Sleep and adenosine: Human studies

Abstract

Adenosine, through A 1 receptors, acts as an inhibitory neuromodulator in the central nervous system. It is also directly linked to the energy metabolism of cells. It codes for energy depletion: adenosine levels increase as sign of problems in energy balance. Extracellular adenosine levels increase as response to prolonged wakefulness, starting locally in the basal forebrain area and later in the cortex. The increased extracellular adenosine concentrations increase signaling through A 1 receptors on the waking-active cells, inhibit their firing and thus promote sleep. Human studies also indicate a connection between adenosine metabolism and sleep regulation. There are functional polymorphisms in adenosine transporters and adenosine deaminase, which will increase extracellular adenosine concentrations. Individuals with the adenosine deaminase variant have more and deeper slow wave sleep as well as more alpha activity in their waking EEG. Interestingly, their vigilance level and performance during waking are compromised. Caffeine, a nonspecific adenosine receptor blocker, modulates effectively vigilance level and sleep in humans. Sensitivity to caffeine is modulated by an adenosine 2a receptor polymorphism: carriers of the different variants respond differently, both behaviorally and in EEG records, to caffeine. Prolonged wakefulness deteriorated performance more in caffeine-sensitive individuals, but their performance also benefitted more from caffeine intake. Sleep problems predispose to depression, and as adenosine is one of the regulators of sleep, changes in adenosine metabolism can be expected also in depressed patients. Indeed, a suggestive finding is that a polymorphism in the adenosine transporter gene SLC29A3 was associated with depressive disorder. Interestingly, this association was found only in women but not in men. In summary, both animal and human experiments evidence that low brain adenosine concentrations are associated with high vigilance levels and wakefulness, while increases in adenosine levels associate with increased sleep propensity and promotion of sleep.