Influence of the Cholinergic Agonist RS 86 on normal sleep: Sex and age effects

Abstract

Abstract. In 36 healthy control subjects (21 females, I5 males; age range 18-65 years; mean age 41.8 years, SD 15.6 years), a bedtime dose of I.5 mg RS 86, an orally acting cholinergic agonist, shortened rapid eye movement (REM) latency, increased REM sleep, and decreased slow-wave sleep. Six of the subjects (> 40 years old) even displayed sleep-onset REM periods after the drug. Results of the present study agree well with those of studies using other cholinomimetics (i.e., physostigmine, arecholine) and confirm the importance of the cholinergic system for REM sleep regulation.Since RS 86 mimicked some of the REM sleep abnormalities specific for patients with depressive disorders, the cholinergic system may play a role in the pathogenesis and pathophysiology of depressive diseases.

Differential Effects of the Muscarinic M1 Receptor Agonist RS-86 and the Acetylcholine-Esterase Inhibitor Donepezil on REM Sleep Regulation in Healthy Volunteers

“…This finding is consistent with those of previous studies investigating the effects of RS-86 on REM latency in healthy subjects (Riemann et al, 1988;Lauer et al, 2004). The finding that numerous ACh-esterase inhibitors shorten REM latency (eg physostigmine; Sitaram et al, 1976) is consistent but does not further contribute to the discussion of the involvement of AChR subtypes.…”

“…Consistently, LDT/PPT neurons demonstrate higher discharge rates during REM sleep (el Mansari et al, 1989). In humans, REM sleep is enhanced after administration of ACh-esterase inhibitors (Sitaram et al, 1976;Riemann et al, 1994) or cholinergic agonists (Spiegel, 1984;Riemann et al, 1988) and inhibited by anticholinergics (Sagales et al, 1969).…”

“…They showed an increase of the number of REMs and REM sleep maintenance after the administration of numerous ACh-esterase inhibitors. Also, preclinical (Velazquez-Moctezuma et al, 1991;Coleman et al, 2004) and clinical (Riemann et al, 1988;Gillin et al, 1991) studies have shown that compounds with a selective affinity for M 1 mAChRs did not affect these parameters. In contrast, the ACh-esterase inhibitor tacrin did not significantly affect REM density or duration (Riemann et al, 1996).…”

“…No serious side effects were observed in studies using up to 20 mg RS-86 (Spiegel, 1984). Based on pharmacological data and following previous studies (eg Riemann et al, 1988), 1.5 mg RS-86 was administered orally at 2200 hours, 1 h prior to 'light-off' time at 2300 hours.…”

“…In humans, numerous ACh-esterase inhibitors (eg physostigmine: Sitaram et al, 1976;galanthamine: Riemann et al, 1994) and selective M 1 mAChR agonists, like pilocarpine (Berkowitz et al, 1990) or RS-86 (Riemann et al, 1988), shorten REM latency. Gillin et al (1991) demonstrated that low doses of the M 1 antagonist biperiden selectively enhanced REM latency without affecting REM duration.…”