Sleep disorders, disturbances, and deprivation affect people of all ages, but are common among the aged. The consequences of such disturbances in sleep are important clinically because of increased morbidity, mortality and decreased quality of life, and economically of reduced levels of productivity, decreased levels of learning and memory, and increased incidences of accidents. Treatments of sleep disorders are made difficult because there are gaps in our knowledge about he neurobiology of sleep- indeed sleep research has been referred to as a frontier of neuroscience because even the most basic of questions """"""""Why do we sleep?"""""""" is unanswered. One substance increasingly implicated in sleep regulation is adenosine, an endogenous purine nucleoside. Multiple mechanisms and processes including its production, metabolism, release, and uptake (transport) regulate the levels of adenosine available to activate cell surface adenosine receptors classified as A2, A2A, A2B, and A3 on the basis of biochemical and pharmacological criteria, and molecular structures, and A1, A2A, A2B, and A2 on the basis of biochemical and pharmacological criteria, and molecular structures, and changes in these mechanisms and processes with age, almost certainly, change the levels and actions of adenosine. Once activated, adenosine receptors have profound effects on many different aspects of neural cells implicated in sleep regulation and sleep need including excitability and glycogen metabolism. However, at present very little is known about regulation of brain levels of adenosine in vivo and how this regulation is affected by age. Moreover, virtually nothing is known about the effects of adenosine on sleep in the aged and how increased wakefulness in the aged affects levels of adenosine and the expression of its actions. Since the early 1980's we have focused our work on determining the mechanisms by which and extent to which adenosine-enzymes and -transporters control the levels and actions of adenosine in vivo. The present application will take full advantage of our extensive background in the adenosine field to test specific hypothesis relating to the control of brain adenosine levels as a function of increased age and wakefulness. Our overall hypothesis are that adenosine is an important regulator of sleep, that with increased age and wakefulness adenosine levels increase, and that increased levels of adenosine will result in increased levels of glycogen in specific sleep- related brain regions.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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University of Pennsylvania
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