Prostaglandins and adenosine in the regulation of sleep and wakefulness

Prostaglandin (PG) D-2 and adenosine are potent humoral sleep-inducing factors that accumulate in the brain during prolonged wakefulness. PGD(2) is produced in the brain by lipocalin-type PGD synthase, which is localized mainly in the leptomeninges, choroid plexus and oligodendrocytes, and circulates in the cerebrospinal fluid as a sleep hormone. It stimulates DID, receptors on leptomeningeal cells of the basal forebrain to release adenosine as a paracrine signaling molecule to promote sleep. Adenosine activates adenosine A(2A) receptor-expressing sleep-active neurons in the basal forebrain and the ventrolateral preoptic area. Sleep-promoting neurons in the ventrolateral preoptic area send inhibitory signals to suppress the histaminergic neurons in the tuberomammillary nucleus, which contribute to arousal through histamine H, receptors. Increased knowledge of the molecular mechanisms by which PGD(2) induces sleep through activation of adenosine A(2A) receptors and inhibition of the histaminergic arousal system will be useful both for a better understanding of sleep/wake regulation and for the development of novel types of sleeping pills or anti-doze drugs.