Alcoholic patients, particularly African American alcoholics, die prematurely due in pat to increased rates of cardiovascular-, neoplastic, and infectious disorders. Sleep disturbance is prominent in alcoholics, and recent observations implicate sleep in the homeostatic regulation of autonomic and visceral physiology. However, the clinical manifestations of untreated sleep disturbance in alcoholics remain largely unknown. We have found that African American alcoholics show disturbances of sleep marked by a profound loss of slow wave sleep and elevated sympathetic nervous system activation as compared to white alcoholics. In addition, disruption of sleep continuity and/or loss of slow wave sleep is associated with elevated circulating concentrations of catecholamines and reduction of natural killer (NK) cell activity and interleukin-2 production. This revised application focuses on the novel hypothesis that sleep disturbance, primarily loss of slow wave sleep, in African American alcoholics leads to evaluations in sympathetic nervous system activity which subsequently leads to impaired NK responses and cytokine production. The project proposed here will: 1) Examine whether sleep loss induced by partial night sleep deprivation elevates sympathetic nervous system activity and reduces NK responses and associated cytokine production in African American and white alcoholics and matched controls independent of effects on neurobehavioral symptoms; 2) Evaluate the association between slow wave sleep and modulation of sympathetic tone and NK responses and associated cytokine production in African American-and white alcoholics and controls. The capacity of alcoholics to exhibit increases of slow wave sleep is hypothesized to be impaired. Following either partial night sleep deprivation or administration of a selective centrally acting serotonin receptor antagonist, alcoholics will show less robust increases of slow wave sleep as compared to controls which correlate with elevations of sympathetic tone and decrements of Nk activity. 3)) Determine whether nocturnal secretion of sympathetic neurotransmitters mediates alterations of cytokine production and NK responses in alcoholics and controls. Using in vivo and in vitro approaches, pharmacologically selective beta-receptor antagonists will test the role of beta2 receptor mechanisms in the modulation of NK cell responses and cytokine secretion in alcoholics and controls at rest and following sleep loss. This application will enhance knowledge of the neurobehavioral and autonomic consequences of sleep loss, generate new information concerning the role of slow wave sleep in the physiologic regulation of sympathetic tone and NK- and cytokine responses during sleep loss and in alcoholism, and test sympathetic mechanisms of potential therapeutic utility in preventing alterations of NK responses and cytokine production in sleep disturbance.
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