Quantitative electroencephalography within sleep/wake states differentiates GABAA modulators eszopiclone and zolpidem from dual orexin receptor antagonists in rats

Neuropsychopharmacology. 2013 Nov;38(12):2401-8. doi: 10.1038/npp.2013.139. Epub 2013 May 31.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azabicyclo Compounds / administration & dosage
  • Azabicyclo Compounds / pharmacology*
  • Brain / drug effects*
  • Brain / physiology
  • Electroencephalography
  • Eszopiclone
  • GABA-A Receptor Agonists / administration & dosage
  • GABA-A Receptor Agonists / pharmacology*
  • Male
  • Orexin Receptor Antagonists*
  • Piperazines / administration & dosage
  • Piperazines / pharmacology*
  • Piperidines / administration & dosage
  • Piperidines / pharmacology*
  • Pyridines / administration & dosage
  • Pyridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Sleep Stages / drug effects*
  • Sleep Stages / physiology
  • Triazoles / administration & dosage
  • Triazoles / pharmacology*
  • Zolpidem

Substances

  • Azabicyclo Compounds
  • DORA-22
  • GABA-A Receptor Agonists
  • Orexin Receptor Antagonists
  • Piperazines
  • Piperidines
  • Pyridines
  • Triazoles
  • Zolpidem
  • Eszopiclone