Abstract
Although we repeat sleep-wake cycles every day and night and spend almost one third of our life time sleeping in bed, little has been known about sleep in the contemporary medicine. In this paper, a brief review is presented covering our recent studies on the mechanism of sleep-wake regulation by prostaglandins (PG)D_2 and E_2 during the past 15 years in my laboratory at the Osaka Bioscience Institute. PGD_2 and E_2 are the major prostanoids in the mammalian brain, the former inducing sleep and the latter wakefulness. When PGD synthase (PGDS) was inhibited in vivo by a specific enzyme inhibitor, both NREM and REM sleep were inhibited almost completely indicating that PGDS is a key enzyme in sleep regulation. This enzyme is mainly, if not exclusively, localized in the membrane system surrounding the brain and is secreted into the cerebrospinal fluid to become β-trace protein. PGD_2 thus produced circulates in the CSF, exerts its somnogenic activity by binding with PGD_2 receptors, exclusively localized at the ventro medial surface of the rostral basal forebrain. When PGD_2 was infused into this area, concurrent with sleep induction, striking expression of c-fos immu- noreactivity was observed in the ventro lateral preoptic area (VLPO). These observations suggest that PGD_2 may induce sleep via leptomeningeal PGD_2 receptors with subsequent activation of the VLPO neurons. This process appears to be mediated by adenosine through adenosine A_<2a> receptor.
