title: Differential effects of the dual orexin receptor antagonist almorexant and the GABA(A)-α1 receptor modulator zolpidem, alone or combined with ethanol, on motor performance in the rat.
abstract: Current insomnia treatments such as γ-aminobutyric acid (GABA) receptor modulators are associated with sedative and muscle-relaxant effects, which increase when drug intake is combined with alcohol. This study compared the novel sleep-enabling compound almorexant (ACT-078573-hydrochloride), a dual orexin receptor antagonist, with the positive GABA(A)-α1 receptor modulator zolpidem. Both compounds were administered alone or in combination with ethanol, and their effects on forced motor performance were determined in Wistar rats upon waking after treatment. To detect substance-induced sedation and myorelaxation, time spent on an accelerating rotating rod (rotarod) and forepaw grip strength were measured. Zolpidem (10, 30, and 100 mg/kg, p.o.) and ethanol (0.32, 1, and 1.5 g/kg, i.p.) dose-dependently decreased rotarod performance and grip strength, whereas almorexant (30, 100, and 300 mg/kg, p.o.) did not. Doses of ethanol (0.32 and 1 g/kg), which were ineffective when administered alone, showed interactions with zolpidem (10 and 30 mg/kg) leading to reduced rotarod performance and grip strength; in contrast, combination of ethanol (0.32 and 1 g/kg) with almorexant (100 and 300 mg/kg) did not reduce performance or grip strength below ethanol alone. We conclude that unlike zolpidem, almorexant does not interfere with forced motor performance or grip strength in the rat, nor does it further increase the sedative effects of ethanol. Our results suggest that the effect of almorexant can be immediately reversed to full alertness like under physiological sleep, and that almorexant is less likely to show strong sedation, excessive myorelaxation, or interaction with alcohol than commonly prescribed hypnotics such as zolpidem.
authors.affiliation: CNS-Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. michel.steiner@actelion.com
authors.forename: Michel A
authors.initials: MA
authors.lastname: Steiner
authors.forename: Hugues
authors.initials: H
authors.lastname: Lecourt
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Strasser
authors.forename: Catherine
authors.initials: C
authors.lastname: Brisbare-Roch
authors.forename: François
authors.initials: F
authors.lastname: Jenck
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D007546:Isoquinolines / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D064446:Orexin Receptors; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism / Q000502:physiology*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077334:Zolpidem
chemical_list: D000081:Acetamides; D058785:GABA-A Receptor Agonists; C546242:Gabra1 protein, rat; D007546:Isoquinolines; D064446:Orexin Receptors; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D018013:Receptors, Neuropeptide; D000431:Ethanol; D000077334:Zolpidem; C519150:almorexant