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。尽管它对社会造成毁灭性影响，但目前有效的药物仍然很少。众所周知，酒精和尼古丁通常一起滥用，并且乙醇和尼古丁对神经元烟碱乙酰胆碱受体（nAChR）有直接影响。这些受体已被证明可以调节中脑边缘多巴胺系统，并有助于增强乙醇和尼古丁的作用。 nAChR 是五聚体配体门控离子通道，在 CNS 中至少有 12 个受体，分别称为 12 至 110 和 22 至 24，它们组装成多种组合。我的实验室发现伐尼克兰（varenicline）是一种主要与 1422 个 nAChR 结合的药物，已被 FDA 批准作为戒烟辅助药物，可减少长期接触乙醇后的自我服用乙醇和大量饮酒。我们将确定长期接触乙醇对自愿大量乙醇消耗、操作性自我给药和应激诱导恢复后 1422 nAChR 的作用和表达的影响。我们将整合行为和生化技术来识别介导长期乙醇暴露对 nAChR 表达影响的大脑区域。长期目标是设计更好的靶向 nAChR 的治疗药物来治疗酒精使用障碍。 公共卫生相关性：酒精使用障碍是全世界最严重的公共卫生问题之一。神经元烟碱乙酰胆碱受体 (nAChR) 已被证明有助于乙醇的作用。我们发现伐尼克兰（一种 1422 nAChR 的调节剂，最近被批准作为戒烟辅助药物）可减少长期而不是短期接触乙醇后的自我服用乙醇和大量饮酒。我们将确定长期乙醇暴露是否会引起 1422 nAChR 表达的变化，以及这是否有助于乙醇的增强作用和/或应激诱导的复发。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.