Roles of adenosine and its receptors in sleep-wake regulation

This chapter summarizes the current knowledge about the role of adenosine in the sleep-wake regulation with a focus on adenosine in the brain, regulation of adenosine levels, adenosine receptors, and manipulations of the adenosine system by the use of pharmacological and molecular biological tools. Adenosine is neither stored nor released as a classical neurotransmitter and is thought to be formed inside cells or on their surface, mostly by breakdown of adenine nucleotides. The extracellular level of adenosine increases in the cortex and basal forebrain (BF) during prolonged wakefulness and decreases during the sleep-recovery period. Therefore, adenosine is proposed to act as a homeostatic regulator of sleep. The endogenous somnogen prostaglandin (PG) D2 increases the extracellular level of adenosine under the subarachnoid space of the BF and promotes physiological sleep. There are four adenosine receptor subtypes: adenosine A1 receptor (R, A1R), A2AR, A2BR, and A3R. Both the A1R and the A2AR have been reported to be involved in sleep induction. The A2AR plays an important role in the somnogenic effects of PGD2. Activation of A2AR by its agonist infused into the brain potently increases sleep and the arousal effect of caffeine, an A1R and A2AR antagonist, was shown to be dependent on the A2AR. On the other hand, inhibition of wake-promoting neurons via the A1R also mediates the sleep-inducing effects of adenosine, whereas activation of A1R in the lateral preoptic area induces wakefulness. These findings indicate that A2AR plays a predominant role in sleep induction, whereas A1R regulates the sleep-wake cycle in a site-dependent manner.