Adenosine A2A receptor deficiency attenuates the somnogenic effect of prostaglandin D2 in mice

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.