Long-Term Ethanol Exposure and Neuronal Nicotinic Acetylcholine Receptors

描述(由申请人提供)： 酒精使用障碍影响着数百万人，并构成全球最严重的公共卫生问题之一。尽管它对社会造成了毁灭性的影响，但目前仍然几乎没有有效的药物可用。众所周知，酒精和尼古丁经常一起滥用，乙醇和尼古丁对神经元烟碱型乙酰胆碱受体(NAChRs)有直接影响。这些受体已被证明调节中脑边缘多巴胺系统，并有助于乙醇和尼古丁的增强作用。NAChRs是五聚体配体门控离子通道，在中枢神经系统中至少有12个受体，分别命名为12到110和22到24，它们组装成多种组合。我的实验室发现，varenicline，一种主要与1422 nAChRs结合的药物，并被FDA批准为戒烟辅助药物，可以减少长期酒精暴露后的酒精自我给药和大量饮酒。我们将确定长期酒精暴露对1422nAChRs的作用和表达的影响，在自愿大量酒精摄入、操作性自我管理和应激诱导的恢复过程中。我们将结合行为和生化技术来确定调节长期酒精暴露对nAChRs表达影响的大脑区域。长期目标是设计更好的针对nAChRs的治疗剂来治疗酒精使用障碍。 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。神经元烟碱型乙酰胆碱受体(NAChRs)已被证明与乙醇的作用有关。我们发现，varenicline，一种1422 nAChRs的调节剂，最近被批准作为戒烟的辅助药物，在长期但不是短期的酒精暴露后，减少了乙醇自我给药和大量饮酒。我们将确定长期酒精暴露是否会导致1422nAChRs表达的变化，以及这是否有助于酒精和/或应激诱导的复发的增强效应。长期目标是设计更有选择性和更有效的药物来治疗酒精使用障碍。

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.