Summary: Researchers found that common benzodiazepine sleep medications can prevent sleepers from waking to alarm-like threats, while a newer class of sleep drugs preserves the ability to wake in the presence of danger.
Source: Frontiers in Behavioral Neuroscience.
Study finds common benzodiazepine sleeping pills blunt threat‑response during sleep, while a novel drug preserves awakenings to danger
A recent study published in Frontiers in Behavioral Neuroscience compared the effects of a traditional benzodiazepine hypnotic and an experimental dual orexin receptor antagonist (DORA) on the ability to wake from sleep when faced with threatening stimuli. The results show that while the benzodiazepine greatly delayed arousal in response to alarm‑like sensory cues, the DORA preserved the sleeper’s capacity to wake quickly and then return to sleep once the threat had passed.
How sleep normally monitors threat
Even during sleep the brain continues to monitor the environment and will rouse the sleeper if it detects signals that indicate danger. Benzodiazepines, the most widely prescribed class of sleep medications, act broadly on GABA‑A receptors and, while promoting sleep, can suppress brain circuits involved in sensory gating—the mechanisms that decide which incoming signals should be processed and which should be ignored. This broad suppression can reduce the brain’s “intruder alert” and make it harder to wake to potentially dangerous events.
By contrast, dual orexin receptor antagonists (DORAs) target the orexin system that regulates sleep and wakefulness more selectively. Because of their more targeted action, DORAs have been developed to offer sleep benefits with fewer next‑day impairments and a lower risk of residual drowsiness compared with some benzodiazepines.
Design of the mouse study
Researchers at Kagoshima University tested the experimental DORA-22 against the benzodiazepine triazolam and a placebo control in mice, administering doses during the animals’ dark (active) period and assessing sleep and arousal responses. Both DORA-22 and triazolam extended deep sleep similarly, increasing deep‑sleep duration by roughly 30–40% compared with placebo.
One to four hours after dosing, when the mice were in deep sleep, the investigators applied one of several threatening stimuli for 30 seconds: a predator odor (fox scent), an ultrasonic auditory cue (similar to a high‑pitched alarm), or mechanical cage trembling designed to mimic a shaking event such as an earthquake. In a separate test, the team induced a non‑sensory, physiological challenge by briefly lowering the oxygen level in the cage.
Key findings
The results showed a striking difference in sensory arousal between treatments. Mice given triazolam were much slower to wake in response to the auditory, olfactory, and vestibular (tremor) threats compared with mice that received DORA‑22 or placebo. In contrast, mice treated with DORA‑22 woke as quickly as untreated mice when presented with these alarm‑like stimuli. Importantly, after being roused by a threat, DORA‑22‑treated mice returned to sleep quickly—comparable to the triazolam group and faster than placebo—indicating that the drug both preserves the ability to respond to danger and still promotes efficient resumption of sleep once the threat has passed.
When the researchers reduced oxygen briefly, all groups awakened with similar timing, suggesting the benzodiazepine’s delayed arousal was specific to sensory gating processes rather than a broad suppression of all waking mechanisms.
Implications and next steps
These observations support the hypothesis that DORAs, by selectively blocking orexin receptors involved in sleep/wake regulation, may offer an improved safety profile compared with GABA‑A‑acting benzodiazepines—at least in this animal model. Preserving the brain’s ability to detect and react to environmental threats while still facilitating restorative sleep is an important safety consideration for hypnotic drugs.
Although some DORA drugs, such as suvorexant, are already approved for clinical use in several countries, concerns remain about cost, dosing, and potential next‑day drowsiness at higher doses. The current study used an experimental DORA (DORA‑22), and human clinical studies are needed to confirm whether the same balance of preserved threat responsiveness and effective sleep promotion occurs in people.
Funding: The research was funded by the Japan Society for the Promotion of Science.
Reporting source: Matt Prior, Frontiers. Organized by Neuroscience News.
Original research: “Orexin Receptor Blockade‑Induced Sleep Preserves the Ability to Wake in the Presence of Threat in Mice” by J. A. E. Hughes, P. Maiolino and F. Iida, published in Frontiers in Behavioral Neuroscience (January 2019).
Abstract
Orexin Receptor Blockade‑Induced Sleep Preserves the Ability to Wake in the Presence of Threat in Mice
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.