With advancing age, human exhibit characteristic changes in the temporal distribution of sleep and wakefulness. The underlying mechanism is not known, but it must reflect fundamental changes in circadian timing and sleep homeostatic processes. There are data to support that adenosine, a neuromodulator in the CNS, is involved in sleep regulation. Although, extracellular adenosine changes across the sleep-wake cycle and increases significantly following sleep deprivation, we do not know how the adenosine level is controlled with respect to these processes. Changes in the rate of adenosine production and/or changes in the activity of the enzymes controlling its levels are the most likely mechanism. We postulate that changes in the levels of adenosine metabolic enzymes and the set of adenosine transports modulate the level of adenosine in the CNS. We suggest that adenosine products its effects by acting within a network comprising cortex, monoaminergic and histaminergic arousal systems, interacting with sleep active neurons in the ventrolateral preoptic area of the hypothalamus. The regulation of adenosine in the brain is affected by age, and we plan to extend these observations to study the effect of age on regulation of adenosine in different critical neuronal groups, and how this regulation is altered across the sleep/wake cycle. It is likely, however, that it is not only the regulation that is affected by age but also neuronal responsiveness to adenosine. Thus, the hypothesis on which this proposal is based is that there are regionally- and temporally- specific regulation of adenosine in different micro-regions of the brain in which adenosine alters control of sleep, and that age may affect these processes in a fundamental way, as well as the responsiveness to adenosine within the relevant circuitry that controls sleep. To address this hypothesis, we have the following specific aims: (1) to establish whether age alters the activity of enzymes involved in adenosine synthesis and degradation in the brain regions relevant to the role of adenosine in sleep regulation, the magnitude of diurnal variations in this activity and their change following a period of prolonged wakefulness; (2) establish whether age alters the expression of the known elements of the adenosinergic system, in the regions relevant to its role in sleep control; (3) evaluate the impact of age on the responsiveness of the adenosinergic system in the CNS by studying the sleep inducing effects of adenosine receptor agonists, specifically of the A1 and A2a subtype, and the density of these receptors.
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