Lipocalin-type prostaglandin D synthase produces prostaglandin D2 involved in regulation of physiological sleep.

Prostaglandin (PG) D 2 has been proposed to be essential for the initiation and maintenance of the physiological sleep of rats because intracerebroventricular administration of selenium tetrachloride (SeCl 4 ), a selective inhibitor of PGD synthase (PGDS), was shown to reduce promptly and effectively the amounts of sleep during the period of infusion. However, gene knockout (KO) mice of PGDS and prostaglandin D receptor (DP 1 R) showed essentially the same circadian profiles and daily amounts of sleep as wild-type (WT) mice, raising questions about the involvement of PGD 2 in regulating physiological sleep. Here we examined the effect of SeCl 4 on the sleep of WT and KO mice for PGDS and DP 1 R and that of a DP 1 R antagonist, ONO-4127Na, on the sleep of rats. The i.p. injection of SeCl 4 into WT mice decreased the PGD 2 content in the brain without affecting the amounts of PGE 2 and PGF 2α . It inhibited sleep dose-dependently and immediately after the administration during the light period when mice normally sleep, increasing the wake time; and the treatment with this compound resulted in a distinct sleep rebound during the following dark period. The SeCl 4 -induced insomnia was observed in hematopoietic PGDS KO mice but not at all in lipocalin-type PGDS KO, hematopoietic and lipocalin-type PGDS double KO or DP 1 R KO mice. Furthermore, the DP 1 R antagonist ONO-4127Na reduced sleep of rats by 30% during infusion into the subarachnoid space under the rostral basal forebrain at 200 pmol/min. These results clearly show that the lipocalin-type PGDS/PGD 2 /DP 1 R system plays pivotal roles in the regulation of physiological sleep.