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Caffeine produces REM sleep rebound in rats
Brain Research, 201 (1980) 497-500 © Elsevmr/North-HoUand Biomedical Press
497
Caffeine produces REM sleep rebound in rats
MIODRAG RADULOVACKI, RICHARD WALOVITCH and GEORGE YANIK Department of Pharmacology, University of Illinois at the Medwal Center, Chicago, IlL 60680 (U.S.A.)
(Accepted July 17th, 1980) Key words: caffeine - - rapid eye movement sleep -- rapid eye movement sleep rebound
Caffeine is a central nervous system stimulant which produces sleep disturbances in humans in the form of reduced sleep time, increased time to fall asleep and increased number of awakenings during a night sleep1,6, a. It has been reported that regular coffee or caffeine caused rapid eye movement (REM) sleep to shift to the early part of the night and sleep stages 3 and 4 to the latter part 6. However, some studies in humans failed to detect an effect of caffeine on REM sleep 3 while others found REM sleep reducedL In order to examine the effect of caffeine on REM sleep in rats we have chosen a situation in which REM sleep 'pressure' is increased by a selective REM sleep deprivation method~ and as a result REM sleep appears in a greater amount. We administered caffeine to rats, deprived of REM sleep for 24 h, in a dose that effectively suppressed R E M sleep for the first 6 h and observed a significant rebound of REM sleep 12 h later. Adult male Sprague-Dawley rats (300-350 g) were implanted with cortical and dorsal neck muscle electrodes for polygraphic recording. One week after surgery animals were selectively deprwed of REM sleep for 24 h by the flower pot technique 5. To standardize the degree of REM sleep deprivation (RD) rats were placed on circular platforms whose surface area corresponded to their body weight4, 7. A surface area to animal weight ratio of 14 sq. cm/100 g was used. After 24 h of RD animals were divided into two groups. The animals in the first group received saline (i.p.) and served as a control RD group, while the animals in the second group received caffeine (anhydrous, 25 mg/kg, i.p.). A third group of animals that were not deprived of REM sleep served as a non-REM deprived control (baseline) and also received saline (i.p.). After saline and caffeine were administered, animals were polygraphically recorded for 36 continuous hours. All records were analyzed for wakefulness, slow-wave sleep (SWS) and R E M sleep. Evaluation of the polygraphic records was made using standard techniques where each epoch of record was determined to be either wakefulness, SWS or R E M sleep. The epochs were 60 sec long and the speed of the paper drive was 120 sec/page of paper. Statistics were performed on 6 h periods by the two-way analysis of variance
498 TABLE I The effects of admmistratton of caffetne (25 mg/kg, t.p ) on wakefulness, S W S and R E M sleep m rats deprived of R E M sleep for 24 h The results are means zE S.E. (ram). Statistics were performed by two way analysm of variance with comparison performed by Newman-Keuls Test. Condition of rat
Hours after RD
Wakefulness 0-6 6-12 12-18 18 24 24-30 30-36 0 36
Baseline
81 116 254 165 56 120 792
± 2_ i ± ± ± ±
10 6 19 11 7 9 31
± :~ ± ~ ± ± ±
10 5 19 11 8 8 25
SWS
0-6 6-12 12-18 18-24 24-30 30-36 0-36
238 211 82 159 262 205 1157
REM sleep
0-6 6-12 12-18 18-24 24-30 30-36 0-36
41 33 13 34 42 35 198
± 4 ± 2 i 3 £ 4 -~ 3 _R 2 ± 7
RD control
Caffeme (25 mg/kg)
Caffeine dtfference front RD control (min)
139 ± 111 £ 165 ± 117 ~ 103 i 114~ 749 ±
298 ± 12" 167 ± 18" 138 ± 13"** 107 ± 7*** 84 ± 8 109 ± 6 903 ± 45
+159"* f 56** 27 --10 --19 --5 154
152 ± 13"** 185 ± 10 153 ± 12"** 202 j- 7*** 222±4 209i4 1123 ± 36
53 % 10" 137 ± 13" 156±9"** 200 ± 6*** 233 ± 8 210±8 990 ± 42
99** --48** t3 --2 + I1 1 --134
69 ± 8*** 64 i 3*** 42 i 4*** 42&4"** 36±4 37 ~ 3 289 ± 11"**
10 ± 3* 56 ± 7*** 66 ± 6* 53 ± 3 " * * 43 £ 4 40£ 3 268 ± 15"**
--59** --8 +24** 11 r7 t3 --22
16"** 11 12"** 10"** 4*** 4 31
* P a t least < 001. ** Caffeine vs RD control. *** Caffeine or RD control vs baseline ( A N O V A ) with the N e w m a n Keuls test used to c o m p a r e the R D c o n t r o l and the caffeine treated groups to the n o n - R D control g r o u p (basehne). Table I shows the effects o f a d m i n i s t r a t i o n o f caffeine on wakefulness, SWS and R E M sleep in rats deprived o f R E M sleep for 24 h. It can be seen that the drug caused a significant increase in wakefulness and a s~gnificant decrease m SWS during the first 12 h following R D . There was no difference a m o n g the 3 animal groups m the total a m o u n t o f wakefulness or SWS during the period f r o m 0 to 36 h, a l t h o u g h a m m a l s in the caffeine g r o u p showed a tendency t o w a r d having less SWS. Table I also shows that R E M sleep deprivation m e t h o d selectively increased only R E M sleep. Thus, a significant elevation o f R E M sleep was found in rats m R D c o n t r o l g r o u p during the 0-24 h period representing R E M sleep rebound. R E M sleep r e b o u n d was suppressed for 12 h after administration o f caffeine to animals m the caffeine group and the suppression was followed by the subsequent appearance o f the reb o u n d o f R E M sleep during the 12-18 h period. Fig. 1 illustrates that a p p r o x i m a t e l y
499 70 60 50 ,
~ 4Om~ 30-
g
,-r 20I0016 t Caffeine
6-112
t2 I- 18
18-'24
24150:50236
T I M E( h r )
Fig. 1. Effect of administration of caffeine (25 mg/kg, l.p.) on REM sleep in rats deprived of REM sleep for 24 h. Solid line, caffeine; dashed hne, control (RD); dotted line, normal REM sleep (baseline). equal amounts of R E M sleep rebound occurred in animals of both R D control and caffeine groups, suggesting that administration of caffeine only shifted the appearance of R E M sleep rebound 12 h later. In contrast to caffeine's suppression of R E M sleep followed by R E M sleep rebound, presented here, administration of bromocriptine, a dopamine stimulant 2 and two a-adrenoreceptor blockers, phenoxybenzamine and phetolaminO0,11, reduced R E M sleep without subsequent appearance of R E M sleep rebound12,13. According to Stern and MorganO 4 absence of R E M sleep rebound upon withdrawal of a drug treatment which decreases R E M sleep could be interpreted as a fulfillment of a possible neurochemical function of R E M sleep. In agreement with that postulate, reported effects of bromocriptine and a-adrenoreceptor blockers on R E M sleep may be indicative of a role for these drugs in fulfillment of R E M sleep 'need'. However, present findings clearly show that no such role could be attributed to caffeine. In conclusion, we found that the administration of caffeine to R E M sleep deprived rats significantly increased wakefulness and decreased SWS during the initial 12 h following R E M sleep deprivation. Administration of caffeine also suppressed R E M sleep which was later followed by R E M sleep rebound. This finding is of interest because it indicates that caffeine only temporarily suppressed R E M sleep rebound by delaying its appearance for 12 h which corresponds to the duration of the drug's action on wakefulness and SWS. Supported by O N R Contract N O O O 14-79-C-0420. 1 Brezinova, V., Effect of caffeine on sleep: EEG study m late middle age people, Brit. J. clin. Pharmacol., 1 (1974) 203-208. 2 Clark, B. J., Fltickiger, E and Loew, D. M., How does bromocriptine work?, Triangle (En.), 17 (1978) 21-32. 3 Gresham, S. C., Webb, W. B. and Williams, R. L., Alcohol and caffeine: effect on inferred visual dreaming, Science, 140 (1963) 1226-1227.
500 4 Hicks, R. A., Okuda, A and Thomsen, D., Depriving rats of REM sleep : the identification of a methodological problem, ,4mer. J. Psychol., 90 (1977) 95-102. 5 Jouvet, D., Vlmont, O., Delorme, F and Jouvet, M , Etude de la privation de phase paradoxale du sommed chez le chat, C. R Soc. Biol (Patio), 158 (1964) 756-759. 6 Karacan, l., Thornby, J 1, Anch, M. A., Booth, G. H., Williams, R. L. and Sahs, P. J , Dose-related sleep disturbances reduced by coffee and caffeine, Chn. Pharmacol. Ther, 20 (1976) 682-689. 7 Morden, B., Mitchell, G and Dement, W. C., Selective REM-sleep deprivation and compensation phenomena m rat, Brain Research, 5 (1967) 339-349. 8 Mtiller-Llmmroth, W., Der Emfluss von coffeinhaltigen und coffeinfrelen Kaffee auf den Schlaf des Menschen, Z. Ernahrungsw., 14, Suppl. (1972) 4 6 5 3 9 Nicholson, A. N. and Stove, B. M., Heterocyclic amphetamine derivatives and caffeine on sleep in man, Brit. J. clin. Pharmacol , 9 (1980) 195-203 10 Nickerson, M. and C61her, B , Drugs inhibiting adrenerglc nerves and structures innervated by them. In L S Goodman and A Gdlman (Eds.), The Pharmacological Basis of Therapeutics, Macmillan, New York, 1975, pp. 533-540. 11 Nlckerson, M and C61her, B , Drugs inhibiting adrenerglc nerves and structures innervated by them. In L. S. Goodman and A. Gillman (Eds.), The Pharmacological Basts of Therapeutics, Macmlllan, New York, 1975, pp. 541-543. 12 Radulovacki, M., Wojcik, J. W. and Fornal, C , Effects of bromocnptme and tt-flupenthlxol on sleep m REM sleep deprived rats, Ltfe Sci., 24 (1979) 1705-1712. 13 Radulovackl, M., Wojok, J. W., Fornal, C. and Mdetlch, R , Elimination of REM sleep rebound in rats by a-adrenoreceptor blockers, phentolamme and phenoxybenzamme, Pharmacol Btochem. Behav, 13 (1980) 51-55. 14 Stern, W C. and Morgane, P. J , Theoretical view of REM sleep function, maintenance of catecholamine systems an the central nervous system, Behav B:ol., 11 (1974) 1 32
497
Caffeine produces REM sleep rebound in rats
MIODRAG RADULOVACKI, RICHARD WALOVITCH and GEORGE YANIK Department of Pharmacology, University of Illinois at the Medwal Center, Chicago, IlL 60680 (U.S.A.)
(Accepted July 17th, 1980) Key words: caffeine - - rapid eye movement sleep -- rapid eye movement sleep rebound
Caffeine is a central nervous system stimulant which produces sleep disturbances in humans in the form of reduced sleep time, increased time to fall asleep and increased number of awakenings during a night sleep1,6, a. It has been reported that regular coffee or caffeine caused rapid eye movement (REM) sleep to shift to the early part of the night and sleep stages 3 and 4 to the latter part 6. However, some studies in humans failed to detect an effect of caffeine on REM sleep 3 while others found REM sleep reducedL In order to examine the effect of caffeine on REM sleep in rats we have chosen a situation in which REM sleep 'pressure' is increased by a selective REM sleep deprivation method~ and as a result REM sleep appears in a greater amount. We administered caffeine to rats, deprived of REM sleep for 24 h, in a dose that effectively suppressed R E M sleep for the first 6 h and observed a significant rebound of REM sleep 12 h later. Adult male Sprague-Dawley rats (300-350 g) were implanted with cortical and dorsal neck muscle electrodes for polygraphic recording. One week after surgery animals were selectively deprwed of REM sleep for 24 h by the flower pot technique 5. To standardize the degree of REM sleep deprivation (RD) rats were placed on circular platforms whose surface area corresponded to their body weight4, 7. A surface area to animal weight ratio of 14 sq. cm/100 g was used. After 24 h of RD animals were divided into two groups. The animals in the first group received saline (i.p.) and served as a control RD group, while the animals in the second group received caffeine (anhydrous, 25 mg/kg, i.p.). A third group of animals that were not deprived of REM sleep served as a non-REM deprived control (baseline) and also received saline (i.p.). After saline and caffeine were administered, animals were polygraphically recorded for 36 continuous hours. All records were analyzed for wakefulness, slow-wave sleep (SWS) and R E M sleep. Evaluation of the polygraphic records was made using standard techniques where each epoch of record was determined to be either wakefulness, SWS or R E M sleep. The epochs were 60 sec long and the speed of the paper drive was 120 sec/page of paper. Statistics were performed on 6 h periods by the two-way analysis of variance
498 TABLE I The effects of admmistratton of caffetne (25 mg/kg, t.p ) on wakefulness, S W S and R E M sleep m rats deprived of R E M sleep for 24 h The results are means zE S.E. (ram). Statistics were performed by two way analysm of variance with comparison performed by Newman-Keuls Test. Condition of rat
Hours after RD
Wakefulness 0-6 6-12 12-18 18 24 24-30 30-36 0 36
Baseline
81 116 254 165 56 120 792
± 2_ i ± ± ± ±
10 6 19 11 7 9 31
± :~ ± ~ ± ± ±
10 5 19 11 8 8 25
SWS
0-6 6-12 12-18 18-24 24-30 30-36 0-36
238 211 82 159 262 205 1157
REM sleep
0-6 6-12 12-18 18-24 24-30 30-36 0-36
41 33 13 34 42 35 198
± 4 ± 2 i 3 £ 4 -~ 3 _R 2 ± 7
RD control
Caffeme (25 mg/kg)
Caffeine dtfference front RD control (min)
139 ± 111 £ 165 ± 117 ~ 103 i 114~ 749 ±
298 ± 12" 167 ± 18" 138 ± 13"** 107 ± 7*** 84 ± 8 109 ± 6 903 ± 45
+159"* f 56** 27 --10 --19 --5 154
152 ± 13"** 185 ± 10 153 ± 12"** 202 j- 7*** 222±4 209i4 1123 ± 36
53 % 10" 137 ± 13" 156±9"** 200 ± 6*** 233 ± 8 210±8 990 ± 42
99** --48** t3 --2 + I1 1 --134
69 ± 8*** 64 i 3*** 42 i 4*** 42&4"** 36±4 37 ~ 3 289 ± 11"**
10 ± 3* 56 ± 7*** 66 ± 6* 53 ± 3 " * * 43 £ 4 40£ 3 268 ± 15"**
--59** --8 +24** 11 r7 t3 --22
16"** 11 12"** 10"** 4*** 4 31
* P a t least < 001. ** Caffeine vs RD control. *** Caffeine or RD control vs baseline ( A N O V A ) with the N e w m a n Keuls test used to c o m p a r e the R D c o n t r o l and the caffeine treated groups to the n o n - R D control g r o u p (basehne). Table I shows the effects o f a d m i n i s t r a t i o n o f caffeine on wakefulness, SWS and R E M sleep in rats deprived o f R E M sleep for 24 h. It can be seen that the drug caused a significant increase in wakefulness and a s~gnificant decrease m SWS during the first 12 h following R D . There was no difference a m o n g the 3 animal groups m the total a m o u n t o f wakefulness or SWS during the period f r o m 0 to 36 h, a l t h o u g h a m m a l s in the caffeine g r o u p showed a tendency t o w a r d having less SWS. Table I also shows that R E M sleep deprivation m e t h o d selectively increased only R E M sleep. Thus, a significant elevation o f R E M sleep was found in rats m R D c o n t r o l g r o u p during the 0-24 h period representing R E M sleep rebound. R E M sleep r e b o u n d was suppressed for 12 h after administration o f caffeine to animals m the caffeine group and the suppression was followed by the subsequent appearance o f the reb o u n d o f R E M sleep during the 12-18 h period. Fig. 1 illustrates that a p p r o x i m a t e l y
499 70 60 50 ,
~ 4Om~ 30-
g
,-r 20I0016 t Caffeine
6-112
t2 I- 18
18-'24
24150:50236
T I M E( h r )
Fig. 1. Effect of administration of caffeine (25 mg/kg, l.p.) on REM sleep in rats deprived of REM sleep for 24 h. Solid line, caffeine; dashed hne, control (RD); dotted line, normal REM sleep (baseline). equal amounts of R E M sleep rebound occurred in animals of both R D control and caffeine groups, suggesting that administration of caffeine only shifted the appearance of R E M sleep rebound 12 h later. In contrast to caffeine's suppression of R E M sleep followed by R E M sleep rebound, presented here, administration of bromocriptine, a dopamine stimulant 2 and two a-adrenoreceptor blockers, phenoxybenzamine and phetolaminO0,11, reduced R E M sleep without subsequent appearance of R E M sleep rebound12,13. According to Stern and MorganO 4 absence of R E M sleep rebound upon withdrawal of a drug treatment which decreases R E M sleep could be interpreted as a fulfillment of a possible neurochemical function of R E M sleep. In agreement with that postulate, reported effects of bromocriptine and a-adrenoreceptor blockers on R E M sleep may be indicative of a role for these drugs in fulfillment of R E M sleep 'need'. However, present findings clearly show that no such role could be attributed to caffeine. In conclusion, we found that the administration of caffeine to R E M sleep deprived rats significantly increased wakefulness and decreased SWS during the initial 12 h following R E M sleep deprivation. Administration of caffeine also suppressed R E M sleep which was later followed by R E M sleep rebound. This finding is of interest because it indicates that caffeine only temporarily suppressed R E M sleep rebound by delaying its appearance for 12 h which corresponds to the duration of the drug's action on wakefulness and SWS. Supported by O N R Contract N O O O 14-79-C-0420. 1 Brezinova, V., Effect of caffeine on sleep: EEG study m late middle age people, Brit. J. clin. Pharmacol., 1 (1974) 203-208. 2 Clark, B. J., Fltickiger, E and Loew, D. M., How does bromocriptine work?, Triangle (En.), 17 (1978) 21-32. 3 Gresham, S. C., Webb, W. B. and Williams, R. L., Alcohol and caffeine: effect on inferred visual dreaming, Science, 140 (1963) 1226-1227.
500 4 Hicks, R. A., Okuda, A and Thomsen, D., Depriving rats of REM sleep : the identification of a methodological problem, ,4mer. J. Psychol., 90 (1977) 95-102. 5 Jouvet, D., Vlmont, O., Delorme, F and Jouvet, M , Etude de la privation de phase paradoxale du sommed chez le chat, C. R Soc. Biol (Patio), 158 (1964) 756-759. 6 Karacan, l., Thornby, J 1, Anch, M. A., Booth, G. H., Williams, R. L. and Sahs, P. J , Dose-related sleep disturbances reduced by coffee and caffeine, Chn. Pharmacol. Ther, 20 (1976) 682-689. 7 Morden, B., Mitchell, G and Dement, W. C., Selective REM-sleep deprivation and compensation phenomena m rat, Brain Research, 5 (1967) 339-349. 8 Mtiller-Llmmroth, W., Der Emfluss von coffeinhaltigen und coffeinfrelen Kaffee auf den Schlaf des Menschen, Z. Ernahrungsw., 14, Suppl. (1972) 4 6 5 3 9 Nicholson, A. N. and Stove, B. M., Heterocyclic amphetamine derivatives and caffeine on sleep in man, Brit. J. clin. Pharmacol , 9 (1980) 195-203 10 Nickerson, M. and C61her, B , Drugs inhibiting adrenerglc nerves and structures innervated by them. In L S Goodman and A Gdlman (Eds.), The Pharmacological Basis of Therapeutics, Macmillan, New York, 1975, pp. 533-540. 11 Nlckerson, M and C61her, B , Drugs inhibiting adrenerglc nerves and structures innervated by them. In L. S. Goodman and A. Gillman (Eds.), The Pharmacological Basts of Therapeutics, Macmlllan, New York, 1975, pp. 541-543. 12 Radulovacki, M., Wojcik, J. W. and Fornal, C , Effects of bromocnptme and tt-flupenthlxol on sleep m REM sleep deprived rats, Ltfe Sci., 24 (1979) 1705-1712. 13 Radulovackl, M., Wojok, J. W., Fornal, C. and Mdetlch, R , Elimination of REM sleep rebound in rats by a-adrenoreceptor blockers, phentolamme and phenoxybenzamme, Pharmacol Btochem. Behav, 13 (1980) 51-55. 14 Stern, W C. and Morgane, P. J , Theoretical view of REM sleep function, maintenance of catecholamine systems an the central nervous system, Behav B:ol., 11 (1974) 1 32