The hypocretins and alcohol dependence

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION (Provided by applicant): Alcohol dependence has long been linked to sleep disorders, including disruption of normal sleep architecture, and reductions of slow wave sleep and frequency of REM sleep episodes. The molecular basis of the effects of alcohol on sleep architecture is completely unknown. Among the substances that modulate sleep, the neuropeptides known as hypocretins/orexins are good candidates to mediate the effects of excessive alcohol consumption. Infusion of the hypocretins decreases deep slow wave sleep and suppresses REM sleep, alterations that are reminiscent to those found in alcoholic patients. Thus, in addition to modulate REM sleep, the hypocretins may also regulate the circuitry involved in addiction, and may be responsible for the sleep disorders associated with excessive alcohol consumption. The effect of alcohol dependence on hcrt signaling will be examined by whole cell and voltage clamp in neurons of the nucleus accumbens, a brain region involved in the brain's reward mechanisms and that contains high levels of hypocretin receptors the sleep patterns of mice with constitutively activated hypocretin cells. The sleep architecture of transgenic mice will be compared in three different states: control, alcohol dependent, and withdrawal. Finally, the reward mechanisms will be analyzed in transgenic mice with constitutive hypocretin activation, and in transgenic mice depleted of hypocretin cells. The development of these mouse models will generate invaluable tools to assess the role of the hypocretins on drug abuse, and may help to design better treatments for sleep disorders associated with alcoholism.