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BMC Neuroscience

, 15:109

Neurobiology of disease

Abstract

BackgroundThe current standard of care for insomnia includes gamma-aminobutyric acid receptor A GABAA 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.

ResultsActive-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 GABAA 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 GABAA receptor modulation. Following REM deprivation in mice, eszopiclone further suppressed REM sleep while DORA-22 facilitated recovery including increased REM sleep.

ConclusionDORAs 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 GABAA 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.

KeywordsOrexin Hypocretin Benzodiazepine Insomnia Sleep Electroencephalography Sleep deprivation REM sleep NREM sleep Suvorexant Belsomra AbbreviationsDORADual orexin receptor antagonist

EEGElectroencephalography

qEEGQuantitative electroencephalography

ECoGElectrocorticogram

EMGElectromyogram

EOGElectrooculogram

GABAAGamma-aminobutyric acid A receptor

NREMNon-rapid eye movement

OX1ROrexin 1 receptor

OX2ROrexin 2 receptor

ORAOrexin receptor antagonist

Ox-Atx Transgene containing cytotoxic poly-Q-ataxin-3gene product driven by the human hypocretin HCRT gene promoter

p.o.Per os, or oral administration

PSGPolysomnography

REMRapid eye movement

TMNTuberomammillary nuclei

TPGSd-alpha-tocopheryl polyethylene glycol 1000 succinate

VLPOVentrolateral preoptic nucleus

ZTZeitgeber time.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2202-15-109 contains supplementary material, which is available to authorized users.

Anthony L Gotter, Susan L Garson contributed equally to this work.

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Autor: Anthony L Gotter - Susan L Garson - Joanne Stevens - Regina L Munden - Steven V Fox - Pamela L Tannenbaum - Lihang Yao

Fuente: https://link.springer.com/



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