The M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) VU0453595 and M4 PAM VU0467154 Normalize Sleep‐Wake Architecture Deficits in Aged Mice

Abstract

AbstractBackgroundDeclining basal forebrain cholinergic integrity has been associated with disturbances in sleep‐wake architecture in Alzheimer’s Disease (AD). Acetylcholinesterase inhibitors (AChEIs) provide symptomatic treatment for the cognitive deficits in AD through nonselective enhancement of cholinergic signaling. Additionally, AChEIs promote wakefulness, but reduce NREM sleep quality and produce dose limiting side effects through nonselective activation of peripheral muscarinic acetylcholine receptors (mAChR). Selectively targeting different mAChRs with positive allosteric modulators (PAMs) provides an alternate approach. In the current study, we assessed the effects of the M1 PAM VU0453595 and the M4 PAM VU0467154 on sleep‐wake architecture and arousal following dosing across the circadian cycle in aged mice.MethodsYoung (3‐4 month‐old, n = 13‐14 per group) and aged (19‐21 month‐old, n = 14 per group) C57/BL6 mice were implanted with HD‐X02 telemetry devices (DSI) for electroencephalography (EEG) recording. The M1 PAM VU0453595 (3‐30mg/kg IP) or the M4 PAM VU0467154 (1‐30mg/kg IP) were dosed 2‐hours into the active or inactive phases of the circadian cycle. EEG was recorded for 24‐hours, with sleep stages scored in 5‐second epochs. Arousal was assessed through changes in gamma power during wake, and sleep quality was measured through changes in delta power during NREM sleep. Statistical comparisons involved repeated measures one‐ or two‐way ANOVAs as appropriate, with Dunnett’s or Sidak’s multiple comparisons applied in all cases.ResultsThe M1 PAM VU0453595 increased wakefulness and arousal with inactive phase dosing in young and aged mice. During the active phase, VU0453595 increased wakefulness and arousal only in aged mice. The M4 PAM VU0467154 increased NREM sleep in young and aged mice when dosed in both phases. In the inactive phase, suppression of REM sleep in young and aged mice is also observed. During NREM sleep, VU0467154 increased delta power in young and aged mice.ConclusionThese findings suggest that M1 and M4 PAMs may be valuable as treatments in AD at different phases of the circadian cycle. M1 PAMs could be beneficial with morning dosing in clinical populations as they enhanced wakefulness and arousal. M4 PAMs could be advantageous with evening dosing in clinical population as they enhanced NREM sleep quantity and quality.