Accumulating evidence suggests that the neuromodulator adenosine (AD) may be an important mediator of sleep. This proposal outlines experiments to identify the neural mechanisms through which AD produced sleep. The ventrolateral pre-optic are (VLPO) may promote sleep by causing widespread inhibition of the cholinergic and monoaminergic arousal systems. We hypothesize that AD produced sleep by indirectly activating VLPO neurons. Specifically, we propose that AD inhibits neurons that tonically inhibit the VLPO during wakefulness; as AD accumulates during wakefulness, these neurons become less active, disinhibiting the VLPO. We will use in situ hybridization histochemistry to determine the distribution and neurochemical phenotype of neurons expressing AD receptors in the rat and human hypothalamus and basal forebrain. We will combine these receptor studies with injections of a retrograde tracer to identify which neurons expressing AD acts to produce or inhibit sleep by then will determine where in the hypothalamus or basal forebrain AD acts to produce or inhibit sleep by microinjecting AD agonists into specific hypothalamic regions and recording sleep/wake behavior. TO determine whether endogenous AD in the HYPO/BF influences sleep, we also will microinject drugs which increase or decrease the local concentration of AD and study their effect on sleep. Finally, we will study the electrophysiologic effects of AD agonists and antagonists on VLPO neurons using an in vitro slice preparation. This technique also will be used to record the response to AD agonists and antagonists of neurons that project to the VLPO. These experiments will help determine the biochemical source of AD, the anatomic sites at which AD induces sleep and the electrophysiologic mechanism through which AD produces sleep.
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