Abstract
The ability to awaken from sleep in response to important stimuli is a critical feature of normal sleep, as is maintaining sleep continuity in the presence of irrelevant background noise. Dual orexin receptor antagonists (DORAs) effectively promote sleep across species by targeting the evolutionarily conserved wake-promoting orexin signaling pathway. This study in dogs investigated whether DORA-induced sleep preserved the ability to awaken appropriately to salient acoustic stimuli but remain asleep when exposed to irrelevant stimuli. Sleep and wake in response to DORAs, vehicle, GABA-A receptor modulators (diazepam, eszopiclone and zolpidem) and antihistamine (diphenhydramine) administration were evaluated in telemetry-implanted adult dogs with continuous electrocorticogram, electromyogram (EMG), electrooculogram (EOG), and activity recordings. DORAs induced sleep, but GABA-A modulators and antihistamine induced paradoxical hyperarousal. Thus, salience gating studies were conducted during DORA-22 (0.3, 1, and 5 mg/kg; day and night) and vehicle nighttime sleep. The acoustic stimuli were either classically conditioned using food reward and positive attention (salient stimulus) or presented randomly (neutral stimulus). Once conditioned, the tones were presented at sleep times corresponding to maximal DORA-22 exposure. In response to the salient stimuli, dogs woke completely from vehicle and orexin-antagonized sleep across all sleep stages but rarely awoke to neutral stimuli. Notably, acute pharmacological antagonism of orexin receptors paired with emotionally salient anticipation produced wake, not cataplexy, in a species where genetic (chronic) loss of orexin receptor signaling leads to narcolepsy/cataplexy. DORA-induced sleep in the dog thereby retains the desired capacity to awaken to emotionally salient acoustic stimuli while preserving uninterrupted sleep in response to irrelevant stimuli.
Highlights
Across the animal kingdom, the ability to awaken from sleep in response to salient signals and maintain sleep continuity in the presence of irrelevant background noise is clearly important for both survival and healthy sleep
During the Food Elicited Cataplexy Test (FECT) studies, the plasma levels at 1–2 h postdose were approximately 1.5 μM, which is >100-fold higher than minimum efficacy exposure levels tested for this compound to induce sleep in adult dogs
SLEEP-WAKE No GABA-A receptor modulator tested produced a sleep effect in dogs when administered during the day; diazepam, eszopiclone and zolpidem all had significant paradoxical hyperarousing effects, as did the antihistamine diphenhydramine (Figure 2)
Summary
The ability to awaken from sleep in response to salient signals (e.g., predator, fire alarm) and maintain sleep continuity in the presence of irrelevant background noise (e.g., environmental noise, traffic noise) is clearly important for both survival and healthy sleep. Laboratory studies involving the presentation of negatively conditioned acoustic stimuli, such as a tone associated with a shock, found animals more likely to awaken to these relevant conditioned versus neutral acoustic stimuli (Buendia et al, 1963; Van Twyver and Garrett, 1972; Halperin and Iorio, 1981) Such studies often invoked an underlying evolutionary drive to awaken in response to danger or predation signals with minimal disruption to sleep continuity in the presence of non-meaningful sounds, with the sleeping brain serving a sentinel function (see Snyder, 1966), as the ultimate benefit of such salience discrimination during sleep.
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