- Email: [email protected]
Human EEG slow-wave sleep increased by a serotonin antagonist
Electroencephalograph), and clinical Neurophysiology, 1982, 54:583 586
583
Elsevier Scientific Publishers Ireland, Ltd.
Clinical note HUMAN
EEG
SLOW-WAVE
SLEEP
INCREASED
BY A SEROTONIN
ANTAGONIST
IAN OSWALD, K I R S T I N E A D A M and RENI~ SPIEGEL
University Department of Psychiatry, Royal Edinburgh Hospital Morningside Park, Edinburgh EHIO 5HF (Scotland) and Pharmaceutical Dit'ision Clinical Research, Sandoz Ltd., Basle (Switzerland) (Accepted for publication: July 19, 1982)
Prolonged periods of EEG slow waves are a normal feature of h u m a n sleep and controversy has surrounded their functional significance and the mechanisms of their control. In the classification of the EEG appearances during sleep proposed by Rechtschaffen and Kales (1968), stages 3 and 4 sleep are defined by the presence of more than 20% or more than 50% of the record consisting of EEG waves at 2 Hz or slower and having an amplitude greater than 75 /~V. Together they are known as slow-wave sleep (SWS), and the presence of the EEG slow waves is correlated, at least in undrugged humans, with general bodily changes indicative of the most extreme rest. In SWS, central nervous system responsiveness is lowest (Williams et al. 1966) and whole body oxygen consumption minimal (Brebbia and Altshuler 1968; Haskell et al. 1981). Comparable states of SWS are seen in animals and the relationship to brain serotonin has been much discussed. It was first reported that the serotonin precursor, L-tryptophan, could affect h u m a n REM sleep (Oswald et al. 1966), but Jouvet (1969) suggested that 'slow-wave sleep requires the presence of serotonin' and that noradrenergic mechanisms might play a more predominant role in R E M sleep. Yet Ross et al. (1976) reported that depletion of brain serotonin following intraventricular 5,7-dihydroxytryptamine had no effect on the sleep of rats, and Mendelson et al. (1977), reviewing the evidence about brain amines and h u m a n sleep, concluded that 'serotonin concentrations are directly correlated with a m o u n t s of R E M sleep.' We here report that a serotonin antagonist selectively increased h u m a n SWS. The drug we have used is an experimental drug known as FU 29-245. F U 29-245 is a 4.4-disubstituted piperidine derivative which demonstrates, in animal experiments, effects typical for certain antidepressant and antiserotonin drugs. Behavioural tests reflect overall sedation after FU 29-245, decreased rectal temperature and locomotor activity; cataleptic effects of tetrabenazine are antagonized and noradrenaline as well as dopamine reuptake in vitro are slightly inhibited. Peripheral and central effects of 5-hydroxytryptophan (5-HTP, a biological precursor of serotonin) and of serotonin (5-HT) are blocked as shown in the following tests (Hill 1977): 5-HT induced paw oedema and uterus contractions in rats, 5-HT induced bronchospasm and death in guinea pigs (for peripheral actions); 5-HTP induced tremor and head-shaking in mice and rats; in addition, neurochemical studies were carried out in rats (see Discussion).
Methods Ten volunteers, 7 women and 3 men, who believed themselves to be poor sleepers and who had a mean age of 59 years (44-69) participated. None had received CNS drugs during the preceding 3 months and all agreed to forego alcohol and other drugs throughout the period of the study. Initially subjects took inert capsules nightly I h before bedtime for 7 nights, following which they took 200 mg of FU 29-245 on 6 consecutive nights and then placebo capsules again for 3 nights. They attended the sleep laboratory on a total of 11 nights, their first 2 laboratory nights being solely for adaptation, then 3 nights being for baseline purposes, 2 nights for 'early drug' data, 2 nights for 'late drug' data and 2 nights for withdrawal data. Thus nights 1 and 2 were for adaptation, nights 4, 5 and 7 were placebo baseline nights; nights 8 and 9 were laboratory recording nights on 200 mg; nights 12 and 13 were recording nights on 200 nag and nights 14 and 16 were placebo recording nights. On all nights the EEG (Cz-Pz), eye movements and submental muscle tone were recorded for 8 h 45 rain. Subjects slept in comfortable, air-conditioned bedrooms. The eventual records were coded and scored blind. Throughout the period of intake of capsules subjects completed daily visual analogue ratings of sleep quality and morning vigilance and a 25-item evening check list of symptoms. The sleep data were treated by averaging the 3 baseline nights, averaging the 2 early drug nights, averaging the 2 late drug nights, looking at the 2 withdrawal nights separately and also by averaging the 2 withdrawal nights. Two-way analysis of variance was performed and, where a significant F value was obtained, differences were examined by correlated t tests. Sleep onset latency, REM latency and intervening wakefulness in the first 3 h of sleep, not being normally distributed, were analyzed using Friedman's analysis of variance by ranks and if a significant X~ value was found then Wilcoxon matched pairs, signedranks tests were employed to find the source of the significant variation. Two-tailed levels of significance were adopted.
Results The principal findings are given in Table 1. The drug caused a large increase of SWS, both in stages 3 and 4. Combining
0013-4649/82/0000-0000/$02.75 ~ 1982 Elsevier Scientific Publishers Ireland, Ltd.
27.1 + 13.6 176.1 + 4 4 . 5 85.7 + 27.3 50.3 ± 34.5 88.8 --+21.2 86.9 (56.2-158.4) 427.9 + 50.7 57.3 (14.2 143.5) 3 5 . 3 " 37.3
7.0 + 1.4
10.3 ! 4.4
43.9 + 16.9 231.9+27.1 48.2 + 13.7 31.1 -+ 19.0
92.3 ± 29.0 83.2 (49.6-149.1) 4 4 7 . 4 + 48.7 40.3 (18.5-72.6)
35.8-34.0
4.9+2.4
20.2+: 10.5
T o t a l m i n stage 1 T o t a l rain stage 2 T o t a l rain stage 3 Total min stage 4 T o t a l rain s t a g e R E M sleep R E M sleep l a t e n c y (and range) T o t a l sleep t i m e Sleep o n s e t [atency (and range) Total wake after sleep onset Shifts i n t o s t a g e 3 in first 3 h o f sleep Shifts into s t a g e 1 in first 3 h of sleep
Early drug mean, nights 1 and 2
Baseline m e a n of 3 nights
Means
12.9 " 6.3
5.3 ~ 2.1
31.1 ÷ 22.9
96.2 -+ 24.3 70.2 ( 5 2 . 3 - 88.3) 442.4 :~ 47.7 50.3 (11.4 137.5)
31.3+20.9 202.4+49.5 63.2 + 23.5 49.4 ÷ 39.2
Late drug mean, nights 5 and 6
M e a s u r e s of sleep before, d u r i n g a n d a f t e r i n t a k e of F U 29-245. M e a n s + S . D .
TABLE I
11.5 ! 5.2
6 . 1 ! 1.6
18.5 + 11.1
4.7+2.4
44.8 ~ 37.8
17.5 35.3 26.2 24.2
33.2 ~ 27.4
+ + ÷ ÷
91.5-+24.4 56.0 ( 2 7 . 3 - 82.8) 419.8+57.9 54.6 (18.1 123.8)
34.4 228.2 39.6 26.0
Night 1
Withdrawal
92.4-+21.4 78.6 (54.3-120.1) 435.2 ~ 43.9 53.8 (14.8 121.1)
2 9 . 2 ± 17.1 189.3+42.3 74.4 + 22.7 49.8 + 35.8
Drug mean. 4 nights
20.9 ' 11.3
5.5 ~2.8
26.0 ~ 24.4
1 0 4 . 4 ± 17.5 77.7 (27.9-175.3) 476.4 ~ 37.5 21.1 (3.4 59.0)
51.7~26.2 248.7 ~ 37.0 36.4 + 18.2 35.1 ' 31.0
Night 3
19.6 ~ 9.4
5.1+2.1
35.5 " 2 8 . 4
9 8 . 0 ± 17.8 66.9 (39.7-112.8) 448.1 + 4 2 . 1 37.9 ( 1 5 . 4 - 75.9)
43.1 - 19.7 238.5+29.7 38.0 ~ 20.0 30.6±25.2
Withdrawal mean, 2 nights
©
SWS INCREASED BY SEROTONIN A N T A G O N I S T these two stages, analysis of variance was highly significant and comparison of the baseline mean with the early drug mean gave t - 7.163, d f - 9 , P < 0.001. There was still a significant effect when late drug nights were compared with the baseline mean ( P =0.012), but a degree of tolerance was already apparent. Comparison of the 2 early drug nights with the 2 late drug nights showed a significant decline of SWS (P - 0.04). Taking the mean of the 2 withdrawal nights, there was a strong suggestion of a rebound decrease below baseline in the amount of SWS ( P - 0 . 0 5 2 ) . Analysis of variance on the number of shifts into stage 3 in the first 3 h of accumulated sleep was significant and t tests showed that the increase in the number of shifts into stage 3 was significantly greater than baseline during the early drug period ( P - 0.004), though this effect had been lost by nights 5 and 6. The drug reduced the number of shifts into stage 1 (drowsiness) in the first 3 h of accumulated sleep, there being a significant effect both during the early drug ( P = 0.006) and during the later drug period ( P - 0.007). The duration of stage 1 sleep in the whole night was likewise significantly decreased throughout the period of drug intake ( P < 0.01 in both cases). There were no significant effects on sleep latency, the total duration of sleep or the amount of wakefulness after first sleep onset. There were no effects on REM sleep. There was no effect of the drug on self-ratings of the subjective quality of sleep nor on subjective morning vigilance. Likewise the 25-item check list failed to reveal any side effects.
Discussion The drug greatly increased SWS, but it did not have the effects of a conventional hypnotic in that there were no effects on, for example, the total duration of sleep. The indication of a rebound reduction of SWS after drug withdrawal is a novel finding. Regarding the reputed connection between serotonin and increased SWS, it is necessary to consider further the actions of the drug we have used. In unpublished animal research HVA (homovanillic acid), a metabolite of dopamine is strongly increased after FU 29-245 in rat striatum, the ED20o being about 3 m g / k g subcutaneously. This is an effect typical of neuroleptic drugs, presumably reflecting blockade of dopamine receptors in the CNS. In addition 5-HIAA (5-hydroxy-indoleacetic acid) in rat cortex is also increased significantly after FU 29-245. This effect has been found after 32 m g / k g of FU 29-245 and suggests blockade of serotonin receptors in the brain. Doses necessary for dopamine blockade are much lower than those needed for serotonin blockade; therefore the drug is not simply a selective serotonin blocker. However, it is very unlikely that the effects observed during sleep are related to dopamine blockade, because strong and fairly specific dopamine blockers such as pimozide and haloperidol do not increase human SWS (Sagal6s and Erril 1975; Spiegel 1979). Our findings confirm the initial report by Spiegel (1981) and provide a reasonable presumption that it was by serotonin antagonism in the human brain that the increase of sleep with
585 large EEG slow waves was brought about. Other drugs, such as benzodiazepines, will reduce SWS. In all such cases one is left uncertain whether the action of a drug is upon some final generating mechanism of the EEG slow waves, or whether there is some action upon the fundamental mechanisms that control sleep.
Summaff Serotonin has been held to play a necessary role in EEG slow-wave sleep. A central serotonin antagonist, known as FU 29-245, 200 mg, was taken nightly for 6 nights by 10 volunteers. mean age 59 years. Compared with baseline sleep the drug significantly increased the duration of slow-wave sleep, with a significant rebound decrease below baseline after withdrawal. The drug also caused fewer transitions into stage 1 and less time in stage 1 and less time in stage 2. There were significant tolerance effects by the fifth and sixth nights. No subjective effects were present.
R6sume Augmentation du sommeil gt ondes lentes chez I'hornme par un antagoniste de la skrotonine La s6rotonine a 6t+ consid+r6e comme devant jouer un r61e d6terminant darts le sommeil lent. Un antagoniste s6rotoninergique central, le FU 29-245, a 6t6 administr~, h une dose de 200 mg, lots de 6 nuits cons6cutives, a I0 volontaires d'un age moyen de 59 ans. Par rapport aux trac6s t6moins, la substance a provoque une augmentation significative de la duree du sommeil lent, suivie d'une baisse en rebond au-dessous des valeurs de contr61e aprbs arr~t du traitement. Le produit a egalement entrain6 une diminution des passages au stade 1 et de la dur6e des stades 1 et 2. Des effets de tol+rance significatifs sont survenus lors des cinquiemes et sixi6mes nuits. Aucun effet subjectif n'a 6te constat&
References Brebbia, D.R. and Altshuler, K.Z. Stage related patterns and nightly trends of energy exchange during sleep. In: N.S. Kline and E. Laska (Eds.), Computers and Electronic Devices is Psychiatry. Grune and Stratton, New York, 1968: 319-335. Haskell, E.H., Palca, J.W., Walker, J.M., Berger, R.J. and Heller, H.C. Metabolism and thermoregulation during stages of sleep in humans exposed to heat and cold. J. appl. Physiol., 1981, 51: 948-954. Hill, R.C. AW 29-245, Pharmacological Expos6, Internal report. Sandoz, Basle, 14 November, 1977. Jouvet, M. Biogenic amines and the stages of sleep. Science, 1969, 163: 32-41.
586 Mendelson, W.B., Gillin, J.C. and Wyatt, R.J. Human Sleep and its Disorders. Plenum Press, New York, 1977. Oswald, I., Ashcroft, G.W., Berger, R.J., Eccleston, D., Evans, J.I. and Thacore, V.R. Some experiments in the chemistry of normal sleep. Brit. J. Psychiat., 1966, 112: 391-399. Rechtschaffen, A. and Kales, A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. U.S. Government Printing Office, Washington, D.C., 1968. Ross. C.A., Trulson, M.E. and Jacobs, B.L. Depletion of brain serotonin following intraventricular 5,7-dihydroxytryptamine fails to disrupt sleep in the rat. Brain Res., 1976, 114: 517--523.
I. OSWALD ET AL. Sagal6s, T. and Erril, S. Effects of central dopaminergic blockade with pimozide upon the EEG stages of sleep in man. Psychopharmacologia (Berl.), 1975.41: 53-56. Spiegel, R. Effects of amphetamines on performance and on polygraphic sleep parameters in man. In: P. Passouant and I. Oswald (Eds.), Pharmacology of the States of Alertness. Pergamon Press, Oxford, 1979: 189-201. Spiegel, R. Increased slow-wave sleep in man after several serotonin antagonists. In: W.P. Koella (Ed.), Sleep 1980. Karger, Basel, 1981: 275-278. Williams, H.L., Morlock, H.C. and Morlock. J.V. Discriminative responses to auditory signals during sleep. Psychophysiology, 1966, 2: 208-215.
583
Elsevier Scientific Publishers Ireland, Ltd.
Clinical note HUMAN
EEG
SLOW-WAVE
SLEEP
INCREASED
BY A SEROTONIN
ANTAGONIST
IAN OSWALD, K I R S T I N E A D A M and RENI~ SPIEGEL
University Department of Psychiatry, Royal Edinburgh Hospital Morningside Park, Edinburgh EHIO 5HF (Scotland) and Pharmaceutical Dit'ision Clinical Research, Sandoz Ltd., Basle (Switzerland) (Accepted for publication: July 19, 1982)
Prolonged periods of EEG slow waves are a normal feature of h u m a n sleep and controversy has surrounded their functional significance and the mechanisms of their control. In the classification of the EEG appearances during sleep proposed by Rechtschaffen and Kales (1968), stages 3 and 4 sleep are defined by the presence of more than 20% or more than 50% of the record consisting of EEG waves at 2 Hz or slower and having an amplitude greater than 75 /~V. Together they are known as slow-wave sleep (SWS), and the presence of the EEG slow waves is correlated, at least in undrugged humans, with general bodily changes indicative of the most extreme rest. In SWS, central nervous system responsiveness is lowest (Williams et al. 1966) and whole body oxygen consumption minimal (Brebbia and Altshuler 1968; Haskell et al. 1981). Comparable states of SWS are seen in animals and the relationship to brain serotonin has been much discussed. It was first reported that the serotonin precursor, L-tryptophan, could affect h u m a n REM sleep (Oswald et al. 1966), but Jouvet (1969) suggested that 'slow-wave sleep requires the presence of serotonin' and that noradrenergic mechanisms might play a more predominant role in R E M sleep. Yet Ross et al. (1976) reported that depletion of brain serotonin following intraventricular 5,7-dihydroxytryptamine had no effect on the sleep of rats, and Mendelson et al. (1977), reviewing the evidence about brain amines and h u m a n sleep, concluded that 'serotonin concentrations are directly correlated with a m o u n t s of R E M sleep.' We here report that a serotonin antagonist selectively increased h u m a n SWS. The drug we have used is an experimental drug known as FU 29-245. F U 29-245 is a 4.4-disubstituted piperidine derivative which demonstrates, in animal experiments, effects typical for certain antidepressant and antiserotonin drugs. Behavioural tests reflect overall sedation after FU 29-245, decreased rectal temperature and locomotor activity; cataleptic effects of tetrabenazine are antagonized and noradrenaline as well as dopamine reuptake in vitro are slightly inhibited. Peripheral and central effects of 5-hydroxytryptophan (5-HTP, a biological precursor of serotonin) and of serotonin (5-HT) are blocked as shown in the following tests (Hill 1977): 5-HT induced paw oedema and uterus contractions in rats, 5-HT induced bronchospasm and death in guinea pigs (for peripheral actions); 5-HTP induced tremor and head-shaking in mice and rats; in addition, neurochemical studies were carried out in rats (see Discussion).
Methods Ten volunteers, 7 women and 3 men, who believed themselves to be poor sleepers and who had a mean age of 59 years (44-69) participated. None had received CNS drugs during the preceding 3 months and all agreed to forego alcohol and other drugs throughout the period of the study. Initially subjects took inert capsules nightly I h before bedtime for 7 nights, following which they took 200 mg of FU 29-245 on 6 consecutive nights and then placebo capsules again for 3 nights. They attended the sleep laboratory on a total of 11 nights, their first 2 laboratory nights being solely for adaptation, then 3 nights being for baseline purposes, 2 nights for 'early drug' data, 2 nights for 'late drug' data and 2 nights for withdrawal data. Thus nights 1 and 2 were for adaptation, nights 4, 5 and 7 were placebo baseline nights; nights 8 and 9 were laboratory recording nights on 200 mg; nights 12 and 13 were recording nights on 200 nag and nights 14 and 16 were placebo recording nights. On all nights the EEG (Cz-Pz), eye movements and submental muscle tone were recorded for 8 h 45 rain. Subjects slept in comfortable, air-conditioned bedrooms. The eventual records were coded and scored blind. Throughout the period of intake of capsules subjects completed daily visual analogue ratings of sleep quality and morning vigilance and a 25-item evening check list of symptoms. The sleep data were treated by averaging the 3 baseline nights, averaging the 2 early drug nights, averaging the 2 late drug nights, looking at the 2 withdrawal nights separately and also by averaging the 2 withdrawal nights. Two-way analysis of variance was performed and, where a significant F value was obtained, differences were examined by correlated t tests. Sleep onset latency, REM latency and intervening wakefulness in the first 3 h of sleep, not being normally distributed, were analyzed using Friedman's analysis of variance by ranks and if a significant X~ value was found then Wilcoxon matched pairs, signedranks tests were employed to find the source of the significant variation. Two-tailed levels of significance were adopted.
Results The principal findings are given in Table 1. The drug caused a large increase of SWS, both in stages 3 and 4. Combining
0013-4649/82/0000-0000/$02.75 ~ 1982 Elsevier Scientific Publishers Ireland, Ltd.
27.1 + 13.6 176.1 + 4 4 . 5 85.7 + 27.3 50.3 ± 34.5 88.8 --+21.2 86.9 (56.2-158.4) 427.9 + 50.7 57.3 (14.2 143.5) 3 5 . 3 " 37.3
7.0 + 1.4
10.3 ! 4.4
43.9 + 16.9 231.9+27.1 48.2 + 13.7 31.1 -+ 19.0
92.3 ± 29.0 83.2 (49.6-149.1) 4 4 7 . 4 + 48.7 40.3 (18.5-72.6)
35.8-34.0
4.9+2.4
20.2+: 10.5
T o t a l m i n stage 1 T o t a l rain stage 2 T o t a l rain stage 3 Total min stage 4 T o t a l rain s t a g e R E M sleep R E M sleep l a t e n c y (and range) T o t a l sleep t i m e Sleep o n s e t [atency (and range) Total wake after sleep onset Shifts i n t o s t a g e 3 in first 3 h o f sleep Shifts into s t a g e 1 in first 3 h of sleep
Early drug mean, nights 1 and 2
Baseline m e a n of 3 nights
Means
12.9 " 6.3
5.3 ~ 2.1
31.1 ÷ 22.9
96.2 -+ 24.3 70.2 ( 5 2 . 3 - 88.3) 442.4 :~ 47.7 50.3 (11.4 137.5)
31.3+20.9 202.4+49.5 63.2 + 23.5 49.4 ÷ 39.2
Late drug mean, nights 5 and 6
M e a s u r e s of sleep before, d u r i n g a n d a f t e r i n t a k e of F U 29-245. M e a n s + S . D .
TABLE I
11.5 ! 5.2
6 . 1 ! 1.6
18.5 + 11.1
4.7+2.4
44.8 ~ 37.8
17.5 35.3 26.2 24.2
33.2 ~ 27.4
+ + ÷ ÷
91.5-+24.4 56.0 ( 2 7 . 3 - 82.8) 419.8+57.9 54.6 (18.1 123.8)
34.4 228.2 39.6 26.0
Night 1
Withdrawal
92.4-+21.4 78.6 (54.3-120.1) 435.2 ~ 43.9 53.8 (14.8 121.1)
2 9 . 2 ± 17.1 189.3+42.3 74.4 + 22.7 49.8 + 35.8
Drug mean. 4 nights
20.9 ' 11.3
5.5 ~2.8
26.0 ~ 24.4
1 0 4 . 4 ± 17.5 77.7 (27.9-175.3) 476.4 ~ 37.5 21.1 (3.4 59.0)
51.7~26.2 248.7 ~ 37.0 36.4 + 18.2 35.1 ' 31.0
Night 3
19.6 ~ 9.4
5.1+2.1
35.5 " 2 8 . 4
9 8 . 0 ± 17.8 66.9 (39.7-112.8) 448.1 + 4 2 . 1 37.9 ( 1 5 . 4 - 75.9)
43.1 - 19.7 238.5+29.7 38.0 ~ 20.0 30.6±25.2
Withdrawal mean, 2 nights
©
SWS INCREASED BY SEROTONIN A N T A G O N I S T these two stages, analysis of variance was highly significant and comparison of the baseline mean with the early drug mean gave t - 7.163, d f - 9 , P < 0.001. There was still a significant effect when late drug nights were compared with the baseline mean ( P =0.012), but a degree of tolerance was already apparent. Comparison of the 2 early drug nights with the 2 late drug nights showed a significant decline of SWS (P - 0.04). Taking the mean of the 2 withdrawal nights, there was a strong suggestion of a rebound decrease below baseline in the amount of SWS ( P - 0 . 0 5 2 ) . Analysis of variance on the number of shifts into stage 3 in the first 3 h of accumulated sleep was significant and t tests showed that the increase in the number of shifts into stage 3 was significantly greater than baseline during the early drug period ( P - 0.004), though this effect had been lost by nights 5 and 6. The drug reduced the number of shifts into stage 1 (drowsiness) in the first 3 h of accumulated sleep, there being a significant effect both during the early drug ( P = 0.006) and during the later drug period ( P - 0.007). The duration of stage 1 sleep in the whole night was likewise significantly decreased throughout the period of drug intake ( P < 0.01 in both cases). There were no significant effects on sleep latency, the total duration of sleep or the amount of wakefulness after first sleep onset. There were no effects on REM sleep. There was no effect of the drug on self-ratings of the subjective quality of sleep nor on subjective morning vigilance. Likewise the 25-item check list failed to reveal any side effects.
Discussion The drug greatly increased SWS, but it did not have the effects of a conventional hypnotic in that there were no effects on, for example, the total duration of sleep. The indication of a rebound reduction of SWS after drug withdrawal is a novel finding. Regarding the reputed connection between serotonin and increased SWS, it is necessary to consider further the actions of the drug we have used. In unpublished animal research HVA (homovanillic acid), a metabolite of dopamine is strongly increased after FU 29-245 in rat striatum, the ED20o being about 3 m g / k g subcutaneously. This is an effect typical of neuroleptic drugs, presumably reflecting blockade of dopamine receptors in the CNS. In addition 5-HIAA (5-hydroxy-indoleacetic acid) in rat cortex is also increased significantly after FU 29-245. This effect has been found after 32 m g / k g of FU 29-245 and suggests blockade of serotonin receptors in the brain. Doses necessary for dopamine blockade are much lower than those needed for serotonin blockade; therefore the drug is not simply a selective serotonin blocker. However, it is very unlikely that the effects observed during sleep are related to dopamine blockade, because strong and fairly specific dopamine blockers such as pimozide and haloperidol do not increase human SWS (Sagal6s and Erril 1975; Spiegel 1979). Our findings confirm the initial report by Spiegel (1981) and provide a reasonable presumption that it was by serotonin antagonism in the human brain that the increase of sleep with
585 large EEG slow waves was brought about. Other drugs, such as benzodiazepines, will reduce SWS. In all such cases one is left uncertain whether the action of a drug is upon some final generating mechanism of the EEG slow waves, or whether there is some action upon the fundamental mechanisms that control sleep.
Summaff Serotonin has been held to play a necessary role in EEG slow-wave sleep. A central serotonin antagonist, known as FU 29-245, 200 mg, was taken nightly for 6 nights by 10 volunteers. mean age 59 years. Compared with baseline sleep the drug significantly increased the duration of slow-wave sleep, with a significant rebound decrease below baseline after withdrawal. The drug also caused fewer transitions into stage 1 and less time in stage 1 and less time in stage 2. There were significant tolerance effects by the fifth and sixth nights. No subjective effects were present.
R6sume Augmentation du sommeil gt ondes lentes chez I'hornme par un antagoniste de la skrotonine La s6rotonine a 6t+ consid+r6e comme devant jouer un r61e d6terminant darts le sommeil lent. Un antagoniste s6rotoninergique central, le FU 29-245, a 6t6 administr~, h une dose de 200 mg, lots de 6 nuits cons6cutives, a I0 volontaires d'un age moyen de 59 ans. Par rapport aux trac6s t6moins, la substance a provoque une augmentation significative de la duree du sommeil lent, suivie d'une baisse en rebond au-dessous des valeurs de contr61e aprbs arr~t du traitement. Le produit a egalement entrain6 une diminution des passages au stade 1 et de la dur6e des stades 1 et 2. Des effets de tol+rance significatifs sont survenus lors des cinquiemes et sixi6mes nuits. Aucun effet subjectif n'a 6te constat&
References Brebbia, D.R. and Altshuler, K.Z. Stage related patterns and nightly trends of energy exchange during sleep. In: N.S. Kline and E. Laska (Eds.), Computers and Electronic Devices is Psychiatry. Grune and Stratton, New York, 1968: 319-335. Haskell, E.H., Palca, J.W., Walker, J.M., Berger, R.J. and Heller, H.C. Metabolism and thermoregulation during stages of sleep in humans exposed to heat and cold. J. appl. Physiol., 1981, 51: 948-954. Hill, R.C. AW 29-245, Pharmacological Expos6, Internal report. Sandoz, Basle, 14 November, 1977. Jouvet, M. Biogenic amines and the stages of sleep. Science, 1969, 163: 32-41.
586 Mendelson, W.B., Gillin, J.C. and Wyatt, R.J. Human Sleep and its Disorders. Plenum Press, New York, 1977. Oswald, I., Ashcroft, G.W., Berger, R.J., Eccleston, D., Evans, J.I. and Thacore, V.R. Some experiments in the chemistry of normal sleep. Brit. J. Psychiat., 1966, 112: 391-399. Rechtschaffen, A. and Kales, A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. U.S. Government Printing Office, Washington, D.C., 1968. Ross. C.A., Trulson, M.E. and Jacobs, B.L. Depletion of brain serotonin following intraventricular 5,7-dihydroxytryptamine fails to disrupt sleep in the rat. Brain Res., 1976, 114: 517--523.
I. OSWALD ET AL. Sagal6s, T. and Erril, S. Effects of central dopaminergic blockade with pimozide upon the EEG stages of sleep in man. Psychopharmacologia (Berl.), 1975.41: 53-56. Spiegel, R. Effects of amphetamines on performance and on polygraphic sleep parameters in man. In: P. Passouant and I. Oswald (Eds.), Pharmacology of the States of Alertness. Pergamon Press, Oxford, 1979: 189-201. Spiegel, R. Increased slow-wave sleep in man after several serotonin antagonists. In: W.P. Koella (Ed.), Sleep 1980. Karger, Basel, 1981: 275-278. Williams, H.L., Morlock, H.C. and Morlock. J.V. Discriminative responses to auditory signals during sleep. Psychophysiology, 1966, 2: 208-215.