In:
Alzheimer's & Dementia, Wiley, Vol. 18, No. S10 ( 2022-12)
Abstract:
Age‐related changes in sleep may directly contribute to cognitive dysfunction and underlying pathological progression contributing to Alzheimer’s Disease or related dementias (AD/ADRDs). While acetylcholinesterase inhibitors (AChEIs) are FDA‐approved for the treatment of AD‐related cognitive impairments, these drugs also disrupt sleep. Positive allosteric modulators (PAMs) targeting the M 1 muscarinic acetylcholine receptor (M 1 mAChR) have produced cognitive and arousal enhancing as well as sleep‐modifying effects in aged and/or AD rodents models. The present study provided the first comparison of baseline sleep measures in young and old monkeys, then examined the effects of novel M 1 mAChR PAMs VU0486846 and VU0453595, compared with the AChEI, Donepezil on sleep in aged monkeys. Method Eight young adult (4 male/4 female, 6‐8 years old) and 10 aged cynomolgus macaques (6 males/4 females, 19‐25 years old) were implanted with subcranial electrodes and a wireless transmitter (L04, DSI) for undisturbed telemetric recording of electroencephalography (EEG) from their home cage. After baseline sleep assessments, aged monkeys were tested once weekly with donepezil (3.0‐10 mg/kg, PO), VU0486846 (3.0‐30 mg/kg, PO), or VU0453595 (1.0‐10 mg/kg, PO), administered 2 hours prior to lights out (0600:1800 light:dark schedule). EEG was recorded and sleep stages including total sleep time (TST), % TST in rapid eye movement sleep (REM), N1, N2, and N3 non‐REM sleep were determined and summed across the 12 hour dark period. Result Aged monkeys showed significantly less % TST in N3 and REM sleep and increased N1 sleep compared to young monkeys. Donepezil dose‐dependently reduced TST, increased % REM and trended toward a decrease in N2 and N3 stage sleep. In contrast, M 1 PAMs, within dose ranges known to be physiologically active in monkeys, did not alter sleep parameters. Conclusion Aged‐related and donepezil‐mediated sleep disruptions in aged monkeys are consistent with the clinical literature. Lack of effects by M 1 mAChR PAMs in aged monkeys when dosed prior to lights out may suggest fewer disruptive effects compared to AChEIs or that there is insufficient cholinergic tone for an M 1 PAM to alter sleep. Future studies will assess the arousal enhancing effects of M 1 PAMs when dosed during waking periods in aged monkeys. Funding: AG054622, DA017763
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2201940-6
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