Minireview: Sleep regulation in adenosine A2A receptor-deficient mice

Yoshihiro Urade; Naomi Eguchi; Wei-Min Qu; Mie Sakata; Zhi-Li Huang; Jiang-Fan Chen; Michael A. Schwarzschild; J. Stephen Fink; Osamu Hayaishi

doi:10.1212/01.WNL.0000095222.41066.5E

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Adenosine in sleep regulation.

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 A_2A receptors (A_2ARs). 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 A_2AR is localized mainly in the striatum, nucleus accumbens, and olfactory bulb. However, we found that A_2AR is also important in sleep regulation by using several A₁R and A_2AR 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 A_2AR (K_i = 14 nmol/L), having a much lower affinity for the A₁R (K_i = 2,600 nmol/L), whereas CPA is selective for the A₁R (K_i = 0.6 nmol/L) and has a lower affinity for the A_2AR (K_i = 462 nmol/L).13,14⇓

Effects of A_2AR agonists and antagonists on sleep regulation in rats.

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 PGD_{2 …}

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Minireview: Sleep regulation in adenosine A_2A receptor-deficient mice

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Adenosine in sleep regulation.

Effects of A_2AR agonists and antagonists on sleep regulation in rats.

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Adenosine in sleep regulation.

Effects of A2AR agonists and antagonists on sleep regulation in rats.

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Minireview: Sleep regulation in adenosine A_2A receptor-deficient mice

Effects of A_2AR agonists and antagonists on sleep regulation in rats.