAChR)，例如 a5 nAChR 亚基在酒精和尼古丁依赖过程中发挥着关键作用，最近的分子研究表明 a5 nAChR 亚基改变了 a4b2* nAChRs 的活性。我们的主要目标是应用整合基础和临床研究的多学科方法来确定 nAChR 在乙醇和尼古丁消耗以及物质使用障碍中作用的分子基础，以期产生药物和治疗策略。在该项目的第一部分，我们将结合行为和电生理学研究，有两个目标：1) 表征 a5* nAChRs 在乙醇、尼古丁和伐尼克兰的行为影响中的作用，2) 测量腹侧被盖区多巴胺神经元中 a4b2* nAChRs 反应的表达和突触特性，腹侧被盖区是一个在强化神经元中发挥关键作用的大脑区域。 尼古丁和乙醇的性质。我们开发的创新饮用模型极大地促进了这些研究，该模型使乙醇和尼古丁可以一起消耗，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，以确定 nAChR 的遗传变异是否与临床特征为尼古丁依赖和有害饮酒的队列中对伐尼克兰的反应相关。主要目标有两个：1) 测量伐尼克兰作为危险饮酒治疗的有效性；2) 对受试者进行基因分型并评估 nAChR 编码基因的多态性是否会调节伐尼克兰减少酗酒的效果。将遗传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，通过该方法我们可以测量伐尼克兰减少酒精使用障碍的功效，并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滥用障碍的治疗策略。 公共健康相关性：我们制定了一项多学科合作研究计划，重点是确定神经元烟碱受体 (nAChR) 在乙醇和尼古丁消耗以及物质使用障碍中作用的分子基础，目标是制定药物和治疗策略。我们建议结合行为学和电生理学来定义 a5* nAChR 在乙醇和尼古丁消耗中的作用的分子基础，并确定 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。该提案的研究将促进针对 nAChR 的药物开发，用于治疗酒精和药物滥用障碍。

项目成果

Varenicline decreases alcohol consumption in heavy-drinking smokers.

• DOI: 10.1007/s00213-012-2717-x
• 发表时间: 2012-10
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Mitchell, Jennifer M.;Teague, Candice H.;Kayser, Andrew S.;Bartlett, Selena E.;Fields, Howard L.
• 通讯作者: Fields, Howard L.