Effects of Physostigmine Infusion on Healthy Volunteers Deprived of ...

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*Lourdes Huerto-Delgadillo, and *Daniel Granados-Fuentes. *Divisi6n de ... the sensitivity of various neurotransmitter systems. In the present article, we.
Sleep 12(3):246--253, Raven Press, Ltd., New York © 1989 Association of Professional Sleep Societies

Effects of Physostigmine Infusion on Healthy Volunteers Deprived of Rapid Eye Movement Sleep *tRafaell. Salin-Pascual, *Amado Nieto-Caraveo, *Gabriel Roldan-Roldan, *Lourdes Huerto-Delgadillo, and *Daniel Granados-Fuentes *Divisi6n de Investigaciones Clinicas, Departamento de Psicobi%gia, Instituto Mexicano de Psiquiatria, and tEscuela Superior de Medicina, Secci6n de Graduados, Instituto Politecnico Nacional, Mexico City, Mexico

Summary: Rapid eye movement sleep (REMS) deprivation is believed to alter the sensitivity of various neurotransmitter systems. In the present article, we studied 20 healthy volunteers divided into three groups. Group A attended the sleep laboratory for three nights: acclimatization, a baseline night, and one night of physostigmine infusion. Group B attended for eight nights; acclimatization, baseline, four nights of REMS deprivation, and two recovery nights. With the exception of the first recovery night, when group C volunteers were administered physostigmine, group C's schedule was identical to group B's. The infusions received by group A and C were composed of 1.0 mg of physostigmine, dissolved in 100 ml of saline solution. These were administered 5 min after sleep onset and thereafter every hour, except when the subjects were either awake or in REMS. All of the subjects receiving the cholinomimetic infusion were given a peripheral anticholinergic. Group A experienced a great number of awakenings with a decrease in REMS percentage. Group B recovery occurred over two nights, with an increase in the average length ofREMS. Group C exhibited maximum REMS rebound on the first recovery night with an increased number ofREMS episodes, as well as significant reductions in the first REMS latency. Our findings suggest that physostigmine alters REMS rebound following REMS deprivation. Key Words: REM sleep deprivationPhysostigmine-Cholinergic-Depression.

Cholinergic mechanisms have been implicated in the neurochemical basis of rapid eye movement sleep (REMS). There is a lot of evidence that a diffuse network of cholinoceptive neurons in the medial pontine reticular formation primes, initiates, and supports the REMS 0-3). The pharmacological studies that implicate cholinergic Accepted for pUblication February 1989. Address correspondence and reprint requests to Dr. R. J. Salin-Pascual, Instituto Mexicano de Psiquiatria, Division de Investigaciones Clinicas, Antiguo Camino a Xochimilco No. !OI, Col San Lorenzo Huipulco, Tlaipan, Mexico City 14370, Mexico.

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mechanisms in REMS only indicate that neurons are sensitive to acetylcholine; it has been suggested that an intrinsic cholinergic input activates the cholinoceptive REMS neurons in the medial pontine reticular formation (4). Thus, this structure may actually represent a final common path in a sequence of events originating elsewhere in the central nervous system. Several lines of evidence have suggested that REMS deprivation is a therapeutic process that can improve endogenous depression (5,6), even though we do not know the underlying neurobiological mechanisms. Changes in receptor sensitivity to different neurotransmitters could be related to the antidepressant effects of REMS deprivations (7-9), but changes in the cholinergic receptor activity after REMS deprivation have been little explored. The present work was done based on the hypothesis that REMS deprivation causes changes in the cholinergic neurons. METHODS

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Twenty healthy volunteers of both sexes between 17 to 30 years of age were studied (4 women and 16 men; mean age of 26.4 ± 2.8 years). All of the subjects were screened by the "Diagnostic Interview Schedule" (10) in the Spanish reliability version (11). They had no history of psychiatric disorders, sleep disturbance, or serious illness. The subjects were nonsmokers and did not have antecedents of alcohol or other drug abuse. They were not kept on a constant sleep-wake schedule prior to the study and also there were no sleep times and wake times selected. The volunteers received a nominal compensation at the end of the study. The subjects were divided into three groups. Group A (n = 6) subjects were studied on the basis of an acclimatization night, a baseline night, an infusion night, and a recovery night. Group B (n = 8) subjects were studied under the following conditions: acclimatization to the sleep unit, baseline night, four nights of REMS deprivation, and the last two nights were recovery. Group C (n = 6) subjects were studied following the same experimental procedure as group B, with the exception of a physostigmine infusion during the first recovery night. Physostigmine infusions (1.0 mg in 100 ml of saline solution) were administered i. v. to groups A and C. Infusions were administered each hour, starting at 5 min after sleep onset. The total volume was injected over 10 min. No infusions were administered if the volunteers were awake or in REMS. The infusions were stopped and the catheter was retired at 0200 h (groups A and C) because there is a higher probability of REMS in the second part of the night than in the first part (12), and because of that it is difficult to say if the infusion was or was not capable of inducing REMS episodes. A 2-m-Iong infusion catheter allowed us to conduct the procedure from a soundproof room, so that volunteers' sleep was undisturbed. All of the subjects in the three groups received anisatropin methylbromide 1 h before starting the polysomnographic recording in order to reduce the peripheral disturbances produced by physostigmine. The sleep recordings started at 2200 h and stopped at 0600 h. Daytime sleep and naps were not permitted. Polysomnographic records included two electroencephalogram (EEG) channels (C3-A2; 01-A2), two electro-oculogram (EOG) channels, one electromyogram (EMG) channel, and one electrocardiogram (ECG) channel. Subjects in the two REMS-deprived groups were awakened as soon as they showed polysomnographic evidence of this stage, and they were not allowed to resume sleep for 5 min, which was necessary in order to prevent an immediate relapse into REMS (in our Sleep, Vol. 12, No.3, 1989

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R. 1. SALiN-PASCUAL ET AL.

experience, relapses happened very often after several nights of REMS deprivation). The sleep recordings were scored visually, according to the standardized criterion (13), by a researcher who was not informed of the experimental procedures for each group. Statistical analysis was performed by two-way ANOV A using groups as one variable and night as the repeated measure intergroup. Student's t tests for repeated measurement with a correction at the a level of significance (Bonferroni's correction) were also performed for intragroup comparison. Infusions followed by REMS within 20 min from its beginning were called "REMS-inducing infusions." These criteria are based on the work of Sitaram and Gillin (15). Those infusions followed by awakenings within 20 min were called "awakening-inducing infusions." Fisher's exact tests were used for each infusion as an independent variable. RESULTS The polysomnographic variables of group A (patients infused with physostigmine without REM sleep deprivation) are shown in Table 1. A significant decrease was observed in the continuity sleep variables: sleep latency (SL), total sleep time (TST), and efficiency sleep index (ESI). In contrast, the total awakening (TA) time was increased. An increase of stage 1 and a significant decrease of the percentage of REM sleep episodes caused a modification in the sleep architecture. Although 11 physostigmine infusions were performed in this group, only two induced a REM sleep episode (18.4%), and the other 9 led to awakening reactions (81.8%) (see Table 7). These awakening reactions were not similar to the spontaneous awakenings observed in the same volunteers during the polysomnographic recordings without pharmacologic ma-

TABLE 1. Po/ysomnographic findings in group A (n = 6) (physostigmine without REM sleep deprivation) Sleep variables Sleep continuity Sleep latency TST Awake time #AW ESI Sleep architecture % SI % S2 % S3 %S4 %SREM REM sleep variables REM sleep latency # REM sleep XREM sleep REM sleep activity REM sleep density

Baseline

Physostigmine infusion

15.4 459 18.6 3.6 93.5

:t 6.7 :t 19.7 :t 17.0

± 2.1 ± 4.6

19.9 349 67.8 4.6 74.7

4.5 51.5 6.6 15.5 22.82

± 1.9 ± 3.2 ± 1.9 ± 2.5 ± 3.5

8.1 ± 2.9 52.3 ± 7.6 8.2±3.1 18.5 ± 7.7 16.6 ± 6.4

92.5 5.1 25.5 204.6 1.96

± 26.7 ± 0.98 ± 3.2 ± 38.5 ± 0.4

94.2 3.3 27.2 120.4 2.04

:t 8.6 :t 61.8

± 27.5 ± 2.2 ± 11.02

± ± ± ± ±

40.1 1.7 6.5 45.3 0.8

Significance" n.s. p p

< 0.01 < 0.01

p

< 0.01

p

< 0.05

n.s.

n.s. n.s. n.s. p < 0.05 n.s. p

< 0.01 n.s. n.s. n.s.

Mean ± SD. TST = total sleep time; # AW = number of awakenings; % S = percentage of each stage (1, 2,3,4, and REM); ESI = efficiency sleep index; # REM = number of REM sleep; XREM = average of REM sleep during the night. a Student's t test for repeated measurements.

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nipulation. First, there was an EEG de synchronization with a waves and after that a total body movement. Table 2 includes the polysomnographic variables at baseline and at two recovery nights of REM sleep deprivation observed in group B (healthy volunteers deprived of REM sleep with no physostigmine infusion). Since the total sleep time was increased due to a decrease in the number of awakenings (#A) and in awakenings time (AT), the ESI was also increased. Mter REMS deprivation, the sleep architecture was modified in two directions: on the one hand, stages 1 and 2 decreased and, on the other hand, stages 4 and REMS increased. Additionally, REMS latency tended to diminish whereas its mean duration and ocular movement activity augmented. Basically, the recovery from REM sleep deprivation occurred in the mean duration of each REM sleep episode, and not in the increment of these episodes' frequencies. There were no significant differences between the first and the second recovery nights in this group. Table 3 shows other polysomnographic variables in group B: basal, first, second, third, and fourth nights of REMS deprivation. The experimental maneuvers provoked an important alteration in the sleep continuity variables. Besides, the sleep architecture was internally rearranged, with a pattern inverse to that observed in the recovery nights: stages 1 and 4 augmented while REMS diminished as soon as the REMS deprivation began; this stage was observed to appear more frequently on the deprivation nights. Table 4 shows the sleep variables recorded during baseline and first and second recovery nights of group C (subjects deprived of REMS with physostigmine infusions). The most significant feature observed during the first and second recovery nights was TABLE 2. Polysomnographic variables in group B (n = 8) (REM sleep deprived

without physostigmine) Sleep variables Continuity variables S.L. (min) TST (min) AT (min) #A ESI (%) Sleep architecture %SI ll)

% S2 % S3 % S4 %SREM REM sleep variables REMS lat. XREMS (min) # REM REM sleep activity REM density

Baseline night

I st recovery night

2nd recovery night

F value

pa

20.1 424.2 38.6 2.7 89.2

± ± ± ± ±

1l.5 47.2 48.6 2.4 9.5

10.8 461.1 10.5 0.6 96.7

± ± ± ± ±

3.9 17.0 9.4 O.