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The Journal of Neuroscience, December 26, 2007, 27(52):14239-14247; doi:10.1523/JNEUROSCI.3878-07.2007

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Behavioral/Systems/Cognitive
Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates

Sam A. Deadwyler,¹ Linda Porrino,¹ Jerome M. Siegel,² and Robert E. Hampson¹

¹Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, and ²Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California Veterans Administration Greater Los Angeles Healthcare System/Sepulveda, North Hills, California 91343

Correspondence should be addressed to Dr. Sam A. Deadwyler, Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157. Email: sdeadwyl{at}wfubmc.edu

Hypocretin-1 (orexin-A) was administered to sleep-deprived (30–36 h) rhesus monkeys immediately preceding testing on a multi-image delayed match-to-sample (DMS) short-term memory task. The DMS task used multiple delays and stimulus images and effectively measures cognitive defects produced by sleep deprivation (Porrino et al., 2005). Two methods of administration of orexin-A were tested, intravenous injections (2.5–10.0 µg/kg, i.v.) and a novel method developed for nasal delivery via an atomizer spray mist to the nostrils (dose estimated 1.0 µg/kg). Results showed that orexin-A delivered via the intravenous and nasal routes significantly improved performance in sleep-deprived monkeys; however, the nasal delivery method was significantly more effective than the highest dose (10 µg/kg) of intravenous orexin-A tested. The improvement in performance by orexin-A was specific to trials classified as high versus low cognitive load as determined by performance difficulty under normal testing conditions. Except for the maximum intravenous dose (10 µg/kg), neither delivery method affected task performance in alert non-sleep-deprived animals. The improved performance in sleep-deprived animals was accompanied by orexin-A related alterations in local cerebral glucose metabolism (CMRglc) in specific brain regions shown previously to be engaged by the task and impaired by sleep deprivation (Porrino et al., 2005). Consistent with the differential effects on performance, nasal delivered orexin-A produced a more pronounced reversal of sleep deprivation induced changes in brain metabolic activity (CMRglc) than intravenous orexin-A. These findings provide strong evidence for the effectiveness of intranasal orexin-A in alleviating cognitive deficits produced by loss of sleep.

Key words: cognition; sleep deprivation; monkeys; orexin-A (hypocretin-1); intranasal delivery; local cerebral glucose utilization; reversed impaired performance

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Received Aug. 24, 2007; revised Oct. 26, 2007; accepted Oct. 28, 2007.

Correspondence should be addressed to Dr. Sam A. Deadwyler, Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157. Email: sdeadwyl{at}wfubmc.edu

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