Frontiers in Neuroscience (Dec 2013)

Dual orexin receptor antagonists show distinct effects on locomotor performance, ethanol interaction and sleep architecture relative to gamma-aminobutyric acid-A receptor modulators

  • Andres D. Ramirez,
  • Anthony L. Gotter,
  • Steven V. Fox,
  • Pamela L. Tannenbaum,
  • Lihang eYao,
  • Spencer J. Tye,
  • Terrence eMcDonald,
  • Joseph eBrunner,
  • Susan L. Garson,
  • Duane R. Reiss,
  • Scott D. Kuduk,
  • Paul J. Coleman,
  • Jason M. Uslaner,
  • Robert eHodgson,
  • Susan E. Browne,
  • John J. Renger,
  • Christopher J. Winrow

DOI
https://doi.org/10.3389/fnins.2013.00254
Journal volume & issue
Vol. 7

Abstract

Read online

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 pharmacologic 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- (0.25–1.25 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.

Keywords