Biperiden Administration I)Uring REM Sleep Deprivation Diminished the Frequency of REM Sle1ep Attempts

Biperiden Administration I)uring REM Sleep Deprivation Diminished the Frequency of REM Sle1ep Attempts

*tRafael1. Salin-Pascual, tDaniel Grandos-Fuentes, tLourdes Galicia-Polo, tEstela Nieves, Downloaded from https://academic.oup.com/sleep/article/15/3/252/2749274 by guest on 30 September 2021 *Timothy A. Roehrs and *Thomas Roth

*Sleep Disorders Center, Henry Ford Hospital, Detroit, Michigan, U.S.A.; and tPsychobiological Department, Mexican Psychiatric Institute, Mexico City, Mexico

Summary: Sixteen subjects were assigned to a group using either placebo or biperiden, with eight subjects in each group. Both groups were studied for one acclimatization night, one baseline night, four nights of rapid eye movement (REM) sleep deprivation and two recovery nights. All the subjects received either placebo or 4 mg biperiden I hour before sleep during the four nights of REM sleep deprivation. During the baseline and the recovery nights both groups received placebo capsules. The results showed that REM sleep time during thl~ REM sleep deprivation was reduced by 70-75% below the baseline night in both groups. The number of attempts to enter REM sleep was significantly reduced by biperiden as compared to placebo for each of the four REM sleep deprivation nights. Because the total sleep time in the biperiden group was reduced, the number of REM sleep attempts was corrected by the total sleep time. The adjusted number of REM sleep attempts was also significantly reduced in the biperiden group. REM sleep latency showed a reduction in the placebo group, whereas in the biperiden group REM sleep latency was unchanged throughout the deprivation nights. In the recovery night REM sleep time was increased in both groups, with no differences between the groups. The REM sleep latency showed a reduction in the first recovery night in both groups that persisted through the second recovery night. The above findings support the role of biperiden as a REM sleep suppressive drug. Key Words: Muscarinic receptors-REM sleep deprivation-Biperiden-Human subjects.

It has been proposed that Ml and M2 muscarinic den did not show a significant increase in REM sleep. receptors as well as nicotinic receptors are involved in It was not until the follow-up night (with no active the regulatory process of rapid eye movement (REM) drug administration) that REM sleep increased in the sleep based on studies in cats (1-3) and humans (4,5). biperiden group. Another group has recently reported Biperiden is an anticholinergic drug with preference a dose-dependent inhibition of REM sleep in normal for Ml muscarinic receptors (6). Biperiden adminis volunteers by biperiden; they used 2-, 4-, and 8-mg tration in healthy normal humans increased REM sleep doses of biperiden and found a significant reduction latency at 4- and 6-mg doses and biperiden 6 mg re even with a 4-mg dose (8). duced REM sleep time (7). In the same study, after six The fact that biperiden modified REM sleep both nights of REM sleep deprivation two groups of normal on baseline and during recovery nights from REM sleep subjects received either placebo or biperiden (4 mg) on deprivation suggests that Ml receptors are involved in the first recovery night. The REM sleep time in the REM sleep mechanisms in humans. The fact that a group that received placebo was increased during the lower biperiden dose altered REM sleep more during recovery night, whereas the group that received biperi- deprivation recovery than on baseline nights might be explained as follows. Normally, acetylcholine is re leased during REM sleep as shown in the cat (9). REM Accepted for publication November 1991. sleep deprivation could modify the release of acetyl Address correspondence and reprint requests to Rafael J. Salin choline and change muscarinic receptor sensitivity, Pascual, M.D., D.MSc., U.e.S.D. Psychiatry Dept. and San Di(:go VA Medical Center-Psychiatry SVC (116 A), 3350 La Iolla Vi11age thereby producing the increased response to a low dose Dr., San Diego, California 92161, U.S.A. ofbiperiden and reduced REM sleep rebound. In sup- 252 BIPERIDEN AND REM SLEEP 253 port of the above idea, it has been reported (10) in tinuous minutes of sleep after lights out. Awake time human volunteers that physostigmine (an indirect cho was defined as the minutes awake after sleep onset. linomimetic drug) infusion after four nights of REM REM sleep latency was defined as the time from sleep sleep deprivation modifies the typical REM sleep re onset to the completion of two epochs of REM sleep covery. If the above is the case, the question arises as (1 minute) (including intermittent awakenings). A REM to whether the combination of REM sleep deprivation sleep attempt was defined as one epoch of continuous and biperiden administration might further reduce REM sleep. cholinergic activity by both suppressing acetylcholine Overall two-way ANOYAs, using group as one vari release and blocking receptors, thereby leading to a able (placebo group vs. biperiden group) and night as lessened pressure for REM sleep during deprivation. the second variable, were performed. Post-hoc Stu

The present study was developed to examine in nor dents' t tests for repeated measures with a correction Downloaded from https://academic.oup.com/sleep/article/15/3/252/2749274 by guest on 30 September 2021 mal volunteers the effects of biperiden when admin to maintain the alpha level of significance at p < 0.05 istered simultaneously with REM sleep deprivation. (Bonferroni's correction) were performed when indi We were interested in biperiden effects during REM cated. sleep deprivation and in the recovery period when REM sleep rebound typically occurs. The main hypotheses RESULTS were that if biperiden blocks M 1 receptors and if they are involved in REM sleep, then biperiden should re Results of the overall two-way ANOYAs and post duce the number of REM sleep attempts during REM hoc tests are presented in Table 1. The means and sleep deprivation, and the drug also should produce a standard deviations of baseline and deprivation nights differential REM sleep rebound in comparison with and baseline and recovery nights are presented in Ta the placebo group. bles 2 and 3, respectively. REM sleep time on deprivation nights was reduced METHODS in both groups by 70-75% below baseline, with no differences between placebo or biperiden groups. Dur Sixteen healthy volunteers were studied [aged: 25.2 ing the recovery nights, this variable was increased ± 2.8 years (mean ± SD)]. All the subjects were between 28 to 30% without differences between the screened by the Diagnostic Interview Schedule in a groups (ANOYA-group effects: F = 0.43, df= 1,14, reliable Spanish version (11). They had no history of p = 0.51; night effects: F = 140.4, df = 6,79, p < psychiatric disorder, sleep disturbances or serious ill 0.00001; interactions: F= 0.255, df= 6,79, p = 0.95). ness. The subjects were nonsmokers and had,no history REM sleep latency on deprivation nights was re of alcohol or other drug abuse. duced in the placebo group (vs. baseline), whereas in The subjects were randomly assigned to one of two the biperiden group it was increased (a trend indicated groups: placebo or biperiden, with eight subjects per by the interaction, p < 0.10). During recovery nights, group. Each volunteer slept in the laboratory on one a reduction in this variable was observed in both groups, acclimatization night, one baseline night, four REM with no differences between them (ANOYA-group sleep deprivation nights and two recovery nights. All effects: F = 5.83, df= 1,14, p < 0.01; night effects: F the subjects received identical capsules with either pla = 3.56, df = 6,79, p < 0.003; interactions: F = 1.8, df cebo or 4 mg biperiden (two commercial tablets of 2 = 6,79, p < 0.10). mg Akineton, Knoll), 1 hour before sleep during the The number of REM sleep attempts on REM sleep four nights of REM sleep deprivation. During the base deprivation nights was significantly increased in both line and recovery nights, both groups received placebo groups. But there was a reduced number of attempts capsules. For the four nights of REM sleep deprivation in the biperiden group in comparison with the other the volunteers were immediately awakened on every group (ANOYA-group effects: F = 27.7, df = 1,14, occasion when they showed polysomnographic evi p < 0.00001; night effects: F= 25.19, df= 6,79, p < dence of REM sleep (one epoch) by technicians who 0.00001; interactions: F = 4.4, df = 6,79, p < 0.001). did not know the treatment that the volunteers were Because the total sleep time was significantly reduced receiving. The sleep recordings started at 2200 hours in the biperiden group (ANOYA-group effects: F = and ran until 0600 hours. They were scored visually 13.03, df= 1,14, p < 0.00001; night effects: F = 27.7, according to standardized criteria (12) by one of us df = 6,79, p < 0.00001; interactions: F = 2.58, df = who was not informed of the experimental procedure 6,79, p < 0.02), the number of REM sleep attempts for each group. The subjects were not allowed to nap was corrected for the total sleep time differences (by during the day and were reminded of this restriction an index: number of REM sleep attempts/total sleep each morning. time). The resulting index was also significantly re Sleep onset was defined as the first epoch of 8 con- duced in the biperiden group.

Sleep, Vol. 15, No.3, 1992 254 R. J. SALIN·PASCUAL ET AL.

TABLE 1. Overall two-way ANOVAs and post-hoc comparisonS"

Overall comparison Baseline vs. deprived Baseline vs. recovery REM sleep A) F = 0.43 p = 0.51 P: Bsl > Depr (1-4) P: Bsl < Rec (1-2) B) F= 140.4 p < 0.00001 B: Bsl > Depr (1-4) B: Bsl < Rec (l-2) C) F= 0.255 p = 0.95 REM sleep latency A) F= 5.83 p < 0.01 P: Bsl = Depr (1-4) P: Bsl > Rec (l-2) B) F= 3.56 p < 0.003 B: Bsl = Depr (1-4) B: Bsl > Rec (1-2) C) F= 1.80 p = 0.1 Placebo < biperiden Placebo = Biperiden REM sleep attempts Downloaded from https://academic.oup.com/sleep/article/15/3/252/2749274 by guest on 30 September 2021 A) F= 27.7 p < 0.00001 P: Bsl < Depr (1-4) P: Bsl = Rec (1-2) B) F= 25.2 p < 0.00001 B: Bsl < Depr (1-4) B: Bsl = Rec (1-2) C) F= 4.4 p < 0.00001 Placebo> biperiden Placebo = Biperiden Stage I A) F= 0.04 P = 0.815 P: Bsl < Depr (1-4) P: Bsl = Rec (1-2) B) F= 14.81 P < 0.00001 B: Bsl < Depr (1-4) B: Bsl = Rec (1-2) C) F= 0.50 p = 0.802 Stage II A) F= 9.29 p < 0.003 Placebo> biperiden Placebo> biperiden B) F= 1.83 p = 0.1 C) F= 0.57 p = 0.75 Delta sleep A) F = 1.96 p = 0.16 B) F= 1.6 p = 0.15 C) F = 1.53 p = 0.17 Total sleep time A) F= 13.03 p < 0.0001 P: Bsl > Depr (1,3,4) P: Bsl = Rec (1-2) B) F = 27.7 P < 0.00001 B: Bsl > Depr (2-4) B: Bsl = Rec (1-2) C) F = 2.5 p < 0.02 Placebo> biperiden Placebo = biperiden

a Two-way ANOV As: A = group effects (df = 1,14); B = night effects (df = 6,79); C = interactions (df = 6,79). Numbers between paren theses are p < 0.05 vs. baseline on Students' t test with Bonferroni corrections (comparisons of each night to baseline). P = placebo group; B = biperiden group; Depr = deprivation nights; Rec = recovery nights.

TABLE 2. Sleep variables during REM sleep deprivationa

Sleep variables Baseline First Second Third Fourth REM sleep Pia 111.4 (25.3) 27.9 (13.2) 29.1 (11.9) 40.4 (21.9) 36.3 (16.5) Bip 116.0 (18.7) 32.6 (13.5) 39.22 (15.8) 39.6 (6.3) 33.1 (6.8) REM lat. PIa 87.7(29.4) 84.5 (31.1) 59.8 (14.3) 85.8 (33.6) 63.8 (15.6) Bip 94.4 (34.6) 120.3 (45.4) 115.7 (38.6) 106.9 (81.1) 92.9 (62.4) REM sleep attempts PIa 4.1 (1.1) 15.2 (6.5) 18.5 (26.1) 15.5 (6.7) 17.6 (4.1) Bip 4.8 (0.8) 8.2 (4.7) 8.8 (2.7) 12.0 (3.4) 10.5 (3.7) Stage I PIa 14.6 (17.1) 35.2 (11.9) 34.7 (13.6) 35.2 (11.4) 42.7(24.9) Bip 17.9 (12.5) 4J.l (23.4) 41.1 (14.1) 33.5 (11.6) 38.0 (13.9) Stage II Pia 201.2 (39.1) 193.4 (46.9) 167.3 (53.6) 195.5 (39.7) 189.6 (15.3) Bip 205.1 (35.4) 170.0 (65.8) 147.6 (31.2) 146.5 (34.8) 154.8 (41.8) Delta sleep Pia 97.2 (26.9) 126.6 (59.7) 141.7 (74.1) 98.8 (42.9) 115.2 (23.1) Bip 115.5 (29.4) 94.5 (30.8) 102.5 (15.9) 100.7 (24.1) 107.8 (33.0) Total sleep PIa 424.2 (47.2) 39D.4 (29.7) 389.7 (46.1) 380.1 (49.9) 384.5 (22.0) Bip 455.1 (15.7) 348.4 (73.3) 329.8 (34.6) 319.8 (47.1) 333.4 (51.9)

a REM lat. = REM sleep latency (minutes); REM attempts = frequency of REM sleep episodes during REM sleep deprivation is equal to the number of awakenings from REM sleep. Pia = placebo; Hip = biperiden. Stages I, II and delta (III + IV) are in minutes. All values are means ± SD.

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BIPERIDEN AND REM SLEEP 255

TABLE 3. Sleep variables after REM sleep deprivation sleep time was observed in both groups with a decrease in REM sleep latency. Sleep variables Baseline First recovery Second recovery The 4-mg dose ofbiperiden was used in the present REM sleep study as it has been previously shown that 4 mg does PIa IlIA (25.3) 142.7 (IS.9) 145.6 (2504) not suppress REM sleep percentage (7). A normal REM Bip 116.0 (IS.7) 150.3 (27.3) 145.3 (2304) sleep percentage is necessary to evaluate the effects of REM lat. biperiden on REM sleep deprivation. The results of PIa S7.7 (2904) 61.S (19.7) 67.06 (17.7) this study showed that although 4 mg biperiden does Bip 9404 (34.6) 43.2 (30.9) 60.6 (lOA) not suppress REM sleep, it does suppress the increased No. REM number of REM attempts associated with REM sleep

PIa 4.1 (1.1) 9.0 (1.3) 5.3 (104) deprivation. Downloaded from https://academic.oup.com/sleep/article/15/3/252/2749274 by guest on 30 September 2021 Bip 4.S (O.S) 5.2 (1.0) 5.3 (0.9) With respect to REM latency, the effects ofbiperiden Stage I and REM sleep deprivation appear to be additive. Al PIa 14.6 (17.1) 7.3 (5.2) 12.2 (904) Bip 17.9 (12.5) 9.6 (6.3) 9.9 (6.S) though 4 mg biperiden alone increased REM sleep la Stage II tency (7) and REM sleep deprivation decreased REM PIa 201.2 (39.1) 176.5 (45.6) 190.3 (5604) sleep latency (placebo group in this study), the com Bip 205.1 (3504) 155.S (34.3) 163.9 (40.6) bination of REM sleep deprivation and biperiden pro Delta duced a REM sleep latency comparable to baseline. PIa 97.2 (26.9) 140.3 (24.7) 121.0 (43.9) These two findings (i.e. suppressing increased REM Bip 115.5 (2904) 133.2 (33.9) 137.6 (35.2) sleep attempts and maintaining a normal REM sleep Total sleep latency) suggest that biperiden at 4 mg is a REM sleep PIa 424.2 (47.2) 461.1 (17.1) 466.6 (7.2) suppressant, when it is administered together with REM Bip 455.1 (15.7) 44S.0 (32.2) 456.5 (1904) sleep deprivation. a REM sleep = minutes; REM lat. = REM sleep latency (minutes); No. REM = frequency of REM sleep episodes during the night; Stages The REM sleep suppressive effect of biperiden was I, II and delta (III, IV) are in minutes. PIa = placebo; Bip = biperiden. not seen in the recovery data. In the biperiden group that received placebo after REM sleep deprivation, the usual REM sleep rebound (in this study a reduced REM sleep latency and increased REM sleep time) was seen, and the rebound endured for both recovery nights. The Sleep stage I was increased during REM sleep de effect of biperiden during chronic administration and privation nights in both groups. During the recovery during withdrawal should be studied in order to rule nights, there were no differences (ANOYA-group ef out the possibility of a rebound phenomenon as a result fects: F = 0.04, df = 1,14, p = 0.81; night effects: F = of the anticholinergic withdrawal as has been described 14.8, df = 6,79, p < 0.00001; interactions: F = 0.5, previously with other antimuscarinic drugs (13). How df = 6,79, p = 0.80). Sleep stage II was reduced on ever, because biperiden is a selective M 1 antagonist a deprivation nights in both groups, with significant dif different result may be found. ferences between both groups. Also during the recovery There were some biperiden-associated changes in nights there was a reduction of this variable in com the sleep continuity and in the non REM sleep archi parison with baseline nights (ANOYA-group effects: tecture. Total sleep time was reduced in the biperiden F = 9.29, df= 1,14, p < 0.003; night effect: F = 1.83, group, which was related to an increase in the number df = 6,79, p = 0.1; interactions: F = 0.57, df = 6,79, of awakenings. It seems that the subjects in the biperi p = 0.75). Finally, delta sleep did not change signifi den group compared to the placebo group had more cantly during deprivation and recovery nights (ANO problems returning to sleep once they had been awak YA group effects: F = 1.96, df = 1,14, p = 0.16; night ened. Biperiden with repeated administration and in effects: F = 1.60, df = 6,79, p = 0.15; interactions: F the REM sleep deprivation situation may have an = 1.53, df = 6,79, p = 0.172). alerting effect. A study with repeated administration of biperiden in sleep could give some clues about the DISCUSSION effect of chronic administration ofbiperiden in human sleep. Stage 1 sleep increased during REM sleep de The 4-day administration ofbiperiden during REM privation, whereas on the recovery nights the opposite sleep deprivation produced a reduction in the fre effect was observed. With Stage 2 sleep a reduction quency of REM sleep attempts, a reduction in the total during the REM sleep deprivation and on the recovery sleep time and an inhibition of changes in the REM nights was observed in both groups. These sleep stage sleep latency typically associated with REM depriva changes are related to the manipulation of REM sleep tion. On the recovery nights a similar rebound in REM and the reorganization of sleep architecture.

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