[Adenosine in sleep regulation]

Sleepiness increases with duration of sleep deprivation. Rebound sleep together with enhancement of slow wave activity are characteristic of the subsequent recovery period. These homeostatic properties of the regulation of sleep-wakefulness are mediated by central adenosinergic modulations. The involvement of adenosine in sleep processes has been known for a long time, as illustrated by the fact that blockade of adenosine receptors by caffeine promotes wakefulness. However, its mechanisms of action in these processes have only recently been thoroughly investigated, notably by use of microdialysis techniques in free-moving animals. In the central nervous system, adenosine acts as a neurotransmitter, but it is not released from synaptic vesicles in specific neurons. Adenosine is synthesized in neurons and glial cells and is released into the extracellular space when energy expenditure exceeds energy production. Adenosine acts at A1 receptors to inhibit target transmitter release and to hyperpolarize neurons, and at A2A receptors, possibly activating GABAergic inhibitory systems. Extracellular concentrations of adenosine in most brain areas are deceased during sleep compared to wakefulness, but these modifications are linked to sleep regulatory mechanisms, essentially in the basal forebrain. In the basal forebrain and in the cortex, adenosine levels are considerably enhanced during sustained prolonged wakefulness and decrease progressively during the recovery period. This enhancement of adenosine concentration would be responsible for sleep rebound and for slow wave activity observed after sleep deprivation, since these effects are mimicked by infusion of A1 agonists into the basal forebrain and are counteracted by treatment with adenosinergic antagonists such as caffeine or theophylline. The action of adenosine on sleep-wakefulness regulation would be accounted for by an inhibitory influence on wakefulness-promoting cholinergic neurons of the basal forebrain and the mesopontine area, and by facilitation of sleep-related neurons in the hypothalamic preoptic nucleus. Through these mechanisms, adenosine would be, more than a sleep modular, a homeostatic signal regulating sleepiness and sleep rebound, which are both associated with prolonged wakefulness.