Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance
Annual rept. 1 Sep 2012-31 Aug 2013
SRI INTERNATIONAL MENLO PARK CA
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Results continued to accumulate that are consistent with the hypothesis that disfacilitation of wake-promoting systems by the hypocretin Hcrt receptor antagonist almorexant ALM results in less functional impairment than the inhibition of neural activity produced by the benzodiazepine receptor agonist zolpidem ZOL. In Year 4, the previously-reported results on spatial reference memory Task 2a and spatial working memory Task 2b were complemented by Psychomotor Vigilance Test studies Task 2c. The wake-active histaminergic and Hcrt neurons, but neither the cholinergic basal forebrain BF neurons nor the serotonergic dorsal raphe neurons, could be activated after sleep deprivation in the presence of ALM however, none of these four cell types could be activated in the presence of ZOL Task 3a. Lesions of the locus coeruleus LC, a wakefulness-promoting area, abolished the ALM-induced decrease in NREM sleep latency without affecting the ZOL-induced decrease Task 3b. High sleep pressure, rather than the actions of ALM or ZOL per se, is critical for activation of sleep-active cortical neurons Task 4a. ALM promoted adenosine release in the BF Task 4b and cortex Task 4c, particularly during waking. Hcrt neurons expressing channelrhodopsin-2 can be excited by blue light pulses in vitro and preliminary in vivo experiments indicate that optogenetic activation of Hcrt cells can cause changes in sleep architecture Tasks 6a.
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