Among the sleep promoting compounds already identified is adenosine. Agonists of adenosine increase sleep, while antagonists decrease it. Extracellular levels of adenosine change across the sleep/wake cycle. Short-term sleep deprivation increases adenosine in an area of the brain known to be critical for sleep (basal forebrain). Although, therefore, there are considerable data to support the role of adenosine in regulation of sleep, we do not know how the level of adenosine is controlled with respect to the sleep/wake cycle. It cannot simply accumulate since it has an extremely short half-life. Rather, there must be changes in the amount of production from ATP or changes in the level of enzymes controlling the adenosine levels. These enzymes are adenosine deaminase (ADA), adenosine kinase (AK), and 5'-nucleotidase (5N). Changes in the activity of these enzymes occur across the 24 hour cycle, although such changes to date have only been described in frontal cortex, an area unlikely to be involved in sleep control. Our preliminary data have, however, extended these observations and we find """"""""circadian"""""""" changes in the levels of ADA in brain areas known to be involved in sleep control. The time course of the changes so far described suggest that during the active period of the cycle the enzyme levels increase thereby acting to limit the increase in adenosine that occur during wakefulness. However, preceding the rest period the enzyme levels decline, thereby, we propose, increasing adenosine to promote sleep. This hypothesis will be addressed initially by examining changes in the time course of the enzymes across the 24 hour cycle in brain regions relevant for sleep control (Protocol 1). We do not know, however, whether the enzymes are regulated by circadian influences, and/or sleep homeostasis. Our preliminary data suggest that both are important, although there is evidence of regional specificity. Extending these observations will be the goal of protococol 2. Specifically, we will determine the relative role of the circadian influence, sleep homeostasis and light/dark information in regulating these enzymes. Although temporal changes in these enzymes have been demonstrated, we do not know how this is achieved. As a first step in this we will seek evidence of transcriptional regulation (Protocol 3). To facilitate this, we have recently cloned segments of the genes for ADA and AK in rats. Thus, this proposal is directed at a fundamental question about sleep/wake regulation, i.e., how the adenosine level in relevant regions of the brain is regulated in relationship to sleep.

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