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Prostaglandin D 2 (PGD 2 ) is one of the most potent endogenous sleep promoting substances. PGD 2 activates the PGD 2 receptor (DPR) and increases the extracellular level of adenosine in wild-type (WT) mice but not DPR knockout (KO) mice, suggesting that PGD 2 -induced sleep is DPR-dependent, and adenosine may be the signaling molecule that mediates the somnogenic effect of PGD 2 . The aim of this study was to determine the involvement of the adenosine A 2A receptor (A 2A R) in PGD 2 -induced sleep. We infused PGD 2 into the lateral ventricle of WT and A 2A R KO mice between 20:00 and 2:00 for 6 h, and electroencephalograms and electromyograms were simultaneously recorded. In WT mice, PGD 2 infusion dose-dependently increased non-rapid eye movement (non-REM, NREM) sleep, which was 139.1%, 145.0% and 202.7% as large as that of vehicle-treated mice at doses of 10, 20 and 50 pmol/min, respectively. PGD 2 infusion at doses of 20 and 50 pmol/min also increased REM sleep during the 6-h PGD 2 infusion and 4-h post-dosing periods in WT mice to 148.9% and 166.7%, respectively. In A 2A R KO mice, however, PGD 2 infusion at 10 pmol/min did not change the sleep profile, whereas higher doses at 20 and 50 pmol/min increased the NREM sleep during the 6-h PGD 2 infusion to 117.5% and 155.6%, respectively, but did not change the sleep in the post-dosing period. Moreover, PGD 2 infusion at 50 pmol/min significantly increased the episode number in both genotypes but only enhanced the episode duration in WT mice. The results demonstrate that PGD 2 -induced sleep in mice is mediated by both adenosine A 2A R-dependent and -independent systems.