Long-Term Ethanol Exposure and Neuronal Nicotinic Acetylcholine Receptors

长期乙醇暴露与神经元烟碱乙酰胆碱受体

• 批准号: 7994236
• 负责人: Selena E. Bartlett
• 金额: $ 37.72万
• 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: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994236
• 关键词: Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Animals; Behavioral; Binding; Biochemical; Brain region; Cell Nucleus; Chimeric Proteins; Chronic; Citrates; Clinical Research; Cocaine; Conotoxin; Cues; Data; Drosophila acetylcholine receptor alpha-subunit; Drug abuse; Ethanol; Exposure to; FDA approved; Figs - dietary; Gated Ion Channel; Genes; Goals; Heavy Drinking; Individual; Knock-in Mouse; Laboratories; Letters; Ligands; Long-Term Effects; Measures; Mediating; Modeling; Mus; Neurons; Nicotine; Nicotinic Receptors; Oral; Pharmaceutical Preparations; Play; Public Health; Quantitative Autoradiography; Rattus; Regulation; Relapse; Research; Role; Self Administration; Smoker; Societies; Stress; Techniques; Testing; Therapeutic Agents; Time; Training; Transgenic Organisms; Ventral Tegmental Area; Yohimbine; addiction; alcohol effect; alcohol exposure; alcohol seeking behavior; alcohol use disorder; design; dopaminergic neuron; drinking; drug reinforcement; drug reward; effective therapy; footshock induced; inhibitor/antagonist; mRNA Expression; mesolimbic system; methyllycaconitine; prevent; protein expression; public health relevance; receptor; smoking cessation; stressor; varenicline

DESCRIPTION (provided by applicant): Alcohol use disorders impact millions of individuals and constitute one of the most serious public health problems worldwide. Despite its devastating impact on society, there are still few effective medications currently available. It is well-known that alcohol and nicotine are commonly abused together, and that ethanol and nicotine have direct affects on neuronal nicotinic acetylcholine receptors (nAChRs). These receptors have been shown to modulate the mesolimbic dopamine system and contribute to the reinforcing actions of both ethanol and nicotine. The nAChRs are pentameric ligand-gated ion channels and in the CNS there are at least twelve receptors, designated 12 to 110, and 22 to 24 that assemble into multiple combinations. My lab discovered that varenicline, a drug that primarily binds to 1422 nAChRs and approved by the FDA as a smoking cessation aid, reduces ethanol self-administration and heavy drinking following long-term ethanol exposure. We will determine the consequences of long-term ethanol exposure on the role and expression of 1422 nAChRs following voluntary heavy ethanol consumption, operant self-administration and in stress- induced reinstatement. We will integrate behavioral and biochemical techniques to identify the brain regions mediating the effects of long-term ethanol exposure on the expression of nAChRs. The long-term goal is to design better therapeutic agents that target nAChRs for the treatment of alcohol use disorders. PUBLIC HEALTH RELEVANCE: Alcohol use disorders are one of the most serious public health problems worldwide. Neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to contribute to the effects of ethanol. We found that varenicline, a modulator of 1422 nAChRs and recently approved as an aid for smoking cessation, reduces ethanol self-administration and heavy drinking following long-term but not short-term ethanol exposure. We will determine whether long-term ethanol exposure induces changes in the expression of 1422 nAChRs and whether this contributes to the reinforcing effects of ethanol and/or stress-induced relapse. The long-term goal is to design more selective and effective medications for the treatment of alcohol use disorders.

描述（由申请人提供）： 酒精使用障碍会影响数百万个人，并构成了全球最严重的公共卫生问题之一。尽管对社会的影响有破坏性，但目前仍然很少有有效的药物。众所周知，酒精和尼古丁通常被一起滥用，并且乙醇和尼古丁直接影响神经元烟碱乙酰胆碱受体（NACHRS）。这些受体已被证明可以调节中唇多巴胺系统，并有助于乙醇和尼古丁的增强作用。 NACHR是五聚体门控离子通道，在中枢神经系统中，至少有十二个受体，指定为12至110，而22至24则组装成多种组合。我的实验室发现，一种主要结合1422 NACHR并被FDA批准的药物是一种吸烟剂，可减少乙醇自我给药和长期乙醇暴露后大量饮酒。我们将确定长期乙醇暴露对1422个NACHR的作用和表达的后果，自愿性重量乙醇消耗，操作剂自我给药以及应力引起的恢复。我们将整合行为和生化技术，以确定介导长期乙醇暴露对NACHR表达的影响的大脑区域。长期目标是设计靶向NACHR的更好的治疗剂，用于治疗酒精使用障碍。 公共卫生相关性：酒精使用障碍是全球最严重的公共卫生问题之一。神经元烟碱乙酰胆碱受体（NACHR）已显示出有助于乙醇的作用。我们发现，Varenicline是1422个NACHRS的调节剂，最近批准作为戒烟的帮助，减少了乙醇自我给药和长期乙醇暴露后的大量饮酒和大量饮酒。我们将确定长期乙醇暴露是否会引起1422 NACHR的表达变化，以及这是否有助于乙醇和/或应激诱导的复发的增强作用。长期的目标是设计更有效和有效的药物来治疗酒精使用障碍。