PROJECT SUMMARY/ABSTRACT Clinical studies have demonstrated that drinking typically begins in adolescence and may lead to alcohol use disorders (AUD). Both younger and older adults with heavy drinking/AUDs are twice as likely to have insomnia that can last for several years. Yet the complex interactions between sleep, drinking, and maintenance of sobriety remain poorly understood despite their profound clinical implications. We postulate that cycles of binge drinking and withdrawal can lead to hyper-arousal states that disrupt sleep and may further drive drinking. One barrier to progress in testing this hypothesis has been the lack of translatable animal models that would allow the control necessary to investigate the long-term effects of alcohol on sleep and daytime functioning. Studies from our laboratory, in rats, have demonstrated that moderate ethanol exposure, either in adolescence or in adulthood, can produce long-term changes in the sleep/wake EEG that mirror the human condition, as well as an enhancement of drinking in adulthood. Alcohol studies in human subjects have recently focused not only on nighttime polysomnographic findings but also on daytime sleepiness and disrupted activity levels, as measured by “fit bit” devices. We propose to further test a “fit bit” system that we have developed in rats to monitor alcohol-induced sleep/wake disturbance, as well as use it to assess the efficacy of potential therapeutic interventions, and to test mechanistic physiological hypotheses related to the etiology of alcohol-induced disturbances of sleep and functional wakefulness. A prominent role of the hypothalamic peptide hypocretin/ orexin (Hct/OX) in homeostatic control of both the sleep/wake cycle and ethanol-seeking and drinking behaviors has been demonstrated. We have also shown partial pharmacological reversal of alcohol-induced sleep pathology by Hct/OX antagonists, however, we do not know if they also impact drinking. New pharmacological studies will test the specificity of the Hct/OX1 vs. Hct/OX2 receptor, vs. dual receptor antagonism, to modify sleep vs. drinking following alcohol. We have also demonstrated that alcohol exposure increases hypothalamic Hct/OX, and RNA-seq/ ATAC-seq studies show that the Hct/OX2 receptor gene is impacted in frontal cortex. The new mechanistic studies we propose will focus on the hypothalamic Hct/OX system using siRNA-mediated hypocretin/ orexin OX1 and OX2 knockdown, gene expression using RNA-seq, and epigenetic changes using ATAC-seq. Such studies could also inform precision/personalized medicine decisions by adding evidenced-based data to the suggestion that Hct/OX1 antagonists could be used for individuals with AUD with enhanced craving and Hct/OX2 antagonists for those with more profound sleep disturbances, and dual receptor antagonists for those with both.