Modulation of arousal and sleep/wake architecture by M₁ PAM VU0453595 across young and aged rodents and nonhuman...

Degeneration of basal forebrain cholinergic circuitry represents an early event in the development of Alzheimer's disease (AD). These alterations in central cholinergic function are associated with disruptions in arousal, sleep/wake architecture, and cognition. Changes in sleep/wake architecture are also present in normal aging and may represent a significant risk factor for AD. M₁ muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs) have been reported to enhance cognition across preclinical species and may also provide beneficial effects for age- and/or neurodegenerative disease-related changes in arousal and sleep. In the present study, electroencephalography was conducted in young animals (mice, rats and nonhuman primates [NHPs]) and in aged mice to examine the effects of the selective M₁ PAM VU0453595 in comparison with the acetylcholinesterase inhibitor donepezil, M₁/M₄ agonist xanomeline (in NHPs), and M₁ PAM BQCA (in rats) on sleep/wake architecture and arousal. In young wildtype mice, rats, and NHPs, but not in M₁ mAChR KO mice, VU0453595 produced dose-related increases in high frequency gamma power, a correlate of arousal and cognition enhancement, without altering duration of time across all sleep/wake stages. Effects of VU0453595 in NHPs were observed within a dose range that did not induce cholinergic-mediated adverse effects. In contrast, donepezil and xanomeline increased time awake in rodents and engendered dose-limiting adverse effects in NHPs. Finally, VU0453595 attenuated age-related decreases in REM sleep duration in aged wildtype mice. Development of M₁ PAMs represents a viable strategy for attenuating age-related and dementia-related pathological disturbances of sleep and arousal.