Adenosine and sleep.

Adenosine is directly linked to the energy metabolism of cells. In the central nervous system an increase in neuronal activity enhances energy consumption as well as extracellular adenosine concentrations. In most brain areas high extracellular adenosine concentrations, through A(1) adenosine receptors, decrease neuronal activity and thus the need for energy. Adenosine seems to act as a direct negative feed-back inhibitor of neuronal activity. Hypoxia and ischemia induce very high extracellular adenosine levels, which may limit further brain damage. In brain areas that regulate cortical vigilance, particularly in the basal forebrain, high extracellular adenosine concentrations, induced by prolonged wakefulness, decrease the activity of presumably cholinergic cells and via this mechanism promote sleep. Our hypothesis is that in the cholinergic basal forebrain prolonged wakefulness induces local energy depletion that generates increases in extracellular adenosine concentrations in this area. In addition to the immediate effects, high extracellular adenosine concentrations also induce intracellular changes in signal transduction and transcription, e.g. increase in A(1) receptor expression and NF-kappaB binding activity. These changes may at least partially mediate the long term effects of prolonged wakefulness. Adenosine may also be a common mediator of the effects of several other sleep-inducing factors.