The broad objective of this program of research is to understand the physiological and pharmacological mechanisms controlling sleep, both the REM and nonREM phases, and thereby provide a sound basis for the understanding and treatment of human sleep disorders, both primary and secondary to medical and psychiatric conditions. The experiments described in this proposal focus on understanding of sleep and wakefulness at the cellular level. The key technique to be used is a novel combination of microdialysis and extracellular single unit recording in freely behaving cats. The nonREM sleep phase. Although data, including those from our laboratory, suggest adenosine is an endogenous sleep factor that acts on the brain to promote the nonREM phase of sleep, the specific cellular mechanisms of adenosine's actions are not known. Adenosine's powerful state-altering effects occur primarily via the basal forebrain cholinergic neurons' widespread and strategic efferent projections to the cortical and thalamic systems that are known to be important for the control of cortical activation. The basal forebrain/preoptic region of the forebrain is widely implicated in behavioral state control. The major hypothesis to be investigated is whether adenosine mediates sleep effect by the selective inhibition of the wake-active neurons in the basal forebrain/preoptic region, without having any effect of non-wake-active and/or sleep-related neurons. Our present preliminary data in cat support the hypothesis that the wake-active neurons of the basal forebrain/preoptic region mediate the sleep-promoting actions of adenosine, acting via A1 receptors. We will also evaluate the extent of noradrenergic control on the basal forebrain regulation of arousal. Preliminary data indicate that norepinephrine increases the discharge activity of basal forebrain wake-active neurons. The REM sleep phase. The hypothesis that norepinephrine-containing locus coeruleus neurons disinhibit cholinergic neurons and allow REM sleep to occur when these locus coeruleus neurons slow discharge during slow wave and REM sleep will also be evaluated. We will test the hypothesis the locus coeruleus input acting through the alpha-2 receptor inhibits discharge of the mesopontine cholinergic zone neurons that have been behaviorally identified to be preferentially active during REM sleep. In contrast, we predict neurons active in both wakefulness and REM sleep will be minimally or not at all affected by microdialysis application of norepinephrine. Finally, using the same unit recording/microdialysis technique, we will examine the degree to which serotonin acts to control the sleep-related slowing of dorsal raphe nucleus neuronal discharge via the 5-HT1A somato-dendritic receptors. Preliminary data suggest a strong suppressive effect of microdialysis-applied 8-OH-DPAT on state-related discharge activity of the dorsal raphe nucleus, and we will also investigate the effects of 5HT1A antagonists.
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