title: Inhibition of Orexin Signaling Promotes Sleep Yet Preserves Salient Arousability in Monkeys.
abstract: OBJECTIVE
  In addition to enhancing sleep onset and maintenance, a desirable insomnia therapeutic agent would preserve healthy sleep's ability to wake and respond to salient situations while maintaining sleep during irrelevant noise. Dual orexin receptor antagonists (DORAs) promote sleep by selectively inhibiting wake-promoting neuropeptide signaling, unlike global inhibition of central nervous system excitation by gamma-aminobutyric acid (GABA)-A receptor (GABAaR) modulators. We evaluated the effect of DORA versus GABAaR modulators on underlying sleep architecture, ability to waken to emotionally relevant stimuli versus neutral auditory cues, and performance on a sleepiness-sensitive cognitive task upon awakening.
  
  
  METHODS
  DORA-22 and GABAaR modulators (eszopiclone, diazepam) were evaluated in adult male rhesus monkeys (n = 34) with continuous polysomnography recordings in crossover studies of sleep architecture, arousability to a classically conditioned salient versus neutral acoustical stimulus, and psychomotor vigilance task (PVT) performance if awakened.
  
  
  RESULTS
  All compounds decreased wakefulness, but only DORA-22 sleep resembled unmedicated sleep in terms of underlying sleep architecture, preserved ability to awaken to salient-conditioned acoustic stimuli while maintaining sleep during neutral acoustic stimuli, and no congnitive impairment in PVT performance. Although GABAaR modulators induced lighter sleep, monkeys rarely woke to salient stimuli and PVT performance was impaired if monkeys were awakened.
  
  
  CONCLUSIONS
  In nonhuman primates, DORAs' targeted mechanism for promoting sleep protects the ability to selectively arouse to salient stimuli and perform attentional tasks unimpaired, suggesting meaningful differentiation between a hypnotic agent that works through antagonizing orexin wake signaling versus the sedative hypnotic effects of the GABAaR modulator mechanism of action.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Tye
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Savitz
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000818:Animals; D001143:Arousal / Q000187:drug effects; D003214:Conditioning, Classical; D018592:Cross-Over Studies; D003975:Diazepam / Q000494:pharmacology; D000069582:Eszopiclone / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008253:Macaca mulatta / Q000502:physiology*; D008297:Male; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D000068797:Orexins / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D017286:Polysomnography; D015398:Signal Transduction / Q000187:drug effects*; D012890:Sleep / Q000187:drug effects* / Q000502:physiology*; D012894:Sleep Stages / Q000187:drug effects / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology; D014851:Wakefulness / Q000187:drug effects* / Q000502:physiology*
chemical_list: C581638:DORA-22; D018682:GABA Agents; D006993:Hypnotics and Sedatives; D000068796:Orexin Receptor Antagonists; D000068797:Orexins; D010880:Piperidines; D014230:Triazoles; D003975:Diazepam; D000069582:Eszopiclone
keywords: arousal; auditory discrimination; nonhuman primates; orexin receptor antagonist; psychomotor vigilance task; sleep