Cellular Mechanisms Mediating the Somnogenic Effects of Ethanol

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DESCRIPTION (provided by applicant): Considerable evidence exists to suggest that ethanol consumption has significant impact on nocturnal sleep and daytime alertness in humans. While low to moderate intake of ethanol in non-alcoholics improves sleep, high doses of ethanol intake produces severe sleep disruptions. Alcoholics, both during drinking period as well as during withdrawal suffer from a multitude of sleep disturbances including difficulty in initiating and maintaining sleep during the night. The broad objective of this program of research is to understand the cellular and molecular mechanisms mediating the somnogenic effects of ethanol and thereby provide a sound basis to the understanding and treatment of ethanol related sleep disorder. The key techniques to be used are novel combinations of multi-disciplinary methods including the: A) in vivo "on-line" microdialysis sampling coupled with HPLC measurement of adenosine and electrographic monitoring of sleep-wakefulness following ethanol administration. B) In vivo "off line" c-Fos immunohistochemistry to determine the neuronal phenotypes mediating the somnogenic effects of ETOH. Our broad hypothesis is that adenosine via A1 receptor is responsible for mediating the somnogenic effects of ethanol. We predict that acute ethanol administration will increase extracellular levels of adenosine in the cholinergic basal forebrain. Increased adenosine, acting via adenosine A1 receptor, will inhibit the wake-promoting cholinergic neurons of the basal forebrain as evidenced by a reduction in number of cholinergic neurons with c-Fos immunoreactivity. Furthermore, blockade of adenosine transmission by local infusion of adenosine A1 receptors antagonist into the basal forebrain will attenuate the somnogenic effects of ethanol. . PUBLIC HEALTH RELEVANCE: The broad objective of this research program is to understand the cellular and molecular mechanisms responsible for the somnogenic effects of ethanol and thereby to provide a sound basis for the understanding and treatment of sleep disorder associated with ethanol.