Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

Abstract

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)September 2014 (From -To) REPORT TYPE Annual DATES COVERED P ERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SRI InternationalMenlo Park, CA 94025-3493 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENT SUPPLEMENTARY NOTES ABSTRACTDuring Year 5, we continued tests of 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). One paper was published (Morairty et al. 2014), another has been accepted for publication (Dittrich et al., in press) and a third is in resubmission (Vazquez-DeRose et al., submitted). Data collection for Aims 2c and 3b.2 have been completed and data analysis ongoing; manuscripts will be written and submitted during Year 6. Data collection and analysis of Aim 3a is nearing completion; an abstract summarizing this work has been submitted for presentation at the 2014 Society for Neuroscience meeting. Data collection for Aims 3b.3, 4c and 6a have been initiated. The overall results obtained to date are consistent with the hypothesis that the hypocretin/orexin antagonist ALM produces less functional impairment than the benzodiazepine receptor agonist zolpidem (ZOL) because ZOL causes a general inhibition of neural activity whereas ALM specifically disfacilitates wake-promoting systems. SUBJECT TERMSSleep, performance, drug, neurotransmitter, hypocretin, orexin, benzodiazepine, zolpidem, neurochemistry, microdialysis INTRODUCTIONAlmorexant (ALM) is a hypocretin/orexin (Hcrt) receptor antagonist with a novel mechanism of action that has shown promise as an effective hypnotic. Preclinical data demonstrate that animals treated with ALM are easily aroused from sleep and are free of ataxia and other behavioral impairments. If this observation is confirmed in humans, it would have enormous implications for the management of disturbed sleep in both military a...