title: Quantitative electroencephalography within sleep/wake states differentiates GABAA modulators eszopiclone and zolpidem from dual orexin receptor antagonists in rats.
abstract: Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABAA modulators from DORA-22, an analog of the DORA MK-6096, in Sprague-Dawley rats. The effects of low, intermediate, and high doses of eszopiclone, zolpidem, and DORA-22 were examined after first defining each compound's ability to promote sleep during active-phase dosing. The EEG spectral frequency power within specific sleep stages was calculated in 1-Hz intervals from 1 to 100 Hz within each sleep/wake state for the first 4 h after the dose. Eszopiclone and zolpidem produced marked, dose-responsive disruptions in sleep stage-specific EEG spectral profiles compared with vehicle treatment. In marked contrast, DORA-22 exhibited marginal changes in the spectral profile, observed only during rapid eye movement sleep, and only at the highest dose tested. Moreover, while eszopiclone- and zolpidem-induced changes were evident in the inactive period, the EEG spectral responses to DORA-22 were absent during this phase. These results suggest that DORA-22 differs from eszopiclone and zolpidem whereby DORA-22 promotes somnolence without altering the neuronal network EEG activity observed during normal sleep.
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, Merck Corporation, West Point, PA, USA.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Tye
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.forename: Alan T
authors.initials: AT
authors.lastname: Savitz
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Brunner
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.forename: Terrence P
authors.initials: TP
authors.lastname: McDonald
authors.forename: Robert
authors.initials: R
authors.lastname: Hodgson
authors.forename: Lihang
authors.initials: L
authors.lastname: Yao
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bowlby
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D004569:Electroencephalography; D000069582:Eszopiclone; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D000068796:Orexin Receptor Antagonists; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012894:Sleep Stages / Q000187:drug effects* / Q000502:physiology; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000077334:Zolpidem
chemical_list: D053961:Azabicyclo Compounds; C581638:DORA-22; D058785:GABA-A Receptor Agonists; D000068796:Orexin Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D014230:Triazoles; D000077334:Zolpidem; D000069582:Eszopiclone