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Biphasic effects of pimozide on sleep-wakefulness in dogs
Life Sclences, Vol. 27, pp. i~69-1475 Printed in the U.S.A.
BIPHASIC EFFECTS A
Wauquler,
Pergamon Press
O F P I M O Z I D E ON S L E E P - W A K E F U L N E S S W A E
Van den Broeck and P A J
IN DOGS
Janssen
D e p a r t m e n t of P h a r m a c o l o g y Janssen Pharmaceutica B-2340 Beerse, Belgium ( R e c e i v e d in final form August 8, 1980) Summa r y S l e e p - w a k e f u l n e s s p a t t e r n s in d o g s w e r e s t u d i e d u s i n g c o m p u t e r i z e d on-hne power spectral analysis and off-hne automatic stage-classification, during control recordings and after oral treatment with three doses of the specific dopamine blocker pimozide A blphasic e f f e c t on s l e e p - w a k e f u l n e s s p a t t e r n s w a s f o u n d A t 0 016 m g / k g (the E D s 0 - v a l u e f o r t h e a n t a g o m s m o f a p o m o r p h l n e - i n d u c e d vomiting in d o g s ) , p i m o z i d e m g m f i c a n t l y i n c r e a s e d t h e t i m e s p e n t a w a k e , a n d slgmficantly decreased slow wave sleep and REM sleep No s l g m ficant effects were obtained with a four times higher dose of plmozlde A t 0. 16 m g / k g , p i m o z i d e s i g m f i c a n t l y d e c r e a s e d t h e t i m e spent awake and sigmficantly increased slow wave sleep and REM sleep T h e e f f e c t s a p p e a r t h e o p p o s i t e of t h o s e d e s c r i b e d f o r a p o m o r p h i n e a n d s u g g e s t t h a t d o p a m i n e p l a y s a r o l e in t h e p h y s i o l o g y of sleep-wakefulness regulation
A l t h o u g h a h m l t e d n u m b e r of s t u d i e s s u g g e s t e d t h a t b r a i n c a t e c h o l a m i n e s p l a y a r o l e i n s l e e p - w a k e f u l n e s s r e g u l a t i o n (1, Z), i t w a s n o t c l e a r w h e t h e r d o p a m i n e (IDA) w a s s l g m f i c a n t l y i n v o l v e d in t h e m e c h a m s m s of s l e e p Recent e x p e r i m e n t s w i t h t h e DA a g o m s t a p o m o r p h i n e s u g g e s t t h a t i n t e r f e r e n c e w i t h DA r e c e p t o r s d o e s a f f e c t t h e s l e e p - w a k e f u l n e s s r e g u l a t i o n (3, 4) D e p e n d i n g on t h e d o s e o f a p o m o r p h i n e , o p p o s i n g e f f e c t s w e r e f o u n d At l o w ( n o n - e m e t i c ) d o s e s a p o m o r p h l n e i n d u c e s i n h i b i t i o n o f b e h a v l o u r (5), i n d u c e s s l e e p l n r a t s (3) a n d s e d a t i o n a n d s l e e p i n h u m a n (6, 7), a t h i g h d o s e s a p o m o r p h l n e c a u s e s h y p e r m o t d l t y (8), s t e r e o t y p y (9) a n d f o l l o w i n g i n f u s i o n in h u m a n s u p p r e s s e s R E M s l e e p a n d r e d u c e s s l o w w a v e s l e e p (4) I n d e p e n d e n t o f t h e q u e s t x o n on t h e p o s i t i o n o f t h e r e c e p t o r s x n v o l v e d , t h e s e e x p e r i m e n t s s u g g e s t t h a t s t i m u l a t i o n o f DA r e c e p t o r s i n d u c e s s l e e p , b u t o v e r s t l m u l a t i o n p r e v e n t s t h e p r o g r e s s i o n i n t o d e e p s l e e p a n d R E M s l e e p (4) B o t h e f f e c t s o f a p o m o r p h i n e in h u m a n a r e a n t a g o m z e d b y IDA b l o c k e r s (3, 7) A slmdar antagomsm of the amphetamine-induced reduction of total sleep and REM sleep has been described (2) With pimozlde, the m o s t speclflc IDA blocker (I0), no effects w e r e found on n o r m a l volunteers (II), w h e r e a s it sigmficantly i m p r o v e d the disturbed sleep patterns in psychiatrlc patients (12) In the hght of the above, one would 0024-3205/80/421469-07502.00/0 Copyright (c) 1980 Pergamon Press Ltd
1470
Effects of Pimozlde on Sleep-Wakefulness
Vol. 27, No. 16, 1980
e x p e c t t h a t p i m o z l d e w o u l d c a u s e t h e o p p o s i t e e f f e c t s to a p o m o r p h i n e . No p r e v i o u s s t u d y h a s r e p o r t e d on t h e e f f e c t s o f d i f f e r e n t d o s e s of p i m o z l d e on t h e sleep-wakefulness patterns lnanlmals, we therefore tested three doses of p l m o z l d e in dogs
Materlals a n d M e t h o d s Subjects The subjects w e r e 7 adult m a l e beagles weighing 13 0 to 18 5 kg a n d approximately 2 years old at the time of surgery.
Surgery The dogs were stereotaxlcally implanted with cortical electrodes (stainl e s s s t e e l s c r e w s in the f r o n t a l , t e m p o r a l and o c c i p i t a l s i d e s of the skull) and subcort, cal electrodes (stainless steel needles of 0 5 mm chameter, insulated e x c e p t f o r 0 . 5 m m o f t h e t i p , in w h i c h a s t a i n l e s s s t e e l w i r e o f 0. Z m m w a s , n s e r t e d and which p r o t u d e d 1 r a m , b e n e a t h the t,p of the n e e d l e ) as p r e v i o u s l y d e s c r , b e d (13) Depth e l e c t r o d e s w e r e i m p l a n t e d in the d o r s a l h i p p o c a m p u s , the l a t e r a l g e n i c u l a t e , the b a s o l a t e r a l a m y g d a l a and the r e t i c u l a r f o r m a t i o n . C i r c u l a r p l a t , h u m w i r e s w e r e p l a c e d o n e d o r s a l l y a n d o n e l a t e r a l l y to o n e e y e to r e c o r d e y e m o v e m e n t s Two c i r c u l a r s t a i n l e s s s t e e l w, r e s w e r e s u t u r e d ,n a n e c k m u s c l e to r e c o r d m u s c l e a c t i v i t y .
Recorchng The a n i m a l s w e r e p l a c e d in a r e l a t i v e l y s m a l l s h i e l d e d c a g e in a r o o m w h e r e t h e l a b o r a t o r y d l u m l n a t l o n w a s c o n t i n u o u s l y on. P a p e r r e c o r d i n g s w e r e m a d e f o r 3 h f r o m 3 p m on a n d o n - h n e c o m p u t e r a n a l y s i s w a s c a r r i e d o u t i n a s e p a r a t e r o o m f r o m 3 p m to 7 a m P a p e r recorchngs of varlous cortlcal and subcortlcal derlvatlons w e r e done on an E l e m a - S c h O n a n d e r m l n g o g r a p h The paper speed w a s 15 m m F i l t e r s a n d t i m e c o n s t a n t s w e r e f o r t h e E E G r e s p e c t i v e l y 30 H z a n d 0 . 3 s e c , f o r t h e E M G r e s p e c t i v e l y 700 Hz a n d 0 . 0 1 5 s e c .
Analys, s Analysis w a s done o n - h n e on 30 sec epochs of one cortlcal derlvatlon (frontal-occlpltal), the h l p p o c a m p a l derlvatlon, the EIV[G and the E O G by a P D P I I / E I0 m l n l c o m p u t e r P o w e r spectral analysls w a s done by m e a n s of a Fast Four,er Transformation, the s p e c t r u m being chvlded in the following f r e q u e n c y b a n d s ( f r e q u e n m e s b e t w e e n b r a c k e t s ) d e l t a (0 5 - 3 . 5 H z ) , t h e t a (3. 5 - 7. 5 Hz), alpha (7 5 - 13. 5 Hz) and beta (13 5 - Z5.0 Hz) for the frontalocclp, tal derlvatlon, the p o w e r in the thetaband w a s calculated for the hlppoc a m p a l derivatlon, a special algor, t h m detected the splndles, the E M G a n d E O G a m p h t u d e w e r e calculated T h e s e data served to autornatlcall7 class,fy off-hne each epoch of 30 sec Into 6 stages of the sleep-wakefulness cycle: w a k e f u l n e s s , m o v e m e n t , w a k e f u l n e s s , r e s t ; t r a n s l t l o n to s l e e p , h g h t s l o w w a v e sleep; deep slow wave sleep and REM sl~ep. The methodology has been de-
ta,led prev,ously
(i 4).
Vol. 27, No. 16, 1980
Effects of Pimozlde on Sleep-Wakefulness
1471
Drug treatment The dogs used ~n this study w e r e recorded overmght several times before any drug treatment and w e r e fully adapted to the s~tuatlon These recordings served to estabhsh the partition of the sleep-wakefulness patterns. O n e control recording preceding each dose of the drug served for comparison wlth the drug effects Each dog w a s orally treated at the start of the recording w~th water or with one of the follow~ng doses of plmoz~de 0 016 mg/kg, 0 063 rng/kg and 0 16 mg/kg, given 1n a volume of I rnl per 2 kg The doses w e r e g~ven randomly w~th a weekly ~nterval between doses. The lowest dose of pIrnozide ~s the ED50-value of ~ts ant~emetic effect agalnst apornorphxne induced vomiting (I0)
Results During the control sessions a normal partition of sleep-wakefulness patterns w a s seen The m e a n (_+ S E M ) percentage of 5 control recordings for the 7 dogs (n = 35) preceding drug treatment w e r e as follows' awake, m o v e m e n t 18.1 (I 6), awake, rest 9 79 (0.9), transltlon stage 14 8 (I.0), 11ght slow w a v e sleep 18.0 (0 7), deep slow w a v e sleep 24 0 (I 0) and R E M sleep. 15.4 (0.9) The control recordings preceding each dose of plmozlde for each Indivldual dog w e r e wlthln the hmlts of the recordings precedlng drug treatment Thus comparlson w a s m a d e between drug treatment and the respective control recording Figure 1 shows the percentage a w a k e ( m o v e m e n t and rest cornblned), sleep (the three stages of sleep comblned) and R E M sleep as c o m p a r e d to the control With the intermediate dose (0 063 rng/kg), no slgmflcant changes w e r e found At the lowest dose (0 016 mg/kg) of p1mozlde there w a s a slgmflcant Increase in wakefulness, a slgmflcant decrease of sleep a n d a decreased REM With the hlghest dose of pirnozlde (0.16 mg/kg) wakefulness slgmflcantly decreased, sleep and R E M sleep slgmflcantly increased T h e s l g m f i c a n t l y i n c r e a s e d w a k e f u l n e s s a f t e r t h e l o w e s t d o s e of p l r n o z l d e a n d t h e s l g n i f l c a n t l y d e c r e a s e d w a k e f u l n e s s a f t e r t h e h l g h e s t d o s e of p l r n o z l d e a r e d u e to a s l g n i f l c a n t e f f e c t on t h e n u m b e r of e p o c h s of m o v e m e n t ( r e s p e c t l r e l y 188 + 8 1 ~o a n d 65. 1 + 23 0 ~o), no s l g n i f l c a n t e f f e c t s on a w a k e - r e s t w e r e found T h e s l g n i f l c a n t l y d e c r e a s e d , c o n v e r s e l y i n c r e a s e d s l e e p l s due to a s l g n l f l c a n t e • e c t o n t h e d u r a t l o n o£ the e p o c h s d e e p s l o w w a v e s l e e p ( r e s p e c t l r e l y 71 4_+ 6 8 ~ a n d 131 _+ 1 3 . 6 ~ ) , no s l g n l f l c a n t e f f e c t s w e r e f o u n d o n the t r a n s 2 t l o n stage or llght slow wave sleep Though the d e c r e a s e d p e r c e n t a g e R E M f o l l o v ~ n g the l o w d o s e of p l m o z l d e w a s n o t s l g m f l c a n t , a s l g m f l c a n t e f f e c t o n t h e d u r a t l o n of t h e e p o c h s REIV[ ( 7 1 . 4 + 6 8 ~o) w a s o b t a l n e d . T a b l e I s h o w s t h e p e r c e n t a g e v e r s u s c o n t r o l of t h e d i f f e r e n t s t a g e s of s l e e p - w a k e f u l n e s s f o r t h e d i f f e r e n t d o s e s of p l r n o z l d e In b l o c k s of 4 h The s l o w o n s e t of a c t l v l t y i s e v l d e n t f r o m T a b l e I The m a l n s i g m f l c a n t c h a n g e s o c c u r r e d a f t e r 4 h , t h o u g h the d e c r e a s e d a m o u n t of d e e p s l e e p a f t e r t h e l o w e s t d o s e of p l m o z l d e a n d t h e i n c r e a s e d a m o u n t of d e e p s l e e p a f t e r t h e h i g h e s t d o s e of p i r n o z i d e w e r e a l r e a d y s l g m f l c a n t d u r l n g t h e f i r s t 4 h of t h e r e c o r d i n g F r o m T a b l e II i t i s s e e n t h a t the R E M l a t e n c y I s d e c r e a s e d w l t h 0 016 rng//kg, t h o u g h t h e e p o c h l e n g t h s l g m f l c a n t l y d e c r e a s e d The slgnlflcantly inc r e a s e d R E M o b s e r v e d a f t e r t h e h l g h e s t d o s e of p l m o z l d e i s p r o b a b l y d u e t o a s i g m ~ c a n t i n c r e a s e i n t h e n u m b e r of e p o c h s R E M . W i t h 0. 063 r n g / k g of p l r n o z i d e t h e d e c r e a s e i n the l a t e n c y of R E M w a s t h e o n l y s l g n l f l c a n t e H e c t o b t a l n e d .
1472
Effects of Pimozide on Sleep-Wakefulness
AWAKE
Vol. 27, No. 16, 1980
SLEEP
REM
T
180160UJ
o 140<[
120-
Z
LU 1000 n,, 80a_ 6040 mg/kg
0.063 0016 016
0.063 0.016 0.16
PIMOZIDE FIG
0.063 0016 016
OR
1
M e a n percentage (+ S E M . ) as c o m p a r e d to the respectlve controls of the tlme a w a k e ( m o v e m e n t and rest comblned), the tlme asleep (transltlon stage, hghr and deep slow w a v e sleep comblned) and R E M sleep, after three doses of plmozlde glven orally at the start (3 p m ) of the 16 h recorchng in dogs
l~scuss~on Paradoxlcal effects of dlfferent doses of plmozlde on sleep in dogs w e r e found at a low dose plmozlde increased wakefulness and decreased slow w a v e sleep and R E M sleep and at a hlgh dose of plmozlde wakefulness d e c r e a s e d and slow w a v e sleep and R E M sleep increased The flndlngs wlth the hlgh dose of plmozlde corroborate the results obtalned wlth prolongedadm,nlstratlon of plmozlde to psychlatrlc patlents (12), but m a r k e d l y contrast to the report that plmozlde dld not effect sleep in n o r m a l volunteers (ii) In the last study, it w a s suggested that IDA is of m l n o r i m p o r t a n c e in the physlology of sleep Thelr flndlngs are ,n contrast to the flnchngs wlth the D A agonlst a p o m o r p h l n e whlch at low doses induce sleep and at hlgh doses decrease sleep in rat and in m a n (3, 4, 7) A s s u m , n g that a p o m o r p h l n e exerts Its effects through an agonlstlc actlon at D A receptors, one w o u l d expect that a speclflc D A blocker such as plmozlde w o u l d cause the opposlte effects, as w a s indeed o b s e r v e d in the present study 1~ne questlon is not resolved, however, whether the effects of
t
Dose
p <
016
(23 3)
(38 2)
(25 3)
111
132
123
8-12
12 - 16
8
4-
12-
16
8-12
4
O-
8
4-
48 8 (10 6) I
99 5 (73 7)
(41 7)
(68 1)
(101)
(52 O)
(50 4)
111
110
107 (19 8)
(18 3)
(18 7)
95 7 (13 3)
225
167
1 46
(29 6)
I
(12 2)
(39 2)
(14 1)
(27 6) (22 8) (11 9)
129 120
(19 l) 144
112
99 9 (20 3)
100
125
112
98 4 (;'4 2)
168
115
1 34
177
1 58
110
105
178
(36 3)
(17 4)
(39 5)
(49 7) ~
(49 9)
(15 2)
(30 4)
(74 6)
94 1 (26 4)
214
158
1 78
1 37
121
107
,(75 4)
(28 4)
(30 5) ~
(41 6)
(17 7)
(19 o)
85 6 <9 7 )
93 8 (8 79)
82 0 (20 o)
84 6 (8 69)
(32 8)
80 i (zz 9)
125
89 3 (15. o)
I
REM
81 4 (24 9)
57 1 (16 8) s
I
51 2 (ll 7) ~
(19 1)
Deep sleep
I
84 6 (12 7)
1'1o
Light sleep
s i g n e d - r a n k s t e s t , one t a i l e d p r o b a b i l i t y
64 6 (23 5)
173
(56 3)
(55 2)
66 2 (25 7)
73 7 (26 8)
125
157
70 7 (18 9)
(21 5)
99 8 (29 4) 112
129
(39 6)
114
4
O-
(27 8)
96 7 (29 0)
121
T r a n m t l o n stage]
(90 4) I
160
41 3 (10 8) t
(1 1 7) I
1 57
12 - 16
(29 5)
(23 O)
69 8 (19 O)
1 44
(146 ) t
362
8-12
146
139
Awake rest
76 9 (24 4)
(98 4) 1
8
4-
259
4
O-
(28 9)
Awake m o v e m e n t
136
Time (hrs)
05, Wxlcoxon m a t c h e d - p a i r
0 063
0 016
(mg/kg)
I
Mean (_+ S E M ) p e r c e n t a g e a s c o m p a r e d to c o n t r o l of the t i m e s p e n t in d i f f e r e n t s t a g e s of s l e e p - w a k e f u l n e s s in b l o c k s of 4 h, a f t e r t r e a t m e n t w~th t h r e e d o s e s of p l m o z l d e g i v e n o r a l l y at t i m e z e r o to s e v e n dogs
TABLE I
t.O
Cn
I
V.J fD fD
0
o N
o
t~
eo
~D O0 0
V-"
FO
0
1474
Effects of Pimozide on Sleep-Wakefulness
TABLE
Vol. 27, No. 16, 1980
II
M e a n ~ S. E M ) latency, n u m b e r of epochs and length of epochs of R E M sleep after saline and three doses of plmozlde given orally to 7 dogs
Dose (mg/kg)
p <
Latency (mln)
Number
of epochs
Saline
87 3
(15 i)
Z6.0
(0 81)
0 016
s3 z
(17 4) ±
24.8
(1 74)
0. 063
z4 z
(6 z3) ~
24 0
(1 76)
0.16
8o i
(30.9)
30 9
(4. z )
05, Wilcoxon matched-palrs
Length of epochs (min)
yt
5.9 4.7 6.1
(0 16) (0.33)" (0 R6)
63
(0.4)
signed-ranks test, one tailed probability
a p o m o r p h l n e and plmozmde on the physiology of sleep are mediated by the same receptors The decreased m o t o r activity (15) and the sleep xnduclng doses of a p o m o r p h l n e in rats (3) are interpreted in t e r m s of a action on 'autoreceptors' (16) which would control firing rate, release of EtA of its o w n neurones W h e t h e r these effects are effects of the low dose of plmozlde is at present an unresolved worthy of further investigation
effects of low preferent/al synthesis and involved tn the questlon,
T h o u g h it is postulated that D A exerts an inhibitory effect on R E M sleep and slow w a v e sleep (4), the present study suggests that there are also effects on wakefulness, whlch might be independent of those observed on sleep. The changes on wakefulness are predominant/}, due to a significant change in the n u m b e r of epochs m o v e m e n t Light slow w a v e sleep and the tranmtlonal stage of sleep are not effected, w h e r e a s the changes in the deep slow w a v e sleep are predomlnantly due to a significant c h a n g e ~ n the duration of the epochs. Thus the actual progresslonlnto deep sleep would not be prevented but the d e c r e a s e d duration of deep slow w a v e sleep possibly prevents the occurrence of R E M . T h e Increased slow w a v e sleep and R E M sleep seen after the hlghest dose of p l m o m d e used in thls study is in h n e with chfferent other stuches on neuroleptlcs Incluchng haloperldol in n o r m a l volunteers and s c h l z o p h r e m c s (17), spemflcally wlth regard to the R E M sleep The overall results descrlbed in the hterature, however, are not very conslstent. Though haloperldol's effects w e r e also b, phaslc in that low doses decreased deep sleep and hlgh doses i n c r e a s e d R E M sleep (17), the effects wlth chlorpromazlne w e r e rather the opposlte (18) It is worth c o n m d e r l n g in thls respect that neuroleptlcs such as chlorpromamne are preferentially noradrenerglc blocking drugs, w h e r e a s h a l o p e r l d o l i s a m o r e s p e c i f i c DA b l o c k e r (19). T h e r e l a t i v e s p e c i f i c i t y of t h e n e u r o l e p t i c s m i g h t t h u s b e a n i m p o r t a n t f a c t o r to c o n s i d e r . In concluslon, in dogs, plmozlde had a blphaslc effect on sleep-wakefulw a k e f u l n e s s a n d d e c r e a s e d slow wave s l e e p a n d R E M , a t a h, gh d o s e , i t d e c r e a s e d w a k e f u l n e s s a n d i n c r e a s e d s l o w wave sleep and REM sleep. These r e s u l t s a r e c o n s l s t e n t wlth the h y p o t h e s l s t h a t DA p l a y s a r o l e , n t h e p h y s l o l o g y of t h e s l e e p - w a k e f u l n e s s r e g u l a t l o n . ness p a t t e r n s , a t a l o w d o s e , i t i n c r e a s e d
Vol. 27, No. 16, 1980
Effects of Pimozide on Sleep-Wakefulness
1475
References I. R.J W Y A T T , T N. C H A S E , D 3 K U P F E R , J SCOTT, F SNYDER, A SJOERDSMA andK E N G E L , Nature Z33 63-65 (1971). Z J C GILLIN, R. Ivl P O S T , R J W Y A T T , F K GOODWIN, F. S N Y D E R and W E B U N N E Y , Eleetroenceph chn Neurophyslol. 3__55 181-186 (1973) 3 G P MEREU, E SCAM~TI, E PAGLIETTI, B PELLEGRINI QUARANTOTTI, P C H E S S A , G DI C H I A R A and G L G E S S A , Electroenceph c h n Neurophyslol 4_66 214-219 (1979) 4 C CIANCHETTI, C MASALA, G U CORSINI, A M A N G O N I and G L G E S S A , Life Scl Z__33403-408 (I 978) 5. R F O G , Psychopharmacologla I_~4299-304 (1969) 6. F F E L D M A N , S SUSSELMAN and S E B A R R E R A , Am J Psychlat 10Z 403-41Z (1945) 7 G U CORSINI, M DEL ZOMPO, S MANCONI, C CIANCHETTI, A MANGONI and G L G E S S A , Non-Strlatal Dopamlnerglc Neurons, ed. by G L Gessa and E Costa, p 645-648, Raven Press, N e w York (1977). 8 C J.E. N I E M E G E E R S and P. A. ff J A N S S E N , A r c h s int Pharmacodyn. Th4r 2 3 6 4 3 - 5 0 (1978). 9 P A J J A N S S E N , C.J E N I E M E G E E R S , K H.L. S C H E L L E K E N S and F.M. LENAERTS, Arznelmlttel-Forsch 17 841-854 (1967). 10 P A J J A N S S E N , C J E N I E M E G E E R S , K H L. S C H E L L E K E N S , A DRESSE, F M LV.NAERTS, A PINCHARD, W K A SCHAPER, J M VAN NUETEN and F J V E R B R U G G E N , Arzne,mlttel-Forsch 18 Z61287 (1968) II T S A G A L E S and S E R I L L , Psychopharmacologla 4_.!I 53-56 (1975) IZ ff C GILLIN, D R. V A N K A M M E N , R P O S T and W E B U N N E Y , C o m m u n s in Psychopharrnac I_ 225-232 (1977) 13 A W A U Q U I E R , W A E VAN DEN BROECK, J L VERHEYEN and P A J J A N S S E N , Eur J P h a r m a c 4._/7 367-377 (1977) 14. A W A U Q U I E R , J L VERHEYEN, W A E V A N D E N B R O E C K and P A Jr J A N S S E N , Electroenceph chn Neurophyslol 4_~633-48 (1979). 15. U S T R O M B O M , Naunyn-Schmledebergs A r c h exp Path P h a r m a k . Z9Z 167-176 (1976) 16 A C A R L S S O N , Pre- and Postsynaptlc Receptors, ed by E Usdln and W E Bunney, Jr , p 49-65, Marcel Dekker, N e w York (1975) 17 T M ITIL, B S A L E T U , S A K P I N A R , Psychotroplc Drugs and the H u m a n EEG Mod Probl Pharmacopsychlat , ed. by T M It11, Vol 8, p 193215, K a r g e r Vasel (1974) 18 J M GAILLARDand S KAFI, Eur J chn P h a r m a c 1 5 8 3 - 8 9 (1979). 19 C J E N I E M E G E E R S a n d P A J J A N S S E N , Life Sc, 2 4 2 Z 0 1 - Z Z I 6 (1979)
BIPHASIC EFFECTS A
Wauquler,
Pergamon Press
O F P I M O Z I D E ON S L E E P - W A K E F U L N E S S W A E
Van den Broeck and P A J
IN DOGS
Janssen
D e p a r t m e n t of P h a r m a c o l o g y Janssen Pharmaceutica B-2340 Beerse, Belgium ( R e c e i v e d in final form August 8, 1980) Summa r y S l e e p - w a k e f u l n e s s p a t t e r n s in d o g s w e r e s t u d i e d u s i n g c o m p u t e r i z e d on-hne power spectral analysis and off-hne automatic stage-classification, during control recordings and after oral treatment with three doses of the specific dopamine blocker pimozide A blphasic e f f e c t on s l e e p - w a k e f u l n e s s p a t t e r n s w a s f o u n d A t 0 016 m g / k g (the E D s 0 - v a l u e f o r t h e a n t a g o m s m o f a p o m o r p h l n e - i n d u c e d vomiting in d o g s ) , p i m o z i d e m g m f i c a n t l y i n c r e a s e d t h e t i m e s p e n t a w a k e , a n d slgmficantly decreased slow wave sleep and REM sleep No s l g m ficant effects were obtained with a four times higher dose of plmozlde A t 0. 16 m g / k g , p i m o z i d e s i g m f i c a n t l y d e c r e a s e d t h e t i m e spent awake and sigmficantly increased slow wave sleep and REM sleep T h e e f f e c t s a p p e a r t h e o p p o s i t e of t h o s e d e s c r i b e d f o r a p o m o r p h i n e a n d s u g g e s t t h a t d o p a m i n e p l a y s a r o l e in t h e p h y s i o l o g y of sleep-wakefulness regulation
A l t h o u g h a h m l t e d n u m b e r of s t u d i e s s u g g e s t e d t h a t b r a i n c a t e c h o l a m i n e s p l a y a r o l e i n s l e e p - w a k e f u l n e s s r e g u l a t i o n (1, Z), i t w a s n o t c l e a r w h e t h e r d o p a m i n e (IDA) w a s s l g m f i c a n t l y i n v o l v e d in t h e m e c h a m s m s of s l e e p Recent e x p e r i m e n t s w i t h t h e DA a g o m s t a p o m o r p h i n e s u g g e s t t h a t i n t e r f e r e n c e w i t h DA r e c e p t o r s d o e s a f f e c t t h e s l e e p - w a k e f u l n e s s r e g u l a t i o n (3, 4) D e p e n d i n g on t h e d o s e o f a p o m o r p h i n e , o p p o s i n g e f f e c t s w e r e f o u n d At l o w ( n o n - e m e t i c ) d o s e s a p o m o r p h l n e i n d u c e s i n h i b i t i o n o f b e h a v l o u r (5), i n d u c e s s l e e p l n r a t s (3) a n d s e d a t i o n a n d s l e e p i n h u m a n (6, 7), a t h i g h d o s e s a p o m o r p h l n e c a u s e s h y p e r m o t d l t y (8), s t e r e o t y p y (9) a n d f o l l o w i n g i n f u s i o n in h u m a n s u p p r e s s e s R E M s l e e p a n d r e d u c e s s l o w w a v e s l e e p (4) I n d e p e n d e n t o f t h e q u e s t x o n on t h e p o s i t i o n o f t h e r e c e p t o r s x n v o l v e d , t h e s e e x p e r i m e n t s s u g g e s t t h a t s t i m u l a t i o n o f DA r e c e p t o r s i n d u c e s s l e e p , b u t o v e r s t l m u l a t i o n p r e v e n t s t h e p r o g r e s s i o n i n t o d e e p s l e e p a n d R E M s l e e p (4) B o t h e f f e c t s o f a p o m o r p h i n e in h u m a n a r e a n t a g o m z e d b y IDA b l o c k e r s (3, 7) A slmdar antagomsm of the amphetamine-induced reduction of total sleep and REM sleep has been described (2) With pimozlde, the m o s t speclflc IDA blocker (I0), no effects w e r e found on n o r m a l volunteers (II), w h e r e a s it sigmficantly i m p r o v e d the disturbed sleep patterns in psychiatrlc patients (12) In the hght of the above, one would 0024-3205/80/421469-07502.00/0 Copyright (c) 1980 Pergamon Press Ltd
1470
Effects of Pimozlde on Sleep-Wakefulness
Vol. 27, No. 16, 1980
e x p e c t t h a t p i m o z l d e w o u l d c a u s e t h e o p p o s i t e e f f e c t s to a p o m o r p h i n e . No p r e v i o u s s t u d y h a s r e p o r t e d on t h e e f f e c t s o f d i f f e r e n t d o s e s of p i m o z l d e on t h e sleep-wakefulness patterns lnanlmals, we therefore tested three doses of p l m o z l d e in dogs
Materlals a n d M e t h o d s Subjects The subjects w e r e 7 adult m a l e beagles weighing 13 0 to 18 5 kg a n d approximately 2 years old at the time of surgery.
Surgery The dogs were stereotaxlcally implanted with cortical electrodes (stainl e s s s t e e l s c r e w s in the f r o n t a l , t e m p o r a l and o c c i p i t a l s i d e s of the skull) and subcort, cal electrodes (stainless steel needles of 0 5 mm chameter, insulated e x c e p t f o r 0 . 5 m m o f t h e t i p , in w h i c h a s t a i n l e s s s t e e l w i r e o f 0. Z m m w a s , n s e r t e d and which p r o t u d e d 1 r a m , b e n e a t h the t,p of the n e e d l e ) as p r e v i o u s l y d e s c r , b e d (13) Depth e l e c t r o d e s w e r e i m p l a n t e d in the d o r s a l h i p p o c a m p u s , the l a t e r a l g e n i c u l a t e , the b a s o l a t e r a l a m y g d a l a and the r e t i c u l a r f o r m a t i o n . C i r c u l a r p l a t , h u m w i r e s w e r e p l a c e d o n e d o r s a l l y a n d o n e l a t e r a l l y to o n e e y e to r e c o r d e y e m o v e m e n t s Two c i r c u l a r s t a i n l e s s s t e e l w, r e s w e r e s u t u r e d ,n a n e c k m u s c l e to r e c o r d m u s c l e a c t i v i t y .
Recorchng The a n i m a l s w e r e p l a c e d in a r e l a t i v e l y s m a l l s h i e l d e d c a g e in a r o o m w h e r e t h e l a b o r a t o r y d l u m l n a t l o n w a s c o n t i n u o u s l y on. P a p e r r e c o r d i n g s w e r e m a d e f o r 3 h f r o m 3 p m on a n d o n - h n e c o m p u t e r a n a l y s i s w a s c a r r i e d o u t i n a s e p a r a t e r o o m f r o m 3 p m to 7 a m P a p e r recorchngs of varlous cortlcal and subcortlcal derlvatlons w e r e done on an E l e m a - S c h O n a n d e r m l n g o g r a p h The paper speed w a s 15 m m F i l t e r s a n d t i m e c o n s t a n t s w e r e f o r t h e E E G r e s p e c t i v e l y 30 H z a n d 0 . 3 s e c , f o r t h e E M G r e s p e c t i v e l y 700 Hz a n d 0 . 0 1 5 s e c .
Analys, s Analysis w a s done o n - h n e on 30 sec epochs of one cortlcal derlvatlon (frontal-occlpltal), the h l p p o c a m p a l derlvatlon, the EIV[G and the E O G by a P D P I I / E I0 m l n l c o m p u t e r P o w e r spectral analysls w a s done by m e a n s of a Fast Four,er Transformation, the s p e c t r u m being chvlded in the following f r e q u e n c y b a n d s ( f r e q u e n m e s b e t w e e n b r a c k e t s ) d e l t a (0 5 - 3 . 5 H z ) , t h e t a (3. 5 - 7. 5 Hz), alpha (7 5 - 13. 5 Hz) and beta (13 5 - Z5.0 Hz) for the frontalocclp, tal derlvatlon, the p o w e r in the thetaband w a s calculated for the hlppoc a m p a l derivatlon, a special algor, t h m detected the splndles, the E M G a n d E O G a m p h t u d e w e r e calculated T h e s e data served to autornatlcall7 class,fy off-hne each epoch of 30 sec Into 6 stages of the sleep-wakefulness cycle: w a k e f u l n e s s , m o v e m e n t , w a k e f u l n e s s , r e s t ; t r a n s l t l o n to s l e e p , h g h t s l o w w a v e sleep; deep slow wave sleep and REM sl~ep. The methodology has been de-
ta,led prev,ously
(i 4).
Vol. 27, No. 16, 1980
Effects of Pimozlde on Sleep-Wakefulness
1471
Drug treatment The dogs used ~n this study w e r e recorded overmght several times before any drug treatment and w e r e fully adapted to the s~tuatlon These recordings served to estabhsh the partition of the sleep-wakefulness patterns. O n e control recording preceding each dose of the drug served for comparison wlth the drug effects Each dog w a s orally treated at the start of the recording w~th water or with one of the follow~ng doses of plmoz~de 0 016 mg/kg, 0 063 rng/kg and 0 16 mg/kg, given 1n a volume of I rnl per 2 kg The doses w e r e g~ven randomly w~th a weekly ~nterval between doses. The lowest dose of pIrnozide ~s the ED50-value of ~ts ant~emetic effect agalnst apornorphxne induced vomiting (I0)
Results During the control sessions a normal partition of sleep-wakefulness patterns w a s seen The m e a n (_+ S E M ) percentage of 5 control recordings for the 7 dogs (n = 35) preceding drug treatment w e r e as follows' awake, m o v e m e n t 18.1 (I 6), awake, rest 9 79 (0.9), transltlon stage 14 8 (I.0), 11ght slow w a v e sleep 18.0 (0 7), deep slow w a v e sleep 24 0 (I 0) and R E M sleep. 15.4 (0.9) The control recordings preceding each dose of plmozlde for each Indivldual dog w e r e wlthln the hmlts of the recordings precedlng drug treatment Thus comparlson w a s m a d e between drug treatment and the respective control recording Figure 1 shows the percentage a w a k e ( m o v e m e n t and rest cornblned), sleep (the three stages of sleep comblned) and R E M sleep as c o m p a r e d to the control With the intermediate dose (0 063 rng/kg), no slgmflcant changes w e r e found At the lowest dose (0 016 mg/kg) of p1mozlde there w a s a slgmflcant Increase in wakefulness, a slgmflcant decrease of sleep a n d a decreased REM With the hlghest dose of pirnozlde (0.16 mg/kg) wakefulness slgmflcantly decreased, sleep and R E M sleep slgmflcantly increased T h e s l g m f i c a n t l y i n c r e a s e d w a k e f u l n e s s a f t e r t h e l o w e s t d o s e of p l r n o z l d e a n d t h e s l g n i f l c a n t l y d e c r e a s e d w a k e f u l n e s s a f t e r t h e h l g h e s t d o s e of p l r n o z l d e a r e d u e to a s l g n i f l c a n t e f f e c t on t h e n u m b e r of e p o c h s of m o v e m e n t ( r e s p e c t l r e l y 188 + 8 1 ~o a n d 65. 1 + 23 0 ~o), no s l g n i f l c a n t e f f e c t s on a w a k e - r e s t w e r e found T h e s l g n i f l c a n t l y d e c r e a s e d , c o n v e r s e l y i n c r e a s e d s l e e p l s due to a s l g n l f l c a n t e • e c t o n t h e d u r a t l o n o£ the e p o c h s d e e p s l o w w a v e s l e e p ( r e s p e c t l r e l y 71 4_+ 6 8 ~ a n d 131 _+ 1 3 . 6 ~ ) , no s l g n l f l c a n t e f f e c t s w e r e f o u n d o n the t r a n s 2 t l o n stage or llght slow wave sleep Though the d e c r e a s e d p e r c e n t a g e R E M f o l l o v ~ n g the l o w d o s e of p l m o z l d e w a s n o t s l g m f l c a n t , a s l g m f l c a n t e f f e c t o n t h e d u r a t l o n of t h e e p o c h s REIV[ ( 7 1 . 4 + 6 8 ~o) w a s o b t a l n e d . T a b l e I s h o w s t h e p e r c e n t a g e v e r s u s c o n t r o l of t h e d i f f e r e n t s t a g e s of s l e e p - w a k e f u l n e s s f o r t h e d i f f e r e n t d o s e s of p l r n o z l d e In b l o c k s of 4 h The s l o w o n s e t of a c t l v l t y i s e v l d e n t f r o m T a b l e I The m a l n s i g m f l c a n t c h a n g e s o c c u r r e d a f t e r 4 h , t h o u g h the d e c r e a s e d a m o u n t of d e e p s l e e p a f t e r t h e l o w e s t d o s e of p l m o z l d e a n d t h e i n c r e a s e d a m o u n t of d e e p s l e e p a f t e r t h e h i g h e s t d o s e of p i r n o z i d e w e r e a l r e a d y s l g m f l c a n t d u r l n g t h e f i r s t 4 h of t h e r e c o r d i n g F r o m T a b l e II i t i s s e e n t h a t the R E M l a t e n c y I s d e c r e a s e d w l t h 0 016 rng//kg, t h o u g h t h e e p o c h l e n g t h s l g m f l c a n t l y d e c r e a s e d The slgnlflcantly inc r e a s e d R E M o b s e r v e d a f t e r t h e h l g h e s t d o s e of p l m o z l d e i s p r o b a b l y d u e t o a s i g m ~ c a n t i n c r e a s e i n t h e n u m b e r of e p o c h s R E M . W i t h 0. 063 r n g / k g of p l r n o z i d e t h e d e c r e a s e i n the l a t e n c y of R E M w a s t h e o n l y s l g n l f l c a n t e H e c t o b t a l n e d .
1472
Effects of Pimozide on Sleep-Wakefulness
AWAKE
Vol. 27, No. 16, 1980
SLEEP
REM
T
180160UJ
o 140<[
120-
Z
LU 1000 n,, 80a_ 6040 mg/kg
0.063 0016 016
0.063 0.016 0.16
PIMOZIDE FIG
0.063 0016 016
OR
1
M e a n percentage (+ S E M . ) as c o m p a r e d to the respectlve controls of the tlme a w a k e ( m o v e m e n t and rest comblned), the tlme asleep (transltlon stage, hghr and deep slow w a v e sleep comblned) and R E M sleep, after three doses of plmozlde glven orally at the start (3 p m ) of the 16 h recorchng in dogs
l~scuss~on Paradoxlcal effects of dlfferent doses of plmozlde on sleep in dogs w e r e found at a low dose plmozlde increased wakefulness and decreased slow w a v e sleep and R E M sleep and at a hlgh dose of plmozlde wakefulness d e c r e a s e d and slow w a v e sleep and R E M sleep increased The flndlngs wlth the hlgh dose of plmozlde corroborate the results obtalned wlth prolongedadm,nlstratlon of plmozlde to psychlatrlc patlents (12), but m a r k e d l y contrast to the report that plmozlde dld not effect sleep in n o r m a l volunteers (ii) In the last study, it w a s suggested that IDA is of m l n o r i m p o r t a n c e in the physlology of sleep Thelr flndlngs are ,n contrast to the flnchngs wlth the D A agonlst a p o m o r p h l n e whlch at low doses induce sleep and at hlgh doses decrease sleep in rat and in m a n (3, 4, 7) A s s u m , n g that a p o m o r p h l n e exerts Its effects through an agonlstlc actlon at D A receptors, one w o u l d expect that a speclflc D A blocker such as plmozlde w o u l d cause the opposlte effects, as w a s indeed o b s e r v e d in the present study 1~ne questlon is not resolved, however, whether the effects of
t
Dose
p <
016
(23 3)
(38 2)
(25 3)
111
132
123
8-12
12 - 16
8
4-
12-
16
8-12
4
O-
8
4-
48 8 (10 6) I
99 5 (73 7)
(41 7)
(68 1)
(101)
(52 O)
(50 4)
111
110
107 (19 8)
(18 3)
(18 7)
95 7 (13 3)
225
167
1 46
(29 6)
I
(12 2)
(39 2)
(14 1)
(27 6) (22 8) (11 9)
129 120
(19 l) 144
112
99 9 (20 3)
100
125
112
98 4 (;'4 2)
168
115
1 34
177
1 58
110
105
178
(36 3)
(17 4)
(39 5)
(49 7) ~
(49 9)
(15 2)
(30 4)
(74 6)
94 1 (26 4)
214
158
1 78
1 37
121
107
,(75 4)
(28 4)
(30 5) ~
(41 6)
(17 7)
(19 o)
85 6 <9 7 )
93 8 (8 79)
82 0 (20 o)
84 6 (8 69)
(32 8)
80 i (zz 9)
125
89 3 (15. o)
I
REM
81 4 (24 9)
57 1 (16 8) s
I
51 2 (ll 7) ~
(19 1)
Deep sleep
I
84 6 (12 7)
1'1o
Light sleep
s i g n e d - r a n k s t e s t , one t a i l e d p r o b a b i l i t y
64 6 (23 5)
173
(56 3)
(55 2)
66 2 (25 7)
73 7 (26 8)
125
157
70 7 (18 9)
(21 5)
99 8 (29 4) 112
129
(39 6)
114
4
O-
(27 8)
96 7 (29 0)
121
T r a n m t l o n stage]
(90 4) I
160
41 3 (10 8) t
(1 1 7) I
1 57
12 - 16
(29 5)
(23 O)
69 8 (19 O)
1 44
(146 ) t
362
8-12
146
139
Awake rest
76 9 (24 4)
(98 4) 1
8
4-
259
4
O-
(28 9)
Awake m o v e m e n t
136
Time (hrs)
05, Wxlcoxon m a t c h e d - p a i r
0 063
0 016
(mg/kg)
I
Mean (_+ S E M ) p e r c e n t a g e a s c o m p a r e d to c o n t r o l of the t i m e s p e n t in d i f f e r e n t s t a g e s of s l e e p - w a k e f u l n e s s in b l o c k s of 4 h, a f t e r t r e a t m e n t w~th t h r e e d o s e s of p l m o z l d e g i v e n o r a l l y at t i m e z e r o to s e v e n dogs
TABLE I
t.O
Cn
I
V.J fD fD
0
o N
o
t~
eo
~D O0 0
V-"
FO
0
1474
Effects of Pimozide on Sleep-Wakefulness
TABLE
Vol. 27, No. 16, 1980
II
M e a n ~ S. E M ) latency, n u m b e r of epochs and length of epochs of R E M sleep after saline and three doses of plmozlde given orally to 7 dogs
Dose (mg/kg)
p <
Latency (mln)
Number
of epochs
Saline
87 3
(15 i)
Z6.0
(0 81)
0 016
s3 z
(17 4) ±
24.8
(1 74)
0. 063
z4 z
(6 z3) ~
24 0
(1 76)
0.16
8o i
(30.9)
30 9
(4. z )
05, Wilcoxon matched-palrs
Length of epochs (min)
yt
5.9 4.7 6.1
(0 16) (0.33)" (0 R6)
63
(0.4)
signed-ranks test, one tailed probability
a p o m o r p h l n e and plmozmde on the physiology of sleep are mediated by the same receptors The decreased m o t o r activity (15) and the sleep xnduclng doses of a p o m o r p h l n e in rats (3) are interpreted in t e r m s of a action on 'autoreceptors' (16) which would control firing rate, release of EtA of its o w n neurones W h e t h e r these effects are effects of the low dose of plmozlde is at present an unresolved worthy of further investigation
effects of low preferent/al synthesis and involved tn the questlon,
T h o u g h it is postulated that D A exerts an inhibitory effect on R E M sleep and slow w a v e sleep (4), the present study suggests that there are also effects on wakefulness, whlch might be independent of those observed on sleep. The changes on wakefulness are predominant/}, due to a significant change in the n u m b e r of epochs m o v e m e n t Light slow w a v e sleep and the tranmtlonal stage of sleep are not effected, w h e r e a s the changes in the deep slow w a v e sleep are predomlnantly due to a significant c h a n g e ~ n the duration of the epochs. Thus the actual progresslonlnto deep sleep would not be prevented but the d e c r e a s e d duration of deep slow w a v e sleep possibly prevents the occurrence of R E M . T h e Increased slow w a v e sleep and R E M sleep seen after the hlghest dose of p l m o m d e used in thls study is in h n e with chfferent other stuches on neuroleptlcs Incluchng haloperldol in n o r m a l volunteers and s c h l z o p h r e m c s (17), spemflcally wlth regard to the R E M sleep The overall results descrlbed in the hterature, however, are not very conslstent. Though haloperldol's effects w e r e also b, phaslc in that low doses decreased deep sleep and hlgh doses i n c r e a s e d R E M sleep (17), the effects wlth chlorpromazlne w e r e rather the opposlte (18) It is worth c o n m d e r l n g in thls respect that neuroleptlcs such as chlorpromamne are preferentially noradrenerglc blocking drugs, w h e r e a s h a l o p e r l d o l i s a m o r e s p e c i f i c DA b l o c k e r (19). T h e r e l a t i v e s p e c i f i c i t y of t h e n e u r o l e p t i c s m i g h t t h u s b e a n i m p o r t a n t f a c t o r to c o n s i d e r . In concluslon, in dogs, plmozlde had a blphaslc effect on sleep-wakefulw a k e f u l n e s s a n d d e c r e a s e d slow wave s l e e p a n d R E M , a t a h, gh d o s e , i t d e c r e a s e d w a k e f u l n e s s a n d i n c r e a s e d s l o w wave sleep and REM sleep. These r e s u l t s a r e c o n s l s t e n t wlth the h y p o t h e s l s t h a t DA p l a y s a r o l e , n t h e p h y s l o l o g y of t h e s l e e p - w a k e f u l n e s s r e g u l a t l o n . ness p a t t e r n s , a t a l o w d o s e , i t i n c r e a s e d
Vol. 27, No. 16, 1980
Effects of Pimozide on Sleep-Wakefulness
1475
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