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

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

GABA A receptor positive allosteric modulators modify the abuse-related behavioral and neurochemical effects of methamphetamine in rhesus monkeys

“…Temazepam and eszopiclone were chosen based on their individual pharmacokinetic profiles (~6–7.5h half-life; ~30 min time to maximum plasma concentration) (Curry et al, 1977; Nutt and Stahl, 2010). The highest dose used for the GABA A receptor modulators was chosen based on previous studies indicating that 3 mg/kg temazepam (Curry et al, 1977) and 3 mg/kg eszopiclone (Uslaner et al, 2013; Gotter et al, 2014) had been proven safe and effective in inducing sleep-promoting effects in rhesus monkeys.…”

Hypnotics with novel modes of action

“…Orexin receptor antagonists do not suffer from drug–drug interactions like the GABA A targeting molecules, especially with alcohol . There is no evidence for cognitive impairment or addiction potential; on the contrary, orexin receptor antagonism appears a viable approach to treat drug dependence, and appears otherwise safe . The fact that DORAs exclusively stimulate REM sleep could be an advantage in disorders where REM sleep is primarily affected, e.g.…”

Effects of the dual orexin receptor antagonist DORA‐22 on sleep in 5XFAD mice

“…In this study, we tested the hypothesis that chronic administration of a dual orexin receptor antagonist (DORA) to 5XFAD mice would lead to sleep enhancement that would be associated with attenuation of cognitive deficits, Aβ accumulation, and neuroinflammation. 5XFAD mice were chosen for study because they exhibit AD‐like sleep disruptions as well as AD‐like neuropathology and cognitive deficits [24‐26]. To improve sleep in 5XFAD mice, DORA‐22 was used.…”

“…The diminution of REM sleep, such as that resulting from traditional insomnia medications, interferes with spatial memory [29,30]. The 5XFAD mice were selected for testing the therapeutic effects of sleep enhancement because they exhibit not only the prominent neuropathologic features [24] but also sleep alterations resembling those seen in patients with AD including reduced total sleep and shorter sleep bouts [25]. Moreover, the 5XFAD mice exhibit increased neuroinflammation and impairments in spatial memory around the age at which they show sleep disruption [24,26]; thus, the 5XFAD mice provide a useful preclinical model to test our hypothesis.…”