Effect of Tetrahydroaminoacridine Healthy Subjects on Sleep in Dieter Riemann, Stefanie Lis, Rosemarie Fritsch-Montero, Thomas Meier, Stefan Krieger, Fritz Hohagen, and Mathias Berger The present study investigated the impact of the cholinesterase inhibitor tetrahydroaminoacri- dine (THA; tacrine) on sleep in healthy subjects. According to the reciprocal interaction model of non-rapid eye movement (NREM) and REM sleep regulation, which postulates a primary role of cholinergic neurotransmission for the initiation and maintenance of REM sleep, it was expected that THA would lead to an earlier onset of REM sleep. In 12 healthy subjects aged from 21 to 50 years two different doses (20 mg, 40 mg) were administered I hour prior to bed time and compared to placebo. Only the higher dose of THA significantly shortened REM latency. No other significant effects on sleep architecture were observed, although adminis- tration of 40 mg tacrine was associated with a decrease in sleep efficiency and a prolongation of sleep latency. Blood plasma levels of tacrine and its metabolite 1-hydroxytacrine measured prior to sleep and during the first 90 min of sleep were significantly correlated with the onset of REM sleep in relation to the timing of drug administration (only for the 20 mg dose). The reversible cholinesterase inhibitor THA exerts effects on REM latency comparable to those observed with other cholinomimetic agents. Key Words: REM latency, cholinergic neurotransmission, tacrine BIOL PSYCHIATRY 1996;39:796--802 Introduction The reciprocal interaction model of sleep regulation as formulated by Hobson and co-workers (1975; Hobson and Steriade 1986) postulates that the regular pattern of non- rapid eye movement/rapid eye movement (NREM/REM) sleep is governed by cell groups located in the brainstem. It is assumed that neurons in the locus ceruleus and the dorsal raph6 inhibit REM sleep via norepinephrenic or serotonergic neurotransmission, whereas cholinergic neu- From the Psychiatric Department of the University of Freiburg, Freiburg, Germany. Address reprint requests to Dieter Riemann, PhD, Psychiatric Clinic of the University of Freiburg, Hauptstrasse 5, 79104 Freiburg, Germany. Received August 3, 1994; revised April 3, 1995. tons mainly in the pontine reticular formation are believed to promote REM sleep. According to the reciprocal interaction model the interplay between these transmitter systems is responsible for the cyclic pattern of NREM sleep/REM sleep. Numerous animal studies have shown that stimulation with cholinergic agonists leads to an earlier onset of REM sleep and a longer maintenance of REM periods (for survey see Hobson et al 1986; Steriade and McCarley 1990). The hypothesis of a cholinergic involvement in the regulation of REM sleep was tested in healthy humans with the cholinesterase inhibitors physostigmine (Sitaram et al 1976, 1977; Berger et al 1983), SDZ-ENA 713 (Holsboer-Trachsler et al 1993), galanthamine (Riemann © 1996 Society of Biological Psychiatry 0006-3223/96/$15.00 SSDI 0006-3223(95)00224-5