Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus

The hypothalamic orexin (hypocretin) neuropeptides are associated with the regulation of sleep and feeding, and disturbances in orexinergic neurotrans mission lead to a narcoleptic phenotype. Histamine has also been shown to p lay a role in the regulation of sleep and feeding. Therefore, we studied th e relationship between the orexin and histamine systems of the CNS using el ectrophysiology, immunocytochemistry, and the reverse transcriptase (RT)-PC R method. Both orexin-A and orexin-B depolarized the histaminergic tuberomammillary n eurons and increased their firing rate via an action on postsynaptic recept ors. The depolarization was associated with a small decrease in input resis tance and was likely caused by activation of both the electrogenic Na+/Ca2 exchanger and a Ca2+ current. In a single-cell RT-PCR study using primers for the two orexin receptors, we found that most tuberomammillary neurons e xpress both receptors and that the expression of the orexin-2 receptor is s tronger than that of the orexin-1 receptor. Immunocytochemical studies show that the histamine and orexin neurons are often located very close to each other. The contacts between these two types of neurons seem to be reciproc al, because the orexin neurons are heavily innervated by histaminergic axon s. These results suggest a functional connection between the two population s of hypothalamic neurons and that they may cooperate in the regulation of rapid-eye-movement sleep and feeding.