title: Differential sleep-promoting effects of dual orexin receptor antagonists and GABAA receptor modulators.
abstract: BACKGROUND
  The current standard of care for insomnia includes gamma-aminobutyric acid receptor A (GABAA) activators, which promote sleep as well as general central nervous system depression. Dual orexin receptor antagonists (DORAs) represent an alternative mechanism for insomnia treatment that induces somnolence by blocking the wake-promoting effects of orexin neuropeptides. The current study compares the role and interdependence of these two mechanisms on their ability to influence sleep architecture and quantitative electroencephalography (qEEG) spectral profiles across preclinical species.
  
  
  RESULTS
  Active-phase dosing of DORA-22 induced consistent effects on sleep architecture in mice, rats, dogs, and rhesus monkeys; attenuation of active wake was accompanied by increases in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Eszopiclone, a representative GABAA receptor modulator, promoted sleep in rats and rhesus monkeys that was marked by REM sleep suppression, but had inconsistent effects in mice and paradoxically promoted wakefulness in dogs. Active-phase treatment of rats with DORA-12 similarly promoted NREM and REM sleep to magnitudes nearly identical to those seen during normal resting-phase sleep following vehicle treatment, whereas eszopiclone suppressed REM even to levels below those seen during the active phase. The qEEG changes induced by DORA-12 in rats also resembled normal resting-phase patterns, whereas eszopiclone induced changes distinct from normal active- or inactive-phase spectra. Co-dosing experiments, as well as studies in transgenic rats lacking orexin neurons, indicated partial overlap in the mechanism of sleep promotion by orexin and GABA modulation with the exception of the REM suppression exclusive to GABAA receptor modulation. Following REM deprivation in mice, eszopiclone further suppressed REM sleep while DORA-22 facilitated recovery including increased REM sleep.
  
  
  CONCLUSIONS
  DORAs promote NREM and importantly REM sleep that is similar in proportion and magnitude to that seen during the normal resting phase across mammalian animal models. While limited overlap exists between therapeutic mechanisms, orexin signaling does not appear involved in the REM suppression exhibited by GABAA receptor modulators. The ability of DORAs to promote proportional NREM and REM sleep following sleep deprivation suggests that this mechanism may be effective in alleviating recovery from sleep disturbance.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.forename: Joanne
authors.initials: J
authors.lastname: Stevens
authors.forename: Regina L
authors.initials: RL
authors.lastname: Munden
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.forename: Lihang
authors.initials: L
authors.lastname: Yao
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.forename: Terrence
authors.initials: T
authors.lastname: McDonald
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Tye
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486-0004, USA. john_renger@merck.com.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D004285:Dogs; D004569:Electroencephalography; D000069582:Eszopiclone; D018757:GABA Modulators / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics; D008253:Macaca mulatta; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics; D000068796:Orexin Receptor Antagonists; D000068797:Orexins; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012890:Sleep / Q000187:drug effects* / Q000502:physiology; D012892:Sleep Deprivation / Q000188:drug therapy / Q000503:physiopathology; D012894:Sleep Stages / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity; D014230:Triazoles / Q000494:pharmacology*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
chemical_list: D053961:Azabicyclo Compounds; D001381:Azepines; D001562:Benzimidazoles; C581638:DORA-22; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068796:Orexin Receptor Antagonists; D000068797:Orexins; D010879:Piperazines; D010880:Piperidines; D014230:Triazoles; C000595055:dual orexin receptor antagonist 12; D000069582:Eszopiclone