Environmental and Genetic Circadian Influences on Alcoholism

描述（由申请人提供）：昼夜节律系统与调节酒精中毒的奖励系统密切相关。用酒精来缓解与工作相关的睡眠/觉醒障碍会造成酒精依赖和昼夜节律紊乱的恶性循环。这一建议将集中描述自然（时钟基因和神经递质张力）和后天（环境）的复合效应，破坏昼夜节律并促进酒精依赖和酒精中毒。将利用Per2缺失小鼠品系，模拟轮班工作的轮换时间表和恒定的黑暗/光条件：(1)首次评估环境破坏和Per2时钟基因缺失对增强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)首次观察到谷氨酸拮抗剂和酒精复发药物阿坎prosate对与环境破坏和/或Per2时钟基因缺失相关的酒精偏好增强和复发风险的挽救作用；(3)首次探索昼夜节律计时和酒精奖励系统介导酒精偏好和复发风险的急剧减少。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，并且这种增强可以通过全身和颅内治疗来挽救。拟议的研究解决了以前轮班工作和现场研究的局限性，并将最理想地提高酒精中毒治疗的药理学和行为疗法的质量。

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.