Minireview: Sleep regulation in adenosine A2A receptor-deficient mice

Adenosine is proposed to be an endogenous sleep-promoting substance based on the results of a variety of pharmacologic and behavioral experiments.1 For example, sleep is induced in rats after administration of metabolically stable adenosine analogues, such as N6-l-(phenylisopropyl)-adenosine, adenosine-5′-N-ethylcarboxamide, and cyclohexyladenosine,2,3⇓ which are agonists for adenosine A1 receptor (A1R) or A2A receptors (A2ARs). Caffeine is considered to inhibit sleep by acting as an antagonist of adenosine receptor.4 Adenosine content is increased in the basal forebrain, one of the sleep centers, after sleep deprivation and is proposed to be a sleep substance accumulating in the brain during prolonged wakefulness.5 Most previous studies on sleep regulation by adenosine have focused on the A1R-mediated pathway1,6⇓ because A1R is widely distributed in the CNS, whereas A2AR is localized mainly in the striatum, nucleus accumbens, and olfactory bulb. However, we found that A2AR is also important in sleep regulation by using several A1R and A2AR agonists, including N6-cyclopentyladenosine (CPA) and 2-(4-(2-carboxyethyl)phenylethylamino)-adenosine-5′- N -ethylcarboxamideadenosine (CGS 21680).7-12⇓⇓⇓⇓⇓ CGS 21680 is highly selective for the A2AR (Ki = 14 nmol/L), having a much lower affinity for the A1R (Ki = 2,600 nmol/L), whereas CPA is selective for the A1R (Ki = 0.6 nmol/L) and has a lower affinity for the A2AR (Ki = 462 nmol/L).13,14⇓ We investigated the molecular mechanism of induction of non-REM (NREM) sleep by prostaglandin (PG) D2, which is also known as a potent endogenous sleep-promoting substance.15-17⇓⇓ In the course of this study, Satoh et al.7 found that PGD2 …