Inhibition of Orexin Signaling Promotes Sleep Yet Preserves Salient Arousability in Monkeys. Issue 3 (1st March 2016)

• Record Type: Journal Article
• Authors: Tannenbaum, Pamela L.; Tye, Spencer J.; Stevens, Joanne; Gotter, Anthony L.; Fox, Steven V.; Savitz, Alan T.; Coleman, Paul J.; Uslaner, Jason M.; Kuduk, Scott D.; Hargreaves, Richard; Winrow, Christopher J.; Renger, John J.
• Is Part Of: Sleep. Volume 39:Issue 3(2016)
• Page Start: 603
• Page End: 612
• Publication Date: 2016-03-01
• Subjects: arousal -- auditory discrimination -- nonhuman primates -- orexin receptor antagonist -- psychomotor vigilance task -- sleep; Sleep -- Physiological aspects -- Periodicals; Sleep disorders -- Periodicals; Sommeil -- Aspect physiologique -- Périodiques; Sommeil, Troubles du -- Périodiques; Sleep disorders; Sleep -- Physiological aspects; Sleep -- physiological aspects; Sleep Wake Disorders; Psychophysiology; Electronic journals; Periodicals; 616.8498
• DOI: 10.5665/sleep.5536
• Languages: English
• ISSNs: 0161-8105

Abstract

Abstract: Study Objectives: In addition to enhancing sleep onset and maintenance, a desirable insomnia therapeutic agent would preserve healthy sleep's ability to wake and respond to salient situations while maintaining sleep during irrelevant noise. Dual orexin receptor antagonists (DORAs) promote sleep by selectively inhibiting wake-promoting neuropeptide signaling, unlike global inhibition of central nervous system excitation by gamma-aminobutyric acid (GABA)-A receptor (GABAaR) modulators. We evaluated the effect of DORA versus GABAaR modulators on underlying sleep architecture, ability to waken to emotionally relevant stimuli versus neutral auditory cues, and performance on a sleepiness-sensitive cognitive task upon awakening. Methods: DORA-22 and GABAaR modulators (eszopiclone, diazepam) were evaluated in adult male rhesus monkeys (n = 34) with continuous polysomnography recordings in crossover studies of sleep architecture, arousability to a classically conditioned salient versus neutral acoustical stimulus, and psychomotor vigilance task (PVT) performance if awakened. Results: All compounds decreased wakefulness, but only DORA-22 sleep resembled unmedicated sleep in terms of underlying sleep architecture, preserved ability to awaken to salient-conditioned acoustic stimuli while maintaining sleep during neutral acoustic stimuli, and no congnitive impairment in PVT performance. Although GABAaR modulators induced lighter sleep, monkeys rarely woke to salient stimuli and PVT performance was impaired if monkeys were awakened. Conclusions: In nonhuman primates, DORAs' targeted mechanism for promoting sleep protects the ability to selectively arouse to salient stimuli and perform attentional tasks unimpaired, suggesting meaningful differentiation between a hypnotic agent that works through antagonizing orexin wake signaling versus the sedative hypnotic effects of the GABAaR modulator mechanism of action. Significance: Dual receptor antagonists (DORAs) enhance sleep onset and sleep maintenance by antagonizing wake signaling mechanisms whereas GABAaR insomnia agents induce sedation with global CNS depressant action. In this study of nonhuman primates, DORA sleep retained unmedicated healthy sleep's desired capacity to appropriately awaken from deep sleep in response to emotionally salient situations and perform attentional tasks unimpaired, yet preserved uninterrupted sleep with irrelevant noise exposure. In contrast, such salience-gated arousability and psychomotor performance retention were lost during GABAaR modulator sleep in monkeys. The translational similarities between nonhuman primate and human sleep architecture suggest a DORA wake-antagonizing mechanism of action may also provide meaningful differentiation from existing sedating insomnia agents for patients under similar middle of the night situations.