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Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

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Technical Report,01 Sep 2009,31 Aug 2015

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SRI International Menlo Park United States

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This grant proposal was based on the hypothesis that hypocretin Hcrt antagonists produce less functional impairment than benzodiazepine receptor agonists BzRA because BzRAs cause a general inhibition of neural activity whereas Hcrt specifically disfacilitates wake-promoting systems. During the funding period, we obtained several lines of evidence that were consistent with this hypothesis. First, we determined that the Hcrt antagonist almorexantALM was most likely promoting sleep by antagonism of both Hcrt receptors 1 and 2 rather than only HcrtR2. Next, in tests of both spatial reference memory and spatial working memory, we found that rats treated with ALM performed far superior to those treated with the BzRA agonist zolpidem ZOLat equipotent doses in terms of sleep induction. Next, we found that this superior performance was likely due to the ability to activate wake-promoting nuclei in the presence of ALM but not ZOL. Furthermore, we explored the neural mechanisms underlying ALM-induced sleep and found that ALM, but not ZOL, requires an intact basal forebrain for maximum NREM-promoting efficacy and that ALM elicits a neurochemical profile more consistent with the transition to normal sleep than does ZOL. Furthermore, lesions of the wake-promoting noradrenergic locus coeruleus or histaminergic tuberomammillary nuclei compromised the hypnotic efficacy of ALM without affecting that of ZOL. Thus, Hcrt neurotransmission influences distinct aspects of NREM and REM sleep at different locations in the sleep-wake regulatory network. By selectively disfacilitating these subcortical wake-promoting populations, Hcrt antagonism effectively promotes sleep without negatively impacting cognitive performance and without globally blocking the capability for arousal.

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