Orexins (hypocretins) directly excite tuberomammillary neurons

Wakefulness has recently been shown to depend upon the newly identified ore xin (or hypocretin) neuropeptides by the findings that alteration in their precursor protein, their receptors or the neurons that produce them leads t o the sleep disorder narcolepsy in both animals and humans. The questions o f how and where these brain peptides act to maintain wakefulness remain unr esolved. The purpose of the present study was to determine whether the orex ins could directly affect hypothalamic histaminergic neurons, which are kno wn to contribute to the state of wakefulness by their diffuse projections t hrough the brain. Using brain slices, we recorded in the ventral tuberomamm illary nuclei from neurons identified as histaminergic on the basis of thei r previously described morphological and electrophysiological characteristi cs and found that they were depolarized and excited by the orexins through a direct postsynaptic action. We then compared the depolarizing effect of o rexin A and B and found that they were equally effective upon these cells. This latter finding suggests that the effect of orexins is mediated by orex in type 2 receptors, which are those lacking in narcoleptic dogs. Our resul ts therefore show that the histaminergic neurons of the tuberomammillary nu clei represent an important target for the orexin system in the maintenance of wakefulness.