Adenosine A_2A receptor deficiency attenuates the somnogenic effect of prostaglandin D₂ in mice

Prostaglandin D₂ (PGD₂) is one of the most potent endogenous sleep promoting substances. PGD₂ activates the PGD2 receptor (DPR) and increases the extracellular level of adenosine in wild-type (WT) mice but not DPR knockout (KO) mice, suggesting that PGD₂- induced sleep is DPR-dependent, and adenosine may be the signaling molecule that mediates the somnogenic effect of PGD₂. The aim of this study was to determine the involvement of the adenosine A_2A receptor (A_2AR) in PGD₂-induced sleep. We infused PGD₂ into the lateral ventricle of WT and A_2AR KO mice between 20:00 and 2:00 for 6 h, and electroencephalograms and electromyograms were simultaneously recorded. In WT mice, PGD₂ 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. PGD₂ infusion at doses of 20 and 50 pmol/min also increased REM sleep during the 6-h PGD₂ infusion and 4-h post-dosing periods in WT mice to 148.9% and 166.7%, respectively. In A_2AR KO mice, however, PGD2 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 PGD₂ infusion to 117.5% and 155.6%, respectively, but did not change the sleep in the post-dosing period. Moreover, PGD₂ 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 PGD₂- induced sleep in mice is mediated by both adenosine A_2AR-dependent and -independent systems.