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Prostaglandin (PG) D2 is the major prostanoid in the mammalian brain, and is the endogenous sleep-promoting substance in mice, rats, and monkeys, and probably in humans as well. When PGD synthase (PGDS), the enzyme responsible for the biosynthesis of PGD2 in the brain, was inhibited in vivo by its selective inhibitors, tetravalent selenium compounds, both slow-wave sleep and rapid-eye-movement sleep were reduced almost completely but reversibly, indicating that PGDS is a key enzyme in sleep regulation. Experiments with transgenic mice also support this contention. Insitu hybridization, immunoperoxidase staining, and direct enzyme assay of tissue samples revealed that PGDS is mainly, if not exclusively, localized in the arachnoid membrane and choroid plexus, from which it is secreted into the cerebrospinal fluid to become β-trace protein. PGD2 exerts its somnogenic activity by binding with PGD2 receptors, exclusively localized at the ventro-rostral surface of the basal forebrain. CGS21680, an adenosine A2a agonist, mimicked the somnogenic activity of PGD2 when applied to the PGD2-sensitive zone. This effect was dose-dependently and selectively abolished by the prior i.p. application of the adenosine A2a antagonist KF 17837. Furthermore, the somnogenic activity of PGD2 was also dose-dependently and selectively attenuated by KF17837, indicating the possibility that the sleep induction by PGD2 may be mediated by adenosine through A2a receptors under these conditions. When PGD2 was infused into the subarachnoid space below the rostral basal forebrain, concurrent with sleep induction, striking expression of Fos immunoreactivity was observed in the ventro-lateral preoptic area. Fos expression in the ventrolateral preoptic area was positively correlated with the preceding amount of sleep and negatively correlated with Fos expression in the tuberomammillary nucleus. PGD2 also increased Fos IR in the basal leptomeninges and several regions implicated in autonomic regulation. These observations suggest that PGD2 may induce sleep via leptomeningeal PGD2 receptors with subsequent activation of the ventrolateral preoptic area neurons.