Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities

Hypocretins/orexins are neuropeptides implicated in sleep regulation and th e sleep disorder narcolepsy. In order to examine how hypocretin activity fl uctuates across 24 h with respect to the sleep-wake cycle, we measured chan ges in extracellular hypocretin-1 levels in the lateral hypothalamus and me dial thalamus of freely moving rats with simultaneous sleep recordings. Hyp ocretin levels exhibited a robust diurnal fluctuation; levels slowly increa sed during the dark period (active phase), and decreased during the light p eriod (rest phase). Levels were not correlated with the amount of wake or s leep in each period. Although an acute 4-h light-shift did not alter hypocr etin levels, 6-h sleep deprivation significantly increased hypocretin relea se during the forced-wake period. Hypocretin activity is, thus, likely to b uild up during wakefulness and decline with the occurrence of sleep. These findings, together with the fact that a difficulty in maintaining wakefulne ss during the daytime is one of the primary symptoms of hypocretin-deficien t narcolepsy, suggest that hypocretin activity may be critical in opposing sleep propensity during periods of prolonged wakefulness.