Alcohol dependence, epigenetic changes and sleep disruptions.

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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.