Abstract
Retention of the ability to wake from sleep in response to dangerous situations is an ideal characteristic of safe hypnotics. We studied the effects of a dual orexin receptor antagonist-22 (DORA-22) and the GABA-A receptor modulator, triazolam, on the ability to wake in response to aversive stimuli. We examined four modalities of sensory inputs, namely, auditory (ultrasonic sound), vestibular (trembling), olfactory (predator odor), and autonomic (hypoxia) stimuli. When the mice fell asleep, one of the four stimuli was applied for 30 s. In the case of auditory stimulation, latency to arousal following vehicle, DORA-22, and triazolam administration was 3.0 (2.0–3.8), 3.5 (2.0–6.5), and 161 (117–267) s (median and 25–75 percentile in the parentheses, n = 8), respectively. Latency to return to sleep after arousal was 148 (95–183), 70 (43–98), and 60 (52–69) s, respectively. Similar results were obtained for vestibular and olfactory stimulation. During the hypoxic stimulation, latencies for arousal and returning to sleep were not significantly different among the groups. The findings of this study are consistent with the distinct mechanisms of these sleep promoting therapies; GABA-A receptor activation by triazolam is thought to induce widespread central nervous system (CNS) suppression while DORA-22 more specifically targets sleep/wake pathways through orexin receptor antagonism. These data support the notion that DORA-22 preserves the ability to wake in response to aversive and consciousness-inducing sensory stimuli, regardless of modality, while remaining effective in the absence of threat. This study provides a unique and important safety evaluation of the potential for certain hypnotics.
Highlights
Living in the modern world allows us to encounter dangerous situations far less frequently than what wild animals may encounter, it is still important for humans to be able to awaken quickly during natural disasters such as earthquakes, volcanic explosions, and fires
The purpose of the present study was to examine the possible effects of a dual orexin receptor antagonist (DORA)-22, on negative valence stimuli-induced arousal which is independent from learning and memory, and compare them with GABA-A receptor modulators, eszopiclone and triazolam
Effect of eszopiclone appeared to have a later onset than dual orexin receptor antagonist-22 (DORA-22) and triazolam
Summary
Living in the modern world allows us to encounter dangerous situations far less frequently than what wild animals may encounter, it is still important for humans to be able to awaken quickly during natural disasters such as earthquakes, volcanic explosions, and fires. This has been demonstrated by brainstem auditory evoked potential recordings (Perrin et al, 1999) and neuroimaging (Portas et al, 2000). The threshold required for the sensory input to reach. Orexin Blocker Preserves Threat-Induced Arousal the cerebral cortex, is higher during sleep than when awake due to thalamic sensory gating (McCormick and Bal, 1994). Central nervous system (CNS) depressants, such as benzodiazepines, affect the threshold required in order for sensory input to evoke arousal. The shortacting benzodiazepine triazolam impaired the ability in sleeping humans to wake up upon exposure to a loud fire alarm (Johnson et al, 1987)
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