Selectively Targeting the M1 and M4 Muscarinic Acetylcholine Receptors for the Treatment of Age-Related Sleep/Wake Architecture and Arousal Deficits

Abstract

Degeneration of the cholinergic basal forebrain is implicated in cognitive deficits and sleep/wake architecture disturbances in non-pathological aging and Alzheimer's Disease (AD). The acetylcholinesterase inhibitors (AChEls) remain the only FDA approved treatment for the cognitive impairments observed in AD that targets the cholinergic system. Novel direct-acting muscarinic cholinergic receptor agonists are currently under clinical development for AD. However, little is known about the effects of direct-acting muscarinic cholinergic receptor agonists on disruptions of sleep/wake architecture and arousal observed in non-pathological aging. In the present dissertation I provide the first assessment of the effects of the direct-acting M1/M4-preferring muscarinic cholinergic receptor agonist xanomeline, the M1 mAChR positive allosteric modulator (PAM) VU0453595 and the M4 mAChR PAM VU0467154 on sleep/wake architecture and arousal in young and non-pathologically aged mice, in comparison with the AChEl donepezil when dosed in either the active or inactive phase of the circadian cycle. Xanomeline and the M1 mAChR PAM VU0453595 reversed disruptions in age-related wake fragmentation and/or arousal deficits during the active phase in 19-20-month-old mice. However, in 26-28-month-old the efficacy of the M1 mAChR PAM VU0453595 is attenuated unless dosed in combination with donepezil. In contrast, donepezil alone had no effect on either age-related wake fragmentation or arousal deficits during the active phase in 19-20-month-old mice. The M4 mAChR PAM VU0467154 increased REM sleep in young and non-pathologically aged mice, reducing NREM sleep fragmentation in non-pathologically aged animals. Importantly, neither PAM mechanisms produced cholinergic adverse side effects in contrast to xanomeline and donepezil. These data suggest a therapeutic role for M1 PAMs in normalizing age-related sleep/wake architecture and arousal deficits during the active period in aging and AD, while M4 PAMs may provide benefit when dosed to improve NREM sleep duration and quality in aging and AD populations.