title: Differential effects of the muscarinic M1 receptor agonist RS-86 and the acetylcholine-esterase inhibitor donepezil on REM sleep regulation in healthy volunteers.
abstract: Broad evidence from preclinical and clinical research indicates that cholinergic neurotransmission contributes significantly to the generation of rapid eye movement (REM) sleep. However, a potential role of different acetylcholine receptor (AChR) subtypes for the regulation of three main aspects of REM sleep, (1) REM onset, (2) REM maintenance, and (3) generation of REMs, are not clear. In the present double-blind, randomized and placebo-controlled study, we investigated the differential effects of the M1 muscarinic AChR (mAChR) agonist RS-86 and the ACh-esterase inhibitor donepezil to further specify the AChR subtype function on REM sleep regulation in n = 20 healthy volunteers. We found that RS-86 selectively shortened REM latency (multivariate analysis of variance post hoc contrast p = 0.024 compared to placebo, not significant for donepezil) and that donepezil specifically enhanced the duration of REM sleep (% sleep period time, p = 0.000 compared to placebo; p = 0.003 compared to RS-86) and the number of REMs (p = 0.000 compared to placebo; p = 0.000 compared to RS-86). These results provide evidence that the onset of REM sleep is, in part, mediated by M1 mAChR activity, whereas the maintenance of REM sleep and the number of REMs are mediated by non-M1, but presumably M2 mAChR activity. These findings are of interest for the understanding of sleep regulation and of neuropsychiatric disorders, such as Alzheimer's dementia and depressive disorders, whose etiopathology may involve alterations in cholinergic neurotransmission.
authors.affiliation: Department of Psychiatry and Psychotherapy, Albert-Ludwigs-University, Freiburg, Germany. nissenc@upmc.edu
authors.forename: Christoph
authors.initials: C
authors.lastname: Nissen
authors.forename: Eric A
authors.initials: EA
authors.lastname: Nofzinger
authors.forename: Bernd
authors.initials: B
authors.lastname: Feige
authors.forename: Bernhard
authors.initials: B
authors.lastname: Waldheim
authors.forename: Marc-Philipp
authors.initials: MP
authors.lastname: Radosa
authors.forename: Dieter
authors.initials: D
authors.lastname: Riemann
authors.forename: Mathias
authors.initials: M
authors.lastname: Berger
mesh_terms: D000328:Adult; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008297:Male; D015999:Multivariate Analysis; D010880:Piperidines / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D012895:Sleep, REM / Q000187:drug effects*; D013388:Succinimides / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D013388:Succinimides; C001886:2-ethyl-8-methyl-2,8-diazaspiro(4,5)decane-1,3-dione; D000077265:Donepezil