562

Brain Research, 122 ~t977~ 562-567 ('? Elsevier/North-Holland Biomedical Press, Amsterdam - Printed in The Netherlands

The time-dependent induction of REM sleep and arousal by physostigmine infusion ,during normal human sleep

NATARAJAN SITARAM, WALLACE B. MENDELSON, RICHARD .lED WYAI'I and J. CHRISTIAN GILLIN Adult Psychiatry Branch, Division of Clinical and Behavioral Research, Natiunal Institute a.l Mental Health, Bethesda, lYld. 20014 and Laboratory of Clinical Psychopharmacok~gy, Natiom¢l Institute of Mental Health, St. Elizabeths Hospital, Washington, D,C. 20032 (U.S.A.,

(Accepted November 19th, 1976)

Understanding the mechanisms which control rapid eye movement (REMI sleep, non-REM sleep and wakefulness is an important biological problem. Recently, Hobson et a15 have proposed a neurophysiological model for the control of desynchronized or REM sleep which postulates a reciprocal interaction between cells in the pontine gigantoce[lular tegmental field (FTG) and cells in the locus coeruleus and subcoeruleus. F T G neurons which are selectively active during R E M sleep respond by increased firing to local injections of carbachoI (a cholinomimetic) ~. This and other evidence from lesion and pharmacological studies on laboratory animals I,reviewed elsewhere 9) suggest a central role for acetylcholine in the mediation of REM sleep. However, there is very little evidence in man indicating a similar role for acetylcholine. Sagales et al. 8 showed R E M sleep suppression by scopolamine (an anticholinergic) and we have recently reported REM induction by physostigrnine (a reversible anticholinesterase which raises the concentration of acetylcholine in central and peripheral nerve synapse) infused 35 min after the onset of sleep in man 9. in this study, taking advantage of the short duration of action of physostigmine (about 30--90 rain) a, we systematically varied its dose and time of infusion during human sleep. Evidence is presented for a time- and dose-dependent mediation by cholinergic mechanisms of R E M sleep and cortical arousal in man. Thirty-three paid normal volunteers (28 males, 5 females) between 20 and 29 years of age (mean ..... 24.2) were studied using a controlled, double-blind experimental design~L After one night of adaptation, subjects received one intravenous infusion per night of either physostigmine 0.5 mg (in 10 ml 0.9 N saline) or placebo, which was 10 ml of 0.9 N saline given over a 3--4 min period. These infusions were given during one of the following time conditions: (a) 5 rain after sleep onset (l0 subjects), (b) 35

* This protocol was approved by the Medical Board of the National Institutes of Health and by Human Research Review Committee of St. Elizabeths Hospital. The Food and Drug Administration approved the study as an Investigational New Drug. Informed consent was obtained from each subject.

563 rain after sleep onset (11 subjects), (c) onset of first REM period (7 subjects; these subjects were included among the 11 subjects in condition (b)), (d) 5 rain after end of first REM period (6 subjects), and (e) 25 rain after end of first REM period (6 subjects). (The data from 7 subjects in conditions (b) and (c) were previously reported°.) Thus, infusions (a) and (b) occurred at times within the first non-REM period (i.e., the time elapsed from sleep onset to the first REM period) and infusions (d) and (e) occurred within the second non-REM period (time from end of first REM period (REMa) to the beginning of the second REM period (REM2)). Each subject received both physostigmine and matched placebo infusions during separate nights in random order. In addition, the 6 subjects in group (e) (25 rain after REM) also received a 0.25 mg physostigmine infusion. A higher dose (I.0 rag) was also given to 5 subjects at 35 rain after sleep onset and to 3 subjects at the onset of the first REM period. In order to block peripheral cholinergic effects of physostigmine (such as increased secretions, vomiting and bronchoconstriction), subjects were given intramuscular injections of methscopolamine bromide (0.5 rag) each night when they retired. Methscopolamine was given on both physostigmine and placebo nights. Methscopolamine is a peripheral anticholinergic agent that does not cross the bloodbrain barrier ~ and is reported to have little or no effect on human sleep as monitored by the EEG 8. Continuous all-night sleep recordings of the electroencephalogram (EEG), electro-oculogram (EOG) and electromyogram (EMG) were obtained and all records were scored according to standard criteria 7 by a single investigator who did not know the drug status of subjects. On the night of an infusion, a 21-gauge scalp vein needle was inserted into a forearm vein and attached to a l0 ft. polyethylene tube extending from each subject's room, and a slow drip of 0.9 N saline was maintained to ensure patency. 'Lights out' was between 11:30 p.m. and 12 midnight. Both infusions of physostigmine (0.5 rag) during the first non-REM period (i.e., at 5 rain and 35 rain after sleep onset) significantly reduced the time from infusion to the onset of the first REM period when compared to matched placebo (Table I). Furthermore, REM sleep appeared significantly sooner after physostigmine infusions given at 35 rain (11.2 :~ 2.1 rain) than at 5 rain after sleep onset (52.4 ~ 10.4 rain, P < 0.05, two-tailed t-test). These data have to be interpreted cautiously since infusions at 35 rain after sleep onset will have a greater natural propensity to bring on REM than infusions at 5 rain after sleep onset. Both of these infusions failed to alter other sleep parameters such as length of first REM period, total REM time, REM density (an estimate of the number of eye movements per minute of REM sleep TM) during the first REM period and for the whole night, total non-REM time and total delta sleep. This is consistent with the short-lived action of physostigmine. in sharp contrast to the above, the same dose of physostigmine (0.5 rag) given at REM onset and during the second non-REM period 'awakened' the subjects*.

* These 'awakenings' were scored by EEG criteria alone. Subjects did not seem to be behaviorally awake. The EKG (monitored on the EMG channel) did not show any change in rate or rhythm nor did subjects report any symptoms that might indicate that the awakenings were caused by peripheral side effects of physostigmine.

564

t- I oc

,~ :,

%,

E

~-~

~-~ ~.

,r!

!-

I

0

E

) ~

,..a .

The time-dependent induction of REM sleep and arousal by physostigmine infusion during normal human sleep.

562 Brain Research, 122 ~t977~ 562-567 ('? Elsevier/North-Holland Biomedical Press, Amsterdam - Printed in The Netherlands The time-dependent induct...
326KB Sizes 0 Downloads 0 Views