Manuel Sanchez-Alavez, Ph.D. - US grants

? DESCRIPTION (provided by applicant): Despite the clear importance of sleep disturbance in the clinical course of alcoholism and the maintenance of sobriety, the complex relationship between insomnia and alcohol dependence continues to remain poorly understood. The reason for this is, in part, because alcohol dependent patients often have co-morbid medical, psychiatric and other substance use disorders, as well as risk factors for insomnia that may have predated their alcohol use. An additional barrier to progress in understanding sleep disturbance associated with alcoholism is the development of translatable animal models that would allow the control necessary to investigate the long term effects of alcohol on sleep and to develop new therapeutics. Studies from our laboratory, in rats, have demonstrated that moderate ethanol exposure via vapor can produce long term changes in sleep and arousal, impairments in anxiety and affective behavior, increases in voluntary ethanol consumption as well as changes in brain levels of key neuropeptides important in the regulation of sleep and arousal. Significant increases in sleep latency, reductions in the mean duration of slow wave sleep (SWS) episodes and the total amount of time spent in SWS, have been found in adult rats treated with vapor. This suggests that alcohol-induced sleep pathology may preferentially affect the homeostatic sleep regulatory system. Studies in this application propose to further develop this model of ethanol exposure-induced sleep disturbance. It is our hypothesis that the hypocretin/orexin (Hct/OX) system interacts with the classical sleep regulatory to produce chronic alcohol-induced sleep and behavioral pathology. We predict that ethanol induced disturbances in these neural pathways leads to hyperarousal, thalamocortical dysrhythmias, signs of anxiety and depression and disruptions in sleep. We have designed behavioral, electrophysiological and neurochemical studies to test this hypothesis. We further propose to test, in this animal model, therapeutic agents that affect these systems. One that has recently been demonstrated to improve sleep disturbances seen in human alcoholics (gabapentin), as well as two new therapeutic drugs for alcohol-induced insomnia that targets Hct/OX receptors will be studied. The studies outlined will establish a model whereby the mechanisms underlying alcohol-induced sleep pathology can be elucidated and new therapeutics tested using electrophysiological measures that are translatable to the human condition.