Environmental and Genetic Circadian Influences on Alcoholism

描述(申请人提供)：昼夜节律系统与调节酒精中毒的奖励系统密切相关。使用酒精来缓解与工作相关的睡眠/清醒障碍会造成酒精依赖和昼夜节律紊乱的恶性循环。这项建议将重点描述自然(时钟基因和神经递质紧张素)和后天(环境)的复合效应，它们扰乱了昼夜节律缠绕，并促进了酒精依赖和酒精中毒。利用PER2缺陷小鼠品系，模拟轮班工作的轮换时间表，以及恒定的暗/光条件，将用于：(1)首次评估环境干扰和PER2时钟基因缺失对增强的酒精偏好和复发风险以及改变昼夜酒精摄入量的相互作用；(2)首次观察谷氨酸拮抗剂和酒精复发药物阿卡米松对与环境干扰和/或PER2时钟基因缺失相关的增强的酒精偏好和复发风险的拯救作用；以及(3)首次探索调节酒精偏好和复发风险降低的昼夜节律和酒精奖励系统的区域。中心假设是，环境干扰、PER2时钟基因缺失和相关的高谷氨酸能状态极大地增强了酒精偏好和复发风险，这种增强可以通过全身和颅内无氨基酚治疗来挽救。这项拟议的研究解决了以前轮班工作和氨基己酸酯研究的局限性，最好的是，将提高可用于治疗酒精中毒的药物和行为疗法的质量。 公共卫生相关性：这项提案将说明环境(轮班工作)和遗传(缺失)对酒精依赖和复发风险的影响。它还将定位中枢神经系统中调节酒精依赖和复发风险的区域。这项研究表明，有必要结合药物和行为疗法来治疗酒精中毒和防止复发。

DESCRIPTION (provided by applicant): The circadian timing system is closely and reciprocally tied to reward systems mediating alcoholism. Using alcohol to mitigate work-related sleep/wake disturbances creates a vicious cycle of alcohol dependence and circadian disruption. This proposal will focus on delineating the compounding effects of nature (clock gene and neurotransmitter tonus) and nurture (environment) that disrupt circadian entrainment and promote alcohol dependence and alcoholism. A Per2-deficent mouse strain, a rotating schedule of simulated shift work, and constant dark/photic conditions will be utilized for: (1) The first assessment of the interactions of environmental disruptions and Per2 clock gene deletions on potentiated alcohol preference and relapse risk and altered circadian alcohol intake; (2) The first observation of the rescuing effects of the glutamate antagonist and alcohol relapse drug, acamprosate, on potentiated alcohol preference and relapse risk associated with environmental disruptions and/ or Per2 clock gene deletions; and (3) The first exploration of areas of the circadian timing and alcohol reward systems mediating acamprosate reduction of alcohol preference and relapse risk. The central hypothesis is that environmental disturbances, Per2 clock gene deletions, and related hyperglutamatergic states greatly potentiate alcohol preference and relapse risk, and that such potentiation can be rescued by systemic and intra-cranial acamprosate treatment. The proposed research addresses limitations from previous shift work and acamprosate studies, and optimally, will improve the quality of pharmacological and behavioral therapies available for the treatment of alcoholism. PUBLIC HEALTH RELEVANCE: This proposal will illustrate environmental (rotating shift work) and genetic (deletions) contributions to alcohol dependence and relapse risk. It will also localize areas of the central nervous system mediating alcohol dependence and relapse risk. This research shows the need for a combination of pharmacological and behavioral therapies for the treatment of alcoholism and prevention of relapse.