Arousal effect of orexin A depends on activation of hte histmic system

Orexin neurons are exclusively localized in the lateral hypothalamic area a nd project their fibers to the entire central nervous system, including the histaminergic tuberomammillary nucleus (TMN). Dysfunction of the orexin sy stem results in the sleep disorder narcolepsy, but the role of orexin in ph ysiological sleep-wake regulation and the mechanisms involved remain to be elucidated. Here we provide several lines of evidence that orexin A induces wakefulness by means of the TMN and histamine H-1 receptor (H1R). Perfusio n of orexin A (5 and 25 pmol/min) for 1 hr into the TMN of rats through a m icrodialysis probe promptly increased wakefulness for 2 hr after starting t he perfusion by 2.5-and 4-fold, respectively, concomitant with a reduction in rapid eye movement (REM) and non-REM sleep. Microdialysis studies showed that application of orexin A to the TMN increased histamine release from b oth the medial preoptic area and the frontal cortex by approximate to2-fold over the baseline for 80 to 160 min in a dose-dependent manner. Furthermor e, infusion of orexin A (1.5 pmol/min) for 6 hr into the lateral ventricle of mice produced a significant increase in wakefulness during the 8 hr afte r starting infusion to the same level as the wakefulness observed during th e active period in wild-type mice, but not at all in H1R gene knockout mice . These findings strongly indicate that the arousal effect of orexin A depe nds on the activation of histaminergic neurotransmission mediated by H1R.