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Histaminergic neurons solely originate from the tuberomammillary nucleus (TMN) in the posterior hypothalamus and send widespread projections to the whole brain.Experiments in rats show that histamine release in the central nervous system is positively correlated with wakefulness and the histamine released is 4 times higher during wake episodes than during sleep episodes.Endogeneous prostaglandin E2 and orexin activate histaminergic neurons in the TMN to release histamine and promote wakefulness.Conversely, prostaglandin D2 and adenosine inhibit histamine release by increasing GABA release in the TMN to induce sleep.This paper reviews the effects and mechanisms of action of the histaminergic system on sleep-wake regulation, and briefly discusses the possibility of developing novel sedative-hypnotics and wakefulness-promoting drugs related to the histaminergic system.