Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance
Annual rept. 1 Sep 2011-31 Aug 2012
SRI INTERNATIONAL MENLO PARK CA
Pagination or Media Count:
During Year 3, 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. Measures of both spatial reference memory Task 2a and spatial working memory Task 2b in rodents treated with ALM were mostly indistinguishable from vehicle whereas impairments were clearly evident under ZOL. Similarly, wake-active Hcrt neurons can be recruited in the presence of ALM after sleep deprivation but not in the presence of ZOL Task 3a. Conversely, although both drugs activate sleep-active cortical neurons, sleep-active cells are more strongly activated by ZOL Task 4a. Lesions of the basal forebrain BF, a wakefulness-promoting area, potentiated the hypnotic effect of ZOL without affecting the response to ALM Task 3b, indicating different neural pathways underlie the actions of these two drugs. ALM promoted adenosine and glutamate release in the BF Task 4b whereas ZOL promoted GABA release, particularly during waking. An In Vivo Cellular Neurophysiology Laboratory was established to perform the electrophysiology and optogenetic experiments Tasks 6a-c.
- Anatomy and Physiology
- Medicine and Medical Research