antagonist ͉ enzyme ͉ knockout mice ͉ receptor ͉ selenium tetrachloride T he somnogenic activity of prostaglandin (PG) D 2 was originally discovered serendipitously when we microinjected nanomolar quantities of PGD 2 in the preoptic area of rats (1). Subsequent studies using a continuous-infusion circadian sleep bioassay system revealed that the effect was specific to PGD 2 because other PGs were almost totally inactive (2). Infusion with as little as picomolar quantities per minute was sufficient to induce excess amounts of both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Sleep induced by PGD 2 was indistinguishable from physiological sleep as judged by several behavioral and electrophysiological criteria, including power spectral analysis (3). PGD 2 was not pyrogenic, and it actually caused a slight decrease in the body temperature, as is observed to occur during physiological sleep. These results suggested the possibility that PGD 2 might be a sleep hormone (4-7).PGD 2 is the most abundant prostanoid in the brains of rats (8) and other mammals, including humans (9); and it is produced in the brain from the substrate PGH 2 , a common intermediate of various prostanoids, by the action of PGD synthase (PGDS; PGH 2 D-isomerase, EC 5.3.99.2). Two distinct types of PGDS were purified from the brain (10) and spleen (11) of rats in our and other laboratories, and their structures were determined by x-ray crystallography (12, 13). One was the lipocalin-type PGDS (L-PGDS) (10, 14, 15), mainly expressed in the arachnoid membrane, choroids plexus, and oligodendrocytes in the brain (14, 16); and the other was hematopoietic PGDS (H-PGDS) (17, 18), localized in mast cells (19) and microglia (20,21). Inorganic tetravalent selenium compounds were found to be potent, relatively specific, and reversible inhibitors of PGDS when tested in vitro (22). These inhibitors seemed to interact with the free sulfhydryl group in the active site of PGDS because the inhibition could be reversed by the addition of excess amounts of SH compounds such as glutathione or DTT. In 1991, Matsumura and coworkers (23) administered selenium tetrachloride (SeCl 4 ) into the third ventricle of sleeping rats, and they found that sleep was inhibited almost completely after Ϸ2 h from the start of the infusion. The effect was reversible because when the infusion was interrupted, sleep was restored. Furthermore, the inhibition was reversed by the simultaneous infusion of SH compounds such as DTT and glutathione, as in the case of the in vitro enzyme activity. These results indicated that PGDS plays an essential role in the maintenance of sleep and, therefore, that PGD 2 is involved in sleep under physiological conditions in rodents.Our recent studies with gene knockout (KO) mice for PGDS and prostaglandin D receptors (DP 1 R) specific for PGD 2 showed that mice depleted of these genes did not exhibit NREM sleep rebound after sleep deprivation, suggesting that PGD 2 is crucial for the homeostatic regulation of NREM sleep (24). However, KO...