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Effects of arginine vasotocin on REM sleep in narcoleptics and in symptomatic hypersomniacs
Electroencephalography and Clinical Neurophysiology, 1982, 5 3 : 3 2 5 - - 3 2 8
325
Elsevier/North-HoUand Scientific Publishers, Ltd. Clinical note EFFECTS OF ARGININE VASOTOCIN ON REM SLEEP IN NARCOLEPTICS AND IN SYMPTOMATIC HYPERSOMNIACS L. POPOVICIU, O.T. CORFARIU, M. TUDOSIE, A. FC)LDES and S. PAVEL
Department of Neurology, University of Medicine, Tirgu-Mure~ and Institute of Endocrinology, Bucharest (Rumania) (Accepted for publication: November 23, 1981)
The human pineal gland contains (Pavel et al. 1973a; Legros et al. 1976) and synthesizes (Pavel et al. 1973b) the nonapeptide hormone arginine vasotocin (AVT). The release of AVT into the cerebrospinal fluid of man, both in healthy subjects (Pavel et al. 1979) and in narcoleptics (Popoviciu et al. 1979), is REM sleep-dependent. AVT is extremely potent in inducing NREM sleep and in suppressing REM sleep in cats (Pavel et al. 1977; Pavel 1979). In man, however, AVT produces opposite effects, increasing the incidence and duration of REM sleep in healthy subjects (Pavel 1980). In order to elucidate further the opposite effects of AVT on REM sleep in cat and man, we investigated its effects in narcoleptics and symptomatic hypersomniacs.
a.m., in a special darkened sound-proof room that provided a comfortable sleep. Continuous polygraphic sleep recording, 180 min long (EEG, eye movements, mental EMG, ECG and pneumograms) were carried out in an adjoining room by means of a 16-channel ECEM polygraph. The sleep stages and periods (REM and NREM) were individualized and evaluated according to the criteria of Rechtschaffen and Kales (1968) and Popoviciu (1978, 1979). During the entire recording the patient was observed and monitored by means of a closed-circuit TV infra-red system. As a preliminary to the experiments, all the patients had been placed many times in the sleepingroom in order to eliminate 'the first night effect'.
Results
Material and Methods The subjects of this study were two narcoleptics (a male, aged 42 years, and a female, aged 35 years) and 5 symptomatic hypersomniacs (3 females and 2 m a l e s - 4 postencephalitic and one with a vascular Steele-Richardson-Olsewsky syndrome), aged 25--57 years. AVT (Organon, The Netherlands, No. TH 223 KM) was administered intranasally in a dose of 1.5 gg in 100 pl of saline solution (50 pl in each nostril). Controls (the same patients) received the same volume of saline .solution. Both AVT and the saline solution were administered twice to each patient, with the exception of a single patient suffering from a cerebro-vascular disease (but in the first narcoleptic it was given 3 times, Table I). The time interval between two successive doses of AVT was at least 24 h. In order to simplify the calculations all the patients were allowed to sleep in quiet darkness only for 3 h and then they were awakened. Thus, the total sleep time was the same in all the patients, i.e., exactly 3 h, and the percentages of REM and NREM sleep were calculated for this total sleep time. All the experiments were performed between 09.00 and 12.00
AVT administrated intranasally very rapidly induced sleep with REM sleep periods at sleep onset in all the 5 records of the two narcoleptics as compared with the records before AVT administration (REM onset only in 2 instances, while in the other 3 records both patients were asleep in NREM)(Table I). All the 5 patients with symptomatic hypersomnia were asleep in NREM during all the 9 records before AVT administration, but after it, in 3 records, in spite of the NREM hypersomnia, 3 patients were in REM sleep (Table I). In some instances the NREM symptomatic hypersomniacs fell asleep in NREM (mainly stages Ia and Ib); however, after a few minutes they manifested a REM sleep period. The instillation of AVT produced an important increase of REM sleep percentages especially in the narcoleptics (26.05-~ 52.92%), but also in all the records in patients with symptomatic hypersomnia (9.26-~ 34.98%) during the 180 rain of recording (Fig. 1), as well as a very significant shortening of the time to the first REM sleep period (t test for narcoleptics = 0.05 > P > 0.025 and for symptomatic hypersomniacs = 0.02 > P > 0.01).
0013-4649/0000--0000/$02.75 © 1982 Elsevier/North-Holland Scientific Publishers, Ltd.
a) b)
c)
a) b)
Recordings
NREM NREM REM NREM REM
Sleep onset
NREM NREM NREM NREM NREM NREM NREM NREM NREM
a) b) a) b) a) b)
a) a) b)
95.73 79.67 81.42
65 rain 4 0 sec 20 m i n 60 min
40 25 12 15
--
rain rain m i n 4 0 sec m i n 20 sec
73.64 79.54 64.79 76.48 75.16 91.55 100 92.05 87.60 96.97 91.60
10 m i n
min m i n 4 0 sec min min rain
SWS (%)
Percentages
4.27 20.33 18.58
8.45 0 7.95 12.40 3.03 8.40
26.36 20.46 35.03 23.52 24.84
R E M sleep (%)
NREM REM NREM
REM NREM REM NREM NREM NREM
REM REM REM REM REM
Sleep onset
53.0 64.15 77.78
20 sec 4 0 sec 19 m i n 4 0 sec 7 min 9 min
48.93 28.0 50.60 46.02 61.87 24.48 63.54 65.27 75.0 83.33 78.55
min rain rain min min min
min min m i n 3 0 sec min min
SWS (%)
47.0 35.85 22.22
75.52 36.46 34.73 25.0 16.67 21.45
51.0.7 72.0 49.40 53.98 38.13
R E M sleep (%)
Percentages
30 sec 20 sec
9 11 5 14 10 14
9 40 2 5 1
T i m e t o first R E M sleep p e r i o d *
After AVT administration
* F r o m t h e s t a r t o f r e c o r d i n g , i.e., f r o m w a k e f u l n e s s , w h e t h e r t h e o n s e t was in R E M or N R E M sleep.
1. O.P. 29 years 2. U.M. 39 years 3. V.C. 25 years 4. P.V. 57 years 5. P.S. 39 years
19 2 10 18 12
T i m e t o first R E M sleep p e r i o d *
Before AVT administration (controls)
Symptomatic hypersomniacs
2. G.E. 35 years
1. G.I. 4 2 years
Narcolep tics
Patients
Sleep onset, t i m e to first R E M sleep p e r i o d a n d sleep p e r c e n t a g e s in n a r c o l e p t i c s a n d in h y p e r s o m n i a c s .
TABLE I
w
© ©
C~ bO
ARGININE VASOTOCIN AND REM SLEEP Percentclges loo 90 8o '73 gS 60 50
•i• L NARCOLEPTICS
~a 30
Percentages loo 90 % 90 80 70 6504~ 60 5292 50 ~0 3 30 20 g l0 0 Before AVT A~ter AVT Afte" AV7 administ rotlon admlnlstrahon e,dministration
2
20 10 0
Before AVT adrnlnistrGtior~
327 ing neurones, it has been proposed (Pavel 1979) that the opposite effects of AVT on REM sleep, most probably, reflect different involvements of the serotonin-containing neurones in the organization of REM sleep in cats and man. Our researches indicate that there is an early increase in REM sleep after AVT administration; this fact, however, is not sufficient to exclude the possibility of a redistribution of the REM phases. Further assessments are needed to provide the necessary data to clarify this aspect.
HYPERSOMNIACS
SYMPTOMATIC
Summary
I
REM
[~
NREM
Fig. 1. The mean values of the amounts of REM and NREM sleep in narcoleptics and in symptomatic hypersomniacs before and after the intranasal administration of a saline solution of synthetic AVT, 1.5 pg.
It is interesting that in symptomatic NREM hypersomnia, AVT administration induced a dramatic decrease of the amount of NREM sleep and an important increase in the amount of REM sleep (from 8.45%, in the patient O.P., to 75.52%). In this respect, no important difference could be detected in REM induction and increase of REM sleep by AVT between the symptomatic hypersomniacs and the narcoleptic patients.
Discussion The present results demonstrate that, in contrast to cats (Pavel et al. 1977; Pavel 1979}, both in narcoleptics and symptomatic hypersomniacs, AVT induces and increases (during the first hours following the administration) REM sleep, further supporting the first results obtained in healthy human subjects (Pavel 1980). However, in contrast to healthy subjects, in whom A V T was unable to induce REM periods at sleep onset, in narcoleptics and sometimes in symptomatic hypersomniacs, AVT was highly potent in inducing REM periods at sleep onset, suggesting an increased sensitivity to AVT of the REM triggering centres in narcoleptics (and sometimes in NREM symptomatic hypersomniacs). In spite of their different aetiopathogeny, AVT induced almost the same effects in both, suggesting that AVT acts on certain REM mechanisms which, in both narcoleptics and symptomatic hypersomniacs, remain unaltered or only a little altered. Since both in cats (Pave11979) and man (Pavel 1980) A V T exerts its hypnogenic effects by acting selectively on the serotonin-contain-
Arginine vasotocin (AVT), in doses of 1.5pg, administered intranasally to two narcoleptics (a male aged 42 years and a female aged 35 years), as well as to 5 symptomatic hypersomniacs (3 females and 2 males), aged 25--57 years, induced very rapidly in most instances a sleep with REM periods at onset and markedly increased the amount of REM sleep during a fixed period of 180 rain of sleep recording. After AVT administration there was a significant shortening of the time of occurrence of the first REM sleep period both in narcoleptics (t test = 0.05 > P > 0.025) and in symptomatic hypersomniacs (t test = 0 . 0 2 > P > 0.01).
R~sumd Effets de l'arginine vasotocine sur le sommeil d mouvements oculaires rapides chez des narcoleptiques et chez des malades avec hypersomnie symptomatique L'arginine vasotocine (AVT) administr6e par voie nasale & la dose de 1,5 pg & 2 narcoleptiques (un h o m m e de 42 ans et une femme de 35 ans), ainsi qu'& 5 patients souffrant d'hypersomnie symptomatique (3 femmes et 2 hommes) ~g~s de 25 ~ 57 ans, a induit tr~s rapidement dans la plupart des cas un sommeil marqu6 d4s son d6but par des p6riodes de sommeil mouvements oculaires rapides (MOR), e t a augment~ de faqon nette le taux de sommeil MOR pendant une pdriode fixe de 180 min d'enregistrement du sommeil. Apr~s administration d ' A V T on a not4 un raccourcissement significatif du d61ai d'apparition de la premiere p6riode de sommeil MOR aussi bien chez les narcoleptiques (test t: 0,05 > P > 0,025) que chez les hypersomniaques {test t: 0,02 > P > 0,01). The authors wish to thank T. Contiu and M. Komjatszegi for their valuable assistance throughout the recordings and I. Kifor for assisting in the preparation of the final form of the manuscript.
328 References
Legros, J.J., Louis, F., Demoulin, A. and Franchimont, P. Immunoreactive neurophysin and vasotocin in human fetal pineal glands. J. Endocr., 1976, 69: 289--290. Pavel, S. Pineal arginine vasotocin: an extremely p o t e n t sleep inducing nonapeptide hormone. Evidence for the involvement of 5-hydroxytryptamine-containing neurons in its mechanism of action. In: L. Popoviciu, B. Asgian and G. Badiu (Eds.), Sleep, 1978. Karger, Basel, 1980: 381-383. Pavel, S. Pineal vasotocin and sleep: involvement of serotonin containing neurons. Brain Res. Bull., 1979, 4: 731--734. Pavei, S., Dumitriu, I., Kleps, I. and Dorcescu, M. A gonadotropin inhibiting principle in the pineal of human fetuses. Evidence for its identity with arginine vasotocin. Neuroendocrinology, 1973a, 13: 41--46. Pavel, S., Dorcescu, M., Petrescu-Holban, R. and Ghinea, E. Biosynthesis of a vasotocin-like peptide in cell cultures from pineal glands of human fetuses. Science, 1973b, 181 : 1252--1253.
L. POPOVICIU ET AL. Pavel, S., Psatta, D. and Goldstein, R. Slow-wavesleep induced in cats by extremely small amounts of synthetic and pineal vasotocin injected into the third ventricle of the brain. Brain Res. Bull., 1977, 2: 251--254. Pavel, S., Goldstein, R., Popoviciu, L., Corfariu, O., FSldes, A. and Farkas, E. Pineal vasotocin: REM sleep dependent release into the cerebrospinal fluid of man. Waking and Sleeping, 1979, 3: 347-352. Popoviciu, L. (Ed.) Manifestari Paroxistice Cerebrale Neepileptice. Editura Medicala, Bucarest, 1978. Popoviciu, L. Somnul normal §i patologic. In: C. Arseni (Ed.), Tratat de Neurologie, Vol. V. Editura Medicala, Bucarest, 1979: 163--302. Popoviciu, L., Corfariu, O., FSldes, A., Farkas, E., Goldstein, R. and Pavel, S. REM-sleep dependent release of vasotocin into the cerebrospinal fluid of narcoleptics. Waking and Sleeping, 1979, 3" 341-346. Rechtschaffen, A. and Kales, A. A Manual for Sleep Stages of Human Subjects. UCLA Brain Information Service/Brain Research Institute, Los Angeles, Calif., 1968.
325
Elsevier/North-HoUand Scientific Publishers, Ltd. Clinical note EFFECTS OF ARGININE VASOTOCIN ON REM SLEEP IN NARCOLEPTICS AND IN SYMPTOMATIC HYPERSOMNIACS L. POPOVICIU, O.T. CORFARIU, M. TUDOSIE, A. FC)LDES and S. PAVEL
Department of Neurology, University of Medicine, Tirgu-Mure~ and Institute of Endocrinology, Bucharest (Rumania) (Accepted for publication: November 23, 1981)
The human pineal gland contains (Pavel et al. 1973a; Legros et al. 1976) and synthesizes (Pavel et al. 1973b) the nonapeptide hormone arginine vasotocin (AVT). The release of AVT into the cerebrospinal fluid of man, both in healthy subjects (Pavel et al. 1979) and in narcoleptics (Popoviciu et al. 1979), is REM sleep-dependent. AVT is extremely potent in inducing NREM sleep and in suppressing REM sleep in cats (Pavel et al. 1977; Pavel 1979). In man, however, AVT produces opposite effects, increasing the incidence and duration of REM sleep in healthy subjects (Pavel 1980). In order to elucidate further the opposite effects of AVT on REM sleep in cat and man, we investigated its effects in narcoleptics and symptomatic hypersomniacs.
a.m., in a special darkened sound-proof room that provided a comfortable sleep. Continuous polygraphic sleep recording, 180 min long (EEG, eye movements, mental EMG, ECG and pneumograms) were carried out in an adjoining room by means of a 16-channel ECEM polygraph. The sleep stages and periods (REM and NREM) were individualized and evaluated according to the criteria of Rechtschaffen and Kales (1968) and Popoviciu (1978, 1979). During the entire recording the patient was observed and monitored by means of a closed-circuit TV infra-red system. As a preliminary to the experiments, all the patients had been placed many times in the sleepingroom in order to eliminate 'the first night effect'.
Results
Material and Methods The subjects of this study were two narcoleptics (a male, aged 42 years, and a female, aged 35 years) and 5 symptomatic hypersomniacs (3 females and 2 m a l e s - 4 postencephalitic and one with a vascular Steele-Richardson-Olsewsky syndrome), aged 25--57 years. AVT (Organon, The Netherlands, No. TH 223 KM) was administered intranasally in a dose of 1.5 gg in 100 pl of saline solution (50 pl in each nostril). Controls (the same patients) received the same volume of saline .solution. Both AVT and the saline solution were administered twice to each patient, with the exception of a single patient suffering from a cerebro-vascular disease (but in the first narcoleptic it was given 3 times, Table I). The time interval between two successive doses of AVT was at least 24 h. In order to simplify the calculations all the patients were allowed to sleep in quiet darkness only for 3 h and then they were awakened. Thus, the total sleep time was the same in all the patients, i.e., exactly 3 h, and the percentages of REM and NREM sleep were calculated for this total sleep time. All the experiments were performed between 09.00 and 12.00
AVT administrated intranasally very rapidly induced sleep with REM sleep periods at sleep onset in all the 5 records of the two narcoleptics as compared with the records before AVT administration (REM onset only in 2 instances, while in the other 3 records both patients were asleep in NREM)(Table I). All the 5 patients with symptomatic hypersomnia were asleep in NREM during all the 9 records before AVT administration, but after it, in 3 records, in spite of the NREM hypersomnia, 3 patients were in REM sleep (Table I). In some instances the NREM symptomatic hypersomniacs fell asleep in NREM (mainly stages Ia and Ib); however, after a few minutes they manifested a REM sleep period. The instillation of AVT produced an important increase of REM sleep percentages especially in the narcoleptics (26.05-~ 52.92%), but also in all the records in patients with symptomatic hypersomnia (9.26-~ 34.98%) during the 180 rain of recording (Fig. 1), as well as a very significant shortening of the time to the first REM sleep period (t test for narcoleptics = 0.05 > P > 0.025 and for symptomatic hypersomniacs = 0.02 > P > 0.01).
0013-4649/0000--0000/$02.75 © 1982 Elsevier/North-Holland Scientific Publishers, Ltd.
a) b)
c)
a) b)
Recordings
NREM NREM REM NREM REM
Sleep onset
NREM NREM NREM NREM NREM NREM NREM NREM NREM
a) b) a) b) a) b)
a) a) b)
95.73 79.67 81.42
65 rain 4 0 sec 20 m i n 60 min
40 25 12 15
--
rain rain m i n 4 0 sec m i n 20 sec
73.64 79.54 64.79 76.48 75.16 91.55 100 92.05 87.60 96.97 91.60
10 m i n
min m i n 4 0 sec min min rain
SWS (%)
Percentages
4.27 20.33 18.58
8.45 0 7.95 12.40 3.03 8.40
26.36 20.46 35.03 23.52 24.84
R E M sleep (%)
NREM REM NREM
REM NREM REM NREM NREM NREM
REM REM REM REM REM
Sleep onset
53.0 64.15 77.78
20 sec 4 0 sec 19 m i n 4 0 sec 7 min 9 min
48.93 28.0 50.60 46.02 61.87 24.48 63.54 65.27 75.0 83.33 78.55
min rain rain min min min
min min m i n 3 0 sec min min
SWS (%)
47.0 35.85 22.22
75.52 36.46 34.73 25.0 16.67 21.45
51.0.7 72.0 49.40 53.98 38.13
R E M sleep (%)
Percentages
30 sec 20 sec
9 11 5 14 10 14
9 40 2 5 1
T i m e t o first R E M sleep p e r i o d *
After AVT administration
* F r o m t h e s t a r t o f r e c o r d i n g , i.e., f r o m w a k e f u l n e s s , w h e t h e r t h e o n s e t was in R E M or N R E M sleep.
1. O.P. 29 years 2. U.M. 39 years 3. V.C. 25 years 4. P.V. 57 years 5. P.S. 39 years
19 2 10 18 12
T i m e t o first R E M sleep p e r i o d *
Before AVT administration (controls)
Symptomatic hypersomniacs
2. G.E. 35 years
1. G.I. 4 2 years
Narcolep tics
Patients
Sleep onset, t i m e to first R E M sleep p e r i o d a n d sleep p e r c e n t a g e s in n a r c o l e p t i c s a n d in h y p e r s o m n i a c s .
TABLE I
w
© ©
C~ bO
ARGININE VASOTOCIN AND REM SLEEP Percentclges loo 90 8o '73 gS 60 50
•i• L NARCOLEPTICS
~a 30
Percentages loo 90 % 90 80 70 6504~ 60 5292 50 ~0 3 30 20 g l0 0 Before AVT A~ter AVT Afte" AV7 administ rotlon admlnlstrahon e,dministration
2
20 10 0
Before AVT adrnlnistrGtior~
327 ing neurones, it has been proposed (Pavel 1979) that the opposite effects of AVT on REM sleep, most probably, reflect different involvements of the serotonin-containing neurones in the organization of REM sleep in cats and man. Our researches indicate that there is an early increase in REM sleep after AVT administration; this fact, however, is not sufficient to exclude the possibility of a redistribution of the REM phases. Further assessments are needed to provide the necessary data to clarify this aspect.
HYPERSOMNIACS
SYMPTOMATIC
Summary
I
REM
[~
NREM
Fig. 1. The mean values of the amounts of REM and NREM sleep in narcoleptics and in symptomatic hypersomniacs before and after the intranasal administration of a saline solution of synthetic AVT, 1.5 pg.
It is interesting that in symptomatic NREM hypersomnia, AVT administration induced a dramatic decrease of the amount of NREM sleep and an important increase in the amount of REM sleep (from 8.45%, in the patient O.P., to 75.52%). In this respect, no important difference could be detected in REM induction and increase of REM sleep by AVT between the symptomatic hypersomniacs and the narcoleptic patients.
Discussion The present results demonstrate that, in contrast to cats (Pavel et al. 1977; Pavel 1979}, both in narcoleptics and symptomatic hypersomniacs, AVT induces and increases (during the first hours following the administration) REM sleep, further supporting the first results obtained in healthy human subjects (Pavel 1980). However, in contrast to healthy subjects, in whom A V T was unable to induce REM periods at sleep onset, in narcoleptics and sometimes in symptomatic hypersomniacs, AVT was highly potent in inducing REM periods at sleep onset, suggesting an increased sensitivity to AVT of the REM triggering centres in narcoleptics (and sometimes in NREM symptomatic hypersomniacs). In spite of their different aetiopathogeny, AVT induced almost the same effects in both, suggesting that AVT acts on certain REM mechanisms which, in both narcoleptics and symptomatic hypersomniacs, remain unaltered or only a little altered. Since both in cats (Pave11979) and man (Pavel 1980) A V T exerts its hypnogenic effects by acting selectively on the serotonin-contain-
Arginine vasotocin (AVT), in doses of 1.5pg, administered intranasally to two narcoleptics (a male aged 42 years and a female aged 35 years), as well as to 5 symptomatic hypersomniacs (3 females and 2 males), aged 25--57 years, induced very rapidly in most instances a sleep with REM periods at onset and markedly increased the amount of REM sleep during a fixed period of 180 rain of sleep recording. After AVT administration there was a significant shortening of the time of occurrence of the first REM sleep period both in narcoleptics (t test = 0.05 > P > 0.025) and in symptomatic hypersomniacs (t test = 0 . 0 2 > P > 0.01).
R~sumd Effets de l'arginine vasotocine sur le sommeil d mouvements oculaires rapides chez des narcoleptiques et chez des malades avec hypersomnie symptomatique L'arginine vasotocine (AVT) administr6e par voie nasale & la dose de 1,5 pg & 2 narcoleptiques (un h o m m e de 42 ans et une femme de 35 ans), ainsi qu'& 5 patients souffrant d'hypersomnie symptomatique (3 femmes et 2 hommes) ~g~s de 25 ~ 57 ans, a induit tr~s rapidement dans la plupart des cas un sommeil marqu6 d4s son d6but par des p6riodes de sommeil mouvements oculaires rapides (MOR), e t a augment~ de faqon nette le taux de sommeil MOR pendant une pdriode fixe de 180 min d'enregistrement du sommeil. Apr~s administration d ' A V T on a not4 un raccourcissement significatif du d61ai d'apparition de la premiere p6riode de sommeil MOR aussi bien chez les narcoleptiques (test t: 0,05 > P > 0,025) que chez les hypersomniaques {test t: 0,02 > P > 0,01). The authors wish to thank T. Contiu and M. Komjatszegi for their valuable assistance throughout the recordings and I. Kifor for assisting in the preparation of the final form of the manuscript.
328 References
Legros, J.J., Louis, F., Demoulin, A. and Franchimont, P. Immunoreactive neurophysin and vasotocin in human fetal pineal glands. J. Endocr., 1976, 69: 289--290. Pavel, S. Pineal arginine vasotocin: an extremely p o t e n t sleep inducing nonapeptide hormone. Evidence for the involvement of 5-hydroxytryptamine-containing neurons in its mechanism of action. In: L. Popoviciu, B. Asgian and G. Badiu (Eds.), Sleep, 1978. Karger, Basel, 1980: 381-383. Pavel, S. Pineal vasotocin and sleep: involvement of serotonin containing neurons. Brain Res. Bull., 1979, 4: 731--734. Pavei, S., Dumitriu, I., Kleps, I. and Dorcescu, M. A gonadotropin inhibiting principle in the pineal of human fetuses. Evidence for its identity with arginine vasotocin. Neuroendocrinology, 1973a, 13: 41--46. Pavel, S., Dorcescu, M., Petrescu-Holban, R. and Ghinea, E. Biosynthesis of a vasotocin-like peptide in cell cultures from pineal glands of human fetuses. Science, 1973b, 181 : 1252--1253.
L. POPOVICIU ET AL. Pavel, S., Psatta, D. and Goldstein, R. Slow-wavesleep induced in cats by extremely small amounts of synthetic and pineal vasotocin injected into the third ventricle of the brain. Brain Res. Bull., 1977, 2: 251--254. Pavel, S., Goldstein, R., Popoviciu, L., Corfariu, O., FSldes, A. and Farkas, E. Pineal vasotocin: REM sleep dependent release into the cerebrospinal fluid of man. Waking and Sleeping, 1979, 3: 347-352. Popoviciu, L. (Ed.) Manifestari Paroxistice Cerebrale Neepileptice. Editura Medicala, Bucarest, 1978. Popoviciu, L. Somnul normal §i patologic. In: C. Arseni (Ed.), Tratat de Neurologie, Vol. V. Editura Medicala, Bucarest, 1979: 163--302. Popoviciu, L., Corfariu, O., FSldes, A., Farkas, E., Goldstein, R. and Pavel, S. REM-sleep dependent release of vasotocin into the cerebrospinal fluid of narcoleptics. Waking and Sleeping, 1979, 3" 341-346. Rechtschaffen, A. and Kales, A. A Manual for Sleep Stages of Human Subjects. UCLA Brain Information Service/Brain Research Institute, Los Angeles, Calif., 1968.