Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs

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.

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

“…Because HcrtR antagonists may act via disfacilitation rather than generalized inhibition, they are predicted to cause less functional impairment than BzRAs (Morairty et al, 2014;Steiner et al, 2011), a hypothesis that has been supported by recent behavioral studies (Morairty et al, 2014;Tannenbaum et al, 2014;Uslaner et al, 2013).…”

“…ALM and other HcrtR antagonists effectively induce sleep (Brisbare-Roch et al, 2007;Cox et al, 2010) but cause less impairment in memory tasks (Dietrich and Jenck, 2010;Morairty et al, 2014) or motor function in rodents (Ramirez et al, 2013;Steiner et al, 2011), dogs (Tannenbaum et al, 2014), and non-human primates (Uslaner et al, 2013) than do traditional hypnotics. Although some degree of impairment may occur at high doses in humans (Hoever et al, 2010(Hoever et al, , 2012Jacobson et al, 2014), HcrtR antagonists are expected to exhibit a favorable safety profile compared with ZOL and other hypnotics, though years of post-market surveillance will be needed to confirm this hypothesis.…”

Structure–Activity Relationship, Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT‐462206: a Potent, Brain‐Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist

“…Both groups, but not rats treated with the muscarinic antagonist scopolamine, used as positive control, established spatial memory. [22] For instance, dogs treated with DORAs are able to wake up just fine when presented with emotionally salient acoustic stimuli, [50] and rats treated with DORAs perform normally on the rotarod after being woken up during their daytime sleeping phase (Figure 12 c and Ref. In comparison with the positive GABA A receptor modulator zolpidem, which is frequently used as sleep medication in the clinic at present, 24 (300 mg kg À1 ) did not impair contextual memory acquisition in the passive avoidance learning paradigm (Figure 12 b), nor forced motor performance in the rotating rod test (Figure 12 c).…”

Hypnotics with novel modes of action

“…Similarly, orexin receptor antagonists have other clear advantages over benzodiazepines or Z drugs: no general dampening on brain activity, no cognitive impairment . Animals or patients treated with orexin receptor antagonists appear to be able to wake up upon adequate stimulation, contrary to most other hypnotics. For the time being, it is unclear whether selective OX 2 R antagonists and DORAs have different effects on sleep architecture in humans; this will be defined in the clinic, based on polysomnography rather than subjective patient‐reported data.…”