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Optical probing of orexin/hypocretin receptor antagonists

Shi-Bin Li1, Natalie Nevárez1, William J Giardino1

  • 1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA.

Sleep
|July 31, 2018
PubMed
Abstract

Insights

Hypocretin (Hcrt) receptor antagonists, particularly dual (DORAs) and OX2R antagonists, stabilize sleep and enhance memory. These findings are crucial for understanding sleep modulation and cognitive function.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Sleep Medicine

Background:

  • Hypocretin (Hcrt) or Orexin (OX) system plays a critical role in regulating wakefulness.
  • Dysfunction of the Hcrt system is implicated in sleep disorders and cognitive impairments.
  • Hcrt receptor antagonists are potential therapeutic agents for sleep modulation.

Purpose of the Study:

  • To investigate the effects of Hcrt receptor antagonists on sleep modulation and memory function.
  • To evaluate the efficacy of dual OX1/2R antagonists (DORAs) and selective OX2R antagonists in stabilizing sleep.
  • To assess the impact of these antagonists on cognitive processes, specifically memory, under conditions of sleep disruption.

Main Methods:

  • Utilized transgenic mice with optogenetically stimulated Hcrt neurons.
  • Administered dual OX1/2R antagonists (DORAs), selective OX2R antagonists, and Zolpidem.
  • Measured wakefulness latencies, Hcrt neuronal activity via fiber photometry, and memory function using the novel object recognition test (NOR).
  • Analyzed electroencephalogram (EEG) power spectra for sleep stages (wake, REM, NREM).

Main Results:

  • Optogenetic stimulation of Hcrt neurons induced wakefulness.
  • DORAs, MK1064 (selective OX2R antagonist), and Zolpidem significantly reduced wakefulness episodes.
  • Hcrt neurons remained active during wakefulness even with OXR antagonist treatment.
  • Dual OX1/2R antagonists improved memory function, counteracting impairments from optogenetic sleep fragmentation.

Conclusions:

  • Dual OX1/2R antagonists and selective OX2R antagonists demonstrate sleep-stabilizing properties.
  • These antagonists can improve sleep-dependent cognitive functions, including memory.
  • The findings support the therapeutic potential of Hcrt receptor antagonists for sleep disorders and related cognitive deficits.

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