title: Dual orexin receptor antagonists show distinct effects on locomotor performance, ethanol interaction and sleep architecture relative to gamma-aminobutyric acid-A receptor modulators.
abstract: Dual orexin receptor antagonists (DORAs) are a potential treatment for insomnia that function by blocking both the orexin 1 and orexin 2 receptors. The objective of the current study was to further confirm the impact of therapeutic mechanisms targeting insomnia on locomotor coordination and ethanol interaction using DORAs and gamma-aminobutyric acid (GABA)-A receptor modulators of distinct chemical structure and pharmacological properties in the context of sleep-promoting potential. The current study compared rat motor co-ordination after administration of DORAs, DORA-12 and almorexant, and GABA-A receptor modulators, zolpidem, eszopiclone, and diazepam, alone or each in combination with ethanol. Motor performance was assessed by measuring time spent walking on a rotarod apparatus. Zolpidem, eszopiclone and diazepam [0.3-30 mg/kg administered orally (PO)] impaired rotarod performance in a dose-dependent manner. Furthermore, all three GABA-A receptor modulators potentiated ethanol- (0.25-1.5 g/kg) induced impairment on the rotarod. By contrast, neither DORA-12 (10-100 mg/kg, PO) nor almorexant (30-300 mg/kg, PO) impaired motor performance alone or in combination with ethanol. In addition, distinct differences in sleep architecture were observed between ethanol, GABA-A receptor modulators (zolpidem, eszopiclone, and diazepam) and DORA-12 in electroencephalogram studies in rats. These findings provide further evidence that orexin receptor antagonists have an improved motor side-effect profile compared with currently available sleep-promoting agents based on preclinical data and strengthen the rationale for further evaluation of these agents in clinical development.
authors.affiliation: Merck Research Laboratories, Department of Neuroscience, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Andres D
authors.initials: AD
authors.lastname: Ramirez
authors.affiliation: Merck Research Laboratories, Department of Neuroscience, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Merck Research Laboratories, Department of In Vivo Pharmacology, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.affiliation: Merck Research Laboratories, Department of In Vivo Pharmacology, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.affiliation: Merck Research Laboratories, Department of In Vivo Pharmacology, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Lihang
authors.initials: L
authors.lastname: Yao
authors.affiliation: Merck Research Laboratories, Department of In Vivo Pharmacology, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Tye
authors.affiliation: Merck Research Laboratories, Department of Neuroscience, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Terrence
authors.initials: T
authors.lastname: McDonald
authors.affiliation: Merck Research Laboratories, Department of Neuroscience, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Brunner
authors.affiliation: Merck Research Laboratories, Department of Neuroscience, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.affiliation: Merck Research Laboratories, Department of Neuroscience, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Duane R
authors.initials: DR
authors.lastname: Reiss
authors.affiliation: Merck Research Laboratories, Department of Medicinal Chemistry, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.affiliation: Merck Research Laboratories, Department of Medicinal Chemistry, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Merck Research Laboratories, Department of In Vivo Pharmacology, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.affiliation: Merck Research Laboratories, Department of In Vivo Pharmacology, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hodgson
authors.affiliation: Merck Research Laboratories, Department of In Vivo Pharmacology, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Browne
authors.affiliation: Merck Research Laboratories, Department of Neuroscience, Merck & Co., Inc. West Point, PA, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Merck Research Laboratories, Department of Neuroscience, Merck & Co., Inc. West Point, PA, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
keywords: GABA; dual orexin receptor antagonist; ethanol; insomnia; locomotor performance; orexin; rats; sleep