Alcohol dependence, epigenetic changes and sleep disruptions.

描述（申请人提供）：酒精饮料的摄入对睡眠有显著影响。非酒精中毒者急性酒精摄入会促进嗜睡。相比之下，酗酒者，无论是在饮酒期间还是在戒断期间，都会遭受严重和长期的失眠和相关的睡眠中断，这些失眠和睡眠中断在戒酒期间持续数月。酗酒者康复期的失眠和相关的睡眠障碍是酗酒复发的主要危险因素。因此，我们必须了解和治疗睡眠障碍，在恢复酗酒者。这项研究计划的主要目标是阐明介导乙醇对睡眠-觉醒影响的分子机制，从而为理解和治疗乙醇相关的睡眠障碍和酒精中毒提供坚实的基础。我们的假设是：在酒精戒断期间观察到的严重失眠和相关的睡眠中断是促进唤醒的基底前脑区域的表观遗传变化的结果。我们预测，表达的转录因子，FosB/δ FosB将增加在唤醒促进基底前脑区在乙醇戒断。我们进一步预测，时钟蛋白的表达，一个关键的睡眠和昼夜调节与组蛋白乙酰转移酶活性，将减少在基底前脑乙醇戒断过程中。此外，我们预测，慢性乙醇暴露将减少乙酰化组蛋白，H3和H4，在基底前脑。在基底前脑中局部和双侧给予组蛋白去乙酰化酶抑制剂，阿司他丁-A，将减轻慢性乙醇诱导的失眠和相关的睡眠中断。 公共卫生相关性：这项研究计划的主要目标是了解在酒精戒断期间导致睡眠中断的分子机制，从而为理解和治疗酒精中毒提供坚实的基础。

DESCRIPTION (provided by applicant): Intake of alcoholic beverages has significant impact on sleep. Acute alcohol intake in non- alcoholics promotes sleepiness. In contrast, alcoholics, both during drinking period as well as during withdrawal suffer from profound and protracted insomnia and associated sleep disruptions that persist for several months during abstinence. Insomnia and associated sleep disturbances in recovering alcoholics are major risk factors for relapse to alcoholism. Thus, it is imperative that we understand and treat sleep disturbances in recovering alcoholics. The broad objective of this program of research is to elucidate the molecular mechanisms mediating the effects of ethanol on sleep-wakefulness and thereby provide a sound basis for the understanding and treatment of ethanol associated sleep disturbances and alcoholism. Our hypothesis: Profound insomnia and associated sleep disruptions observed during alcohol withdrawal are the result of epigenetic changes in the wake-promoting basal forebrain region. We predict that the expression of transcription factor, FosB/delta FosB will be increased in the wake-promoting basal forebrain region during ethanol withdrawal. We further predict that the expression of Clock protein, a key sleep and circadian regulator with histone acetyltransferase activity, will be reduced in the basal forebrain during ethanol withdrawal. Furthermore, we predict that chronic ethanol exposure will decrease acetylation of histones, H3 and H4, in the basal forebrain. Local and bilateral administration of histone deacetylase inhibitor, trichostatin-A, in the basal forebrain will attenuate chronic ethanol induced insomnia and associated sleep disruptions. PUBLIC HEALTH RELEVANCE: The broad objective of this research program is to understand the molecular mechanisms responsible for causing sleep disruptions during alcohol withdrawal and thereby provide a sound basis for the understanding and treatment of alcoholism.