Hypocretin (Hcrt or orexin) somas are located in the hypothalamus and project widely to forebrain and brainstem regions, densely innervating monoaminergic and cholinergic cells. Loss of Hcrt function results in the sleep disorder narcolepsy. However, the normal pattern of Hcrt release across the sleep-wake cycle is unknown. We monitored Hcrt-1 release in the basal forebrain, perifornical hypothalamus, and locus ceruleus (LC) across the sleep-wake cycle using microdialysis in freely moving cats and a sensitive solid phase radioimmunoassay. We found that the peptide concentration in dialysates from the hypothalamus was significantly higher during active waking (AW) than during slow-wave sleep (SWS). Moreover, Hcrt-1 release was significantly higher during rapid eye movement (REM) sleep than during SWS in the hypothalamus and basal forebrain. We did not detect a significant difference in release across sleep-waking states in the LC, perhaps because recovered levels of the peptide were lower at this site. Because there was a trend toward higher levels of Hcrt-1 release during AW compared with quiet waking (QW) in our 10 min dialysis samples, we compared Hcrt-1 levels in CSF in 2 hr AW and QW periods. Hcrt-1 release into CSF was 67% higher during AW than during QW. Elevated levels of Hcrt during REM sleep and AW are consistent with a role for Hcrt in the central programming of motor activity.

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release in normal and narcoleptic dogs after food and sleep deprivation, eating, and movement. Am

Hypocretin (Hcrt) cell loss is responsible for narcolepsy, but Hcrt's role in normal behavior is unclear. We found that Hcrt KO mice were unable to work for food or water reward during the light phase. However, they were unimpaired relative to wild type (WT) mice when working for reward during the dark phase or when working to avoid shock in the light or dark phases. In WT, expression of Fos in Hcrt neurons occurs only in the light phase when working for positive reinforcement. Expression was seen throughout the medio-lateral extent of the Hcrt field. Fos was not expressed when expected or unexpected, unearned rewards were presented, when working to avoid negative reinforcement, or when given or expecting shock, even though these conditions elicit maximal electroencephalographic (EEG) arousal. Fos was not expressed in the light phase when light was removed. This may explain the lack of light induced arousal in narcoleptics and its presence in normal individuals. This is the first demonstration of such specificity of arousal system function and has implications for understanding the motivational and circadian consequences of arousal system dysfunction. The current results also indicate that comparable and complementary specificities must exist in other “arousal” systems.