Differential sleep-promoting effects of dual orexin receptor antagonists and GABAA receptor modulators

BMC Neuroscience

John J Renger³  Christopher J Winrow³  Paul J Coleman¹  Spencer J Tye²  Jason M Uslaner²  Terrence McDonald³  Scott D Kuduk⁵  Lihang Yao³  Pamela L Tannenbaum²  Steven V Fox²  Regina L Munden⁴  Joanne Stevens²  Susan L Garson³  Anthony L Gotter³ 

[1] Department of Medicinal Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486-0004, USA;Department of In Vivo Pharmacology, Merck Research Laboratories, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486-0004, USA;Department of Neuroscience, Merck Research Laboratories, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486-0004, USA;Current affiliation: Department of Comparative Medicine, Penn State University College of Medicine, Hershey, PA, USA;Current affiliation: Novira Therapeutics, Doylestown, PA, USA

关键词: Belsomra;    Suvorexant;    NREM sleep;    REM sleep;    Sleep deprivation;    Electroencephalography;    Sleep;    Insomnia;    Benzodiazepine;    Hypocretin;    Orexin;   

Others  :  1091017
DOI  :  10.1186/1471-2202-15-109

 received in 2014-07-11, accepted in 2014-09-17,  发布年份 2014

【 摘 要 】

Background

The current standard of care for insomnia includes gamma-aminobutyric acid receptor A (GABA_A) activators, which promote sleep as well as general central nervous system depression. Dual orexin receptor antagonists (DORAs) represent an alternative mechanism for insomnia treatment that induces somnolence by blocking the wake-promoting effects of orexin neuropeptides. The current study compares the role and interdependence of these two mechanisms on their ability to influence sleep architecture and quantitative electroencephalography (qEEG) spectral profiles across preclinical species.

Results

Active-phase dosing of DORA-22 induced consistent effects on sleep architecture in mice, rats, dogs, and rhesus monkeys; attenuation of active wake was accompanied by increases in both non─rapid eye movement (NREM) and rapid eye movement (REM) sleep. Eszopiclone, a representative GABA_A receptor modulator, promoted sleep in rats and rhesus monkeys that was marked by REM sleep suppression, but had inconsistent effects in mice and paradoxically promoted wakefulness in dogs. Active-phase treatment of rats with DORA-12 similarly promoted NREM and REM sleep to magnitudes nearly identical to those seen during normal resting-phase sleep following vehicle treatment, whereas eszopiclone suppressed REM even to levels below those seen during the active phase. The qEEG changes induced by DORA-12 in rats also resembled normal resting-phase patterns, whereas eszopiclone induced changes distinct from normal active- or inactive-phase spectra. Co-dosing experiments, as well as studies in transgenic rats lacking orexin neurons, indicated partial overlap in the mechanism of sleep promotion by orexin and GABA modulation with the exception of the REM suppression exclusive to GABA_A receptor modulation. Following REM deprivation in mice, eszopiclone further suppressed REM sleep while DORA-22 facilitated recovery including increased REM sleep.

Conclusion

DORAs promote NREM and importantly REM sleep that is similar in proportion and magnitude to that seen during the normal resting phase across mammalian animal models. While limited overlap exists between therapeutic mechanisms, orexin signaling does not appear involved in the REM suppression exhibited by GABA_A receptor modulators. The ability of DORAs to promote proportional NREM and REM sleep following sleep deprivation suggests that this mechanism may be effective in alleviating recovery from sleep disturbance.

【 授权许可】

   
2014 Gotter et al.; licensee BioMed Central Ltd.

【 图 表 】

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