Adenosine in sleep and wakefulness.

Sleep propensity increases in the course of wakefulness: the longer the previous wakefulness period is, the longer and deeper (measured as delta power in EEG recordings) is the following sleep. The mechanisms that regulate the need of sleep at the cellular level are largely unknown. The inhibitory neuromodulator, adenosine, is a promising candidate for a sleep-inducing factor: its concentration is higher during wakefulness than during sleep, it accumulates in the brain during prolonged wakefulness, and local perfusions as well as systemic administration of adenosine and its agonists induce sleep and decrease wakefulness. Adenosine receptor antagonists, caffeine and theophylline, are widely used as stimulants of the central nervous system to induce vigilance and increase the time spent awake. Our hypothesis is that adenosine accumulates in the extracellular space of the basal forebrain during wakefulness, increasing the sleep propensity. The increase in extracellular adenosine concentration decreases the activity of the wakefulness-promoting cell groups, especially the cholinergic cells in the basal forebrain. When the activity of the wakefulness-active cells decreases sufficiently sleep is initiated. During sleep the extracellular adenosine concentrations decrease, and thus the inhibition of the wakefulness-active cells also decreases allowing the initiation of a new wakefulness period.