Long-Term Ethanol Exposure and Neuronal Nicotinic Acetylcholine Receptors

描述（由申请人提供）： 酒精使用障碍影响到数百万人，是全世界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）具有直接影响。这些受体已被证明可以调节中脑边缘多巴胺系统，并有助于乙醇和尼古丁的强化作用。nAChR是五聚体配体门控离子通道，并且在CNS中存在至少十二种受体，指定为12至110和22至24，其组装成多种组合。我的实验室发现，伐尼克兰，一种主要与1422 nAChR结合的药物，并被FDA批准为戒烟辅助药物，减少了长期乙醇暴露后的乙醇自我管理和大量饮酒。我们将确定长期乙醇暴露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的作用和表达的后果。我们将整合行为和生物化学技术，以确定大脑区域介导的长期乙醇暴露对nAChRs表达的影响。长期目标是设计更好的治疗药物，靶向nAChR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.