Effect of chronic chlorpromazine administration of prior treatment with reserpine on brain apomorphine concentrations and apomorphine-induced sterotyped behaviour in the rat

European Journal o f Pharmacology, 43 (1977) 173--179 © Elsevier/North-Holland Biomedical Press

173

EFFECT OF CHRONIC CHLORPROMAZINE ADMINISTRATION OR PRIOR TREATMENT WITH RESERPINE ON BRAIN APOMORPHINE CONCENTRATIONS AND APOMORPHINE-INDUCED STEREOTYPED BEHAVIOUR IN THE RAT

ASTON L. SYMES *,t, SAMARTHJI LAL *, SIMON N. YOUNG **, DAVID TSANG * and THEODORE L. SOURKES ** Departments o f Psychiatry, * Montreal General Hospital and ** McGill University, Montreal, P.Q., Canada Received 28 September 1976, revised MS received 26 January 1977, accepted 31 January 1977

A.L. SYMES, S. LAL, S.N. YOUNG, D. TSANG and T.L. SOURKES, Effect o f chronic chlorpromazine administration or prior treatment with reserpine on brain apomorphine concentrations and apomorphine-induced stereotyped behaviour in the rat, European J. Pharmacol. 43 (1977) 173--179. Rats were pretreated with a single dose of reserpine (10 mg/kg i.p.) or were given daily injections of chlorpromazine (15 mg/kg s.c.) for 3 weeks. Controls received distilled water. 72 h after reserpine and 1 week after withdrawal from chlorpromazine apomorphine was administered (10 mg/kg i.p.). Both the intensity and duration of apomorphine-induced stereotyped behaviour (ASB) and the concentration of apomorphine in brain were measured. Further groups of rats pretreated with reserpine or chlorpromazine as well as corresponding controls, received 0.25 mg/kg apomorphine and the development of ASB was rated. 14 of 16 reserpine-pretreated rats and 4 of 16 control rats developed ASB after 0.25 mg/kg apomorphine (p < 0.001). After withdrawal from chlorpromazine, apomorphine (0.25 mg/kg) induced ASB in 12 out of 14 experimental and 5 out of 14 control rats (p < 0.05). Following 10 mg/kg of apomorphine there was a significant enhancement of motor activity associated with ASB in rats exposed to reserpine or withdrawn from chlorpromazine, compared to controls. This enhancement could not be explained by differences in brain apomorphine concentrations. The results are not inconsistent with the concept of neuroleptic-induced supersensitivity of dopamine receptors. Brain apomorphine concentration

Neuroleptic drugs

1. Introduction Following a course of chronic treatment with haloperidol or chlorpromazine there is an alteration in behavioural response of animals to the dopamine-receptor agonist apomorphine. Thus, several authors have shown that following withdrawal from chronic neuroleptic therapy the threshold doses of apomorphine needed to induce stereotyped behaviour in the guinea pig (Klawans and Rubovits, 1972) and cage-climbing in the mouse (Von t Correspondence and reprint requests to A.L. Symes, Department of Psychiatry, Montreal General Hospital, Montreal, P.Q., Canada H3G 1A4.

Apomorphine

Stereotyped behaviour

Voigtlander et al., 1975) are decreased and the intensity of apomorphine-induced stereotyped behaviour (ASB) in the rat is increased (Tarsy and Baldessarini, 1973; Smith and Davis, 1975; Gianutsos et al., 1974). Apomorphine effects are also enhanced following treatment with reserpine (Rotrosen et al., 1972; Ungerstedt, 1971). These behavioural observations have been taken as evidence for increased dopamine-receptor sensitivity. Such a phenomenon is believed to subserve the development of tardive dyskinesia in patients receiving chronic treatment with major tranquillizers (Klawens and Rubovits, 1972). Unfortunately, the possibility that the

174 e n h a n c e m e n t o f a p o m o r p h i n e effects m a y be related to alterations in t h e biodisposition o f a p o m o r p h i n e in brain has n o t been extensively e x p l o r e d . In the present s t u d y we have e x a m i n e d t h e effects o f (a) prior t r e a t m e n t with reserpine and (b) w i t h d r a w a l f r o m c h l o r p r o m a z i n e a f t e r a c h r o n i c course o f t h a t drug on the biodisposition o f a p o m o r p h i n e in brain and on ASB in the rat.

2. Materials and m e t h o d s

2.1. Behavioural studies 2.1.1. Effect of reserpine pretreatment Male S p r a g u e - - D a w l e y rats were used in all e x p e r i m e n t s . G r o u p s o f rats with b o d y weights o f a b o u t 140 g was injected with reserpine (Serpasil a m p o u l e s , Ciba, 10 m g / k g i.p.) or distilled water. 72 h later the rats, h o u s e d in individual wire cages, were injected with a p o m o r p h i n e HC1 (Merck Frosst, 0.25 m g / k g i.p., as t h e base) and t h e d e v e l o p m e n t o f ASB evaluated b y 2 i n d e p e n d e n t observers. The animals were rated at 15, 30 and 45 min a f t e r i n j e c t i o n a c c o r d i n g to the scoring s y s t e m o f T a r s e y and Baldessarini ( 1 9 7 3 ) : 0 = absent or d i s c o n t i n u o u s sniffing; 1 = c o n t i n u o u s sniffing, d i s c o n t i n u o u s licking; 2 = d i s c o n t i n u o u s biting, restricted l o c o m o t o r activity; 3 = cont i n u o u s biting, a b s e n t l o c o m o t o r activity. Average scores o f the 2 observers were s u m m e d for each animal for the 3 t i m e intervals. T h e dose o f 0.25 mg/kg a p o m o r p h i n e was c h o s e n on the basis o f p r e l i m i n a r y studies u n d e r t a k e n to establish a t h r e s h o l d dose t o i n d u c e ASB. In a f u r t h e r series o f e x p e r i m e n t s groups of rats were t r e a t e d with reserpine or distilled w a t e r in the same way. 72 h later pairs o f animals (1 e x p e r i m e n t a l and 1 c o n t r o l ) were placed in a Stoelting E l e c t r o n i c Activity M o n i t o r Model No. 3 1 4 0 4 and m o v e m e n t c o u n t s r e c o r d e d b y 2 separated recording channels b e f o r e and a f t e r a d m i n i s t r a t i o n of a p o m o r p h i n e (10 m g / k g i.p.). T h e sensors for

A.L. SYMES ET AL. c o n t r o l and e x p e r i m e n t a l animals were consecutively a l t e r n a t e d for each pair o f rats tested. The sensitivity was k e p t at 30. Counts r e c o r d e d in an electric activity m o n i t o r are d e p e n d e n t on mass m o v e d and speed o f movement. Following a 15 rain period o f acclimatisation baseline activity was r e c o r d e d for 15 rain and t h e n a p o m o r p h i n e injected. T h e movem e n t c o u n t s were r e c o r d e d b y a u t o m a t i c p r i n t - o u t at 1 rain intervals. During the recording the animals were u n d e r c o n t i n u o u s d i r e c t observation. A f t e r a p o m o r p h i n e injection the rats develop ASB within a m i n u t e or 2 and this behavioural p a t t e r n remains c o n t i n u o u s until the t e r m i n a t i o n phase. T h e e n d - p o i n t of ASB, as r e c o r d e d by d i r e c t o b s e r v a t i o n , corresp o n d s to m o v e m e n t r e c o r d e d as 5 or less c o u n t s per rain b y a u t o m a t i c counting. Within a m i n u t e or 2 o f this end p o i n t s o m e locom o t o r activity m a y o c c u r b u t it lacks the characteristics o f ASB (Lal and Sourkes, 1973). Thus, with a c o m b i n a t i o n o f direct observation and a u t o m a t i c r e c o r d i n g o f m o v e m e n t s it is possible to evaluate the i n t e n s i t y and duration of ASB u n d e r various e x p e r i m e n t a l conditions.

2.1.2. Effect o f chlorpromazine withdrawal G r o u p s o f rats with b o d y weights of a b o u t 150 g were injected with c h l o r p r o m a z i n e HCI (Largactil, Poulenc, 15 m g / k g as the base) or distilled w a t e r s.c. daily for 3 weeks. The dose o f c h l o r p r o m a z i n e was adjusted to the b o d y weight at the beginning of each week o f treatm e n t . One w e e k after d i s c o n t i n u a t i o n o f treatm e n t the d u r a t i o n and i n t e n s i t y o f ASB following a p o m o r p h i n e 10 mg/kg and the d e v e l o p m e n t o f ASB after a p o m o r p h i n e 0.25 mg/kg were investigated as in the reserpine study. 2.2. Biochemical studies 72 h after reserpine (or distilled water) t r e a t m e n t and 1 week a f t e r d i s c o n t i n u a t i o n o f c h l o r p r o m a z i n e or c o n t r o l t r e a t m e n t , groups

BRAIN APOMORPHINE CONCENTRATIONS

o f rats were injected with a p o m o r p h i n e (10 mg/kg i.p.) and killed at 5, 10, 20 and 50 min and also at 90 min in the chlorpromazine experiment. The brains were immediately removed and assayed for a p o m o r p h i n e exactly as described previously (Symes et al., 1975). Experimental and control rats were sacrificed and brains assayed as the same time. Chlorpromazine or reserpine t r e a t m e n t alone did n o t interfere with the assay. The doses o f reserpine and chlorpromazine, the duration of t r e a t m e n t and interval between drug discontinuation and administration of a p o m o r p h i n e were based on those previously shown to result in enhanced apom o r p h i n e effects (Ungerstedt, 1971; Tarsy and Baldessarini, 1973).

3. Results

17 5

80O

600E

~. 400:

J 200~

.10

0

10

20

30 40 Time (rain)

50

60

70

80

Fig. l . Effect of reserpine pretreatment on apomorphine-induced stereotyped behaviour. Rats were pretreated with reserpine (o o) (10 mg/kg) (n = 7) or distilled water (o O) (n = 10) i.p. 72 h before

apomorphine (10 mg/kg i.p.)and the activity recorded by an electronic activity monitor. The counts have been summed for each 5 min period. *p < 0.05; ** p < 0.01.

3.1. Effect of reserpine pretreatment Following t r e a t m e n t with reserpine all rats developed s y m p t o m s of catalepsy and lost weight. At the time of a p o m o r p h i n e administration the control rats weighed 159 + 2 g {means + S.E.) and the reserpine-treated animals 144 -+ 2 g (p < 0.001). Administration of 0.25 mg/kg of a p o m o r p h i n e induced ASB in 14 o f 16 reserpine-pretreated rats and 4 of 16 control animals X 2 = 11.46; df 1; p < 0.001). The mean score of s t e r e o t y p e d behaviour was 0.50-+ 0.27 in controls and 2.86-+ 0.63 in experimental rats (p < 0.01). Baseline levels ' o f activity were similar in b oth groups of animals prior to a p o m o r p h i n e (10 mg/kg) administration (fig. 1). After a p o m o r p h i n e was given 1 of 11 control and 4 o f 11 experimental rats failed to develop ASB X 2 = 2 . 7 5 ; d f = 1; p > 0.05). In the rats which develop ASB the onset occurred within 1--2 min o f injection. Fig. 1 depicts the record of m o v e m e n t counts during the first 70 min, the period during which ASB was observed. As can be seen between 10 and 70 min the mean counts for each 5 min period were higher in the experimental animals than in controls and

significantly so at 50, 55 and 60 min. The mean m o v e m e n t counts in the control rats remained fairly constant bet w een 5 and 60 min and then rapidly declined (fig. 1). In the experimental animals the mean counts were more variable; the peak activity was present at 50 min but this was not significantly greater than activity recorded at o t h e r times between 20 and 60 min. By direct observation of ASB, it was n o t e d t hat its termination corresponded to a transient decrease o f activity to less than 5 counts/ min. With this end-point, the duration o f ASB in controls was 70.9 + 1.0 min and in reserpine-treated rats 72.8 -+ 1.2 min (p > 0.05). Because the counts have been summed over 5 min intervals for graphic purposes this end-point is not evident in fig. 1. Following termination of ASB, intermittent l o c o m o t o r activity emerged but this did not c o n f o r m to the pattern of s t e r e o t y p e d behaviour. The l o c o m o t o r activity quickly subsided and the animals rested. The concentrations of a p o m o r p h i n e in brain are given in table 1. At 5 min the concentration of a p o r m o r p h i n e was significantly

176

A.L. SYMES ET AL.

TABLE 1 Effect of reserpine pretreatment on brain apomorphine concentration. Rats were pretreated with distilled water or reserpine (10 mg/kg) i.p. 72 h before injection of apomorphine (10 mg/kg i.p.) and the concentration of apomorphine measured in brain. Values are expressed as ~tg/g and are given as the mean ± S.E. of 8 determinations. Min after apomorphine 5 10 20 50

Treatment Control

Reserpine

4.14 5.59 4.18 0.76

6.84 6.72 2.64 0.64

+ 0.24 ± 0.58 ± 0.49 ± 0.28

, 0.67 ~ 1.62 * 0.99 ± 0.24

1

1 Significantly higher than control rats at 5 rain (p < 0.01) but not significantly higher than control mean peak value. higher in rats p r e t r e a t e d with reserpine t h a n in c o n t r o l s ; at o t h e r time intervals there was n o significant difference. The peak values for t h e 2 g r o u p s o f animals, h o w e v e r , were n o t significantly d i f f e r e n t . There was no correlat i o n b e t w e e n i n t e n s i t y o f ASB and a p o m o r p h i n e c o n c e n t r a t i o n o f t h e brain. Thus, in c o n t r o l s the peak c o n c e n t r a t i o n o f a p o m o r phine o c c u r r e d at 10 min and t h e n rapidly declined. Despite the decline in a p o m o r p h i n e c o n c e n t r a t i o n t h e i n t e n s i t y o f m o t o r activity associated with ASB r e m a i n e d r e m a r k e d l y u n i f o r m b e t w e e n 5 and 60 min after a p o m o r phine injection. In e x p e r i m e n t a l rats the peak c o n c e n t r a t i o n o f a p o m o r p h i n e o c c u r r e d at 5 min b u t the peak i n t e n s i t y o f ASB o c c u r r e d at 50 min at which time a p o m o r p h i n e levels were o n l y 10% o f peak values. A l t h o u g h the i n t e n s i t y o f m o t o r activity associated with ASB was significantly higher t h a n in c o n t r o l s at 50 min the c o n c e n t r a t i o n o f a p o m o r p h i n e was similar in e x p e r i m e n t a l and c o n t r o l brains.

3.2. Effect of chlorpromazine withdrawal F o l l o w i n g c h l o r p r o m a z i n e t r e a t m e n t the animals s h o w e d a smaller weight gain t h a n

c o n t r o l s . The g r o u p o f e x p e r i m e n t a l rats receiving a p o m o r p h i n e 10 m g / k g weighed 310 -+ 4 g and the c o r r e s p o n d i n g controls, 3 5 0 ± 8 g ( p < 0.001). In the s e c o n d e x p e r i m e n t in w h i c h the rats received 0.25 m g / k g a p o m o r p h i n e the animals w i t h d r a w n f r o m n e u r o leptic t r e a t m e n t weighed 268-+ 6 g and the c o n t r o l s 318 + 6 g at the time o f a p o m o r p h i n e injection (p < 0.001). A d m i n i s t r a t i o n o f the t h r e s h o l d dose o f a p o m o r p h i n e i n d u c e d ASB in 5 o u t of 14 c o n t r o l s and 12 o u t o f 14 e x p e r i m e n t a l rats (?(2 = 5.39; d f = 1; p < 0.05). The m e a n score o f ASB was 0.64 ± 0.11 for c o n t r o l s and 3.20 -+ 1.04 for e x p e r i m e n t a l animals (p < 0.01). The baseline level o f activity prior to apom o r p h i n e (10 m g / k g a d m i n i s t r a t i o n was similar in b o t h groups o f animals (fig. 2). Apom o r p h i n e i n d u c e d ASB in 15 o f the 16 animals w i t h d r a w n f r o m c h l o r p r o m a z i n e and in 13 o f 16 controls. O n s e t o f ASB o c c u r r e d within 1--2 min. In c o n t r o l animals t h e m o v e m e n t c o u n t s (fig. 2) were fairly c o n s t a n t b e t w e e n 5 and 50 min, increased t o a maxim u m b e t w e e n 55 and 75 min and t h e n

800

~oo~ lo- o

\ ,o 2 o

3o 4o ~o io

Joio

90~oo

,me Im~n;

Fig. 2. Effect of withdrawal from chronic chlorpromazine treatment on apomorphine-induced stereotyped behaviour. Rats were treated with chlorpromazine (15 mg/kg) (© o) (n = 15) or distilled water (© ©) (n = 13) s.c. daily for 3 weeks. 1 week after discontinuation of treatment apomorphine (10 mg/kg) was injected i.p. and the activity recorded by an electronic activity monitor. The counts have been summed for each 5 min period. * p < 0.05; **p < 0.01; *** p < 0.001.

BRAIN APOMORPHINE CONCENTRATIONS rapidly declined to baseline levels. In experimental animals the counts remained fairly constant from 15 to 100 min. The duration of ASB was 84.5 -+ 4.8 min in controls and 98.2 + 5.3 min in the experimental animals (p > 0.05). The termination of ASB was associated with m o v e m e n t counts transiently decreasing to less than 5 counts/min. Following this, l o c o m o t o r activity which lacked the characteristics o f s t e r e o t y p e d behaviour emerged. The m o v e m e n t counts associated with ASB were similar in b o t h groups of animals during t he first 55 min after a p o m o r p h i n e injection. However, at 60 and 70 min control rats had a significantly higher c o u n t than experimental rats. Thereafter counts associated with ASB rapidly decreased in controls b u t remained elevated in experimental animals. The counts were significantly higher at 85, 90, 95 and 100 min in the neuroleptic pretreated rats than in the controls. Brain a p o m o r p h i n e levels were similar in b o t h groups of animals at all time intervals studied (table 2). The peak c o n c e n t r a t i o n of a p o m o r p h i n e occurred at 10 min in controls and at 20 min in experimental rats. The intensity of ASB, however, was n o t correlated with TABLE 2 Effect of withdrawal from chronic chlorpromazine treatment on brain apomorphine concentration. Rats were treated with chlorpromazine (15 mg/kg) or distilled water s.c. daily for 3 weeks; 1 week after discontinuation of chlorpromazine apomorphine (10 mg/kg) was injected i.p. and the concentration of apomorphine measured in brain. Values are expressed as pg/g and are given as the mean ± S.E. of 6 determinations. There is no statistically significant difference between the 2 groups of rats at any of the time intervals studied. Min after apomorphine 5 10 20 50 90

Treatment Control

Chlorpromazine

1.20 2.72 1.63 0.50 0.04

1.18 1.89 2.46 0.38 0.17

± 0.53 +- 0.37 ± 0.26 ± 0.10 ± 0.01

± 0.31 ± 0.78 ± 0.25 ± 0.07 -+ 0.10

177 the concent rat i on of a p o m o r p h i n e in brain. Thus in control animals, despite a rapid decrease associated with ASB was remarkably stable between 5 and 50 min. The peak activity was present between 60 and 75 min. In experimental rats the intensity of ASB was stable between 15 and 100 min; there was no clearly identifiable peak phase of activity. The onset and duration of ASB paralleled the presence of a p o m o r p h i n e in brain.

3.3. Comparison of control groups The control animals in the 2 experiments differed in age and their response.to apomorphine. The baseline counts recorded were higher in the older rats ( p < 0.05--0.01) which may in part have been related to their greater b o d y weight. The duration of ASB was longer in the older animals (p < 0.05). The intensity of m o t o r activity associated with ASB was not significantly different for the first 55 min but thereafter was significantly higher in the older animals (p < 0.001). The concentrations of a p o m o r p h i n e in brain were significantly higher in the younger animals at 5 ( p < 0 . 0 0 1 ) , 10 and 20 min ( p < 0.01). 4. Discussion A pom orphi ne is a dopamine-receptor agon±st (Sourkes and Lal, 1975). Following treatm ent with reserpine the intensity and duration of ASB in the rat is enhanced {Rotrosen et al., 1972), and the threshold doses of apomorphine needed to induce agression (McKenzie, 1971) and turning behaviour in the rat with a unilateral lesion of the nigrostriatal pathway (Ungerstedt, 1971) are decreased. Alterations in behavioural response to a p o m o r p h i n e have also been observed 2--28 days after withdrawal from chronic t r e a t m e n t (2--13 weeks) with chlorpromazine or haloperidol. Thus m any activities induced by apom orphi ne: cage-climing in mice (Von Voigtlander et al., 1975), s t e r e o t y p e d behaviour in the rat {Smith and Davis, 1975); Tarsy and Baldes-

178 sarini, 1973) and guinea pig (Klawans and Rubovits, 1972}, and aggression in the rat (Gianutsos et al., 1974), are enhanced after a course of treatment with a neuroleptic. These observations have been taken as evidence that treatment with neuroleptics results in increased dopamine receptor sensitivity. Such a mechanism is believed responsible for the development of tardive dyskinesia in patients treated with prolonged neuroleptic therapy (Klawans and Rubovits, 1972) though recent work questions this hypothesis (Ettigi et al., 1976). Interpretations of m a n y of the behavioural observations in animals are limited by the fact that brain apomorphine concentrations were not measured except in the study by Von Voigtlander et al. (1975). The latter investigators assayed apomorphine only at the time of peak apomorphine effect (10 min) in mice withdrawn from haloperidol. Our data provide some additional evidence to support the view that the enhancement of apomorphine effects by prior t r e a t m e n t with reserpine or chlorpromazine is not related to alterations in the biodisposition of apomorphine. Reserpine and withdrawal from chlorpromazine treatment enhanced the development of ASB in rats administered a threshold dose of apomorphine. Although the concentration of apomorphine was significantly higher in reserpinepretreated rats at 5 min compared with controls the peak concentrations in the 2 groups were similar. It is, of course, possible that with a dose of 0.25 mg/kg of apomorphine adequate brain concentrations of apomorphine are present for arequisite period of time to induce ASB in reserpine-pretreated rats but not in controls. Following 10 mg/kg apomorphine there was a significant terminal enhancement of m o t o r activity associated with ASB in reserpine- and chlorpromazine-pretreated rats compared with controls. The significant enhancement is seen independent of the greater body weight of the controls. This enhancement could not be accounted for by differences in

A.L. SYMES ET AL. brain apomorphine concentrations in experimental and control rats, but may be explained by the presence of supersensitive dopamine receptors in experimental animals. The relatively constant intensity of motor activity associated with ASB during the first 10--55 min, despite the marked decline in brain apomorphine concentrations, suggests that above a certain concentration of brain apomorphine ASB is maximally stimulated. When the concentration falls below a critical level animals with supersensitive dopamine receptors may continue to show intense ASB, but the same brain concentration of apomorphine in controls may be insufficient to maintain the same intensity of ASB. The very rapid decline in brain apomorphine concentration below the necessary threshold to maintain ASB may account for the absence of a detectable prolongation of ASB even in the presence of increased dopamine receptor sensitivity. The interpretation of our data is complicated by 2 obsercations. In the chlorpromazine experiment following injection of apomorphine 10 mg/kg ASB reached a peak activity in controls just prior to the termination of ASB. This late peak activity was significantly higher than in experimental animals. The reason for this is probably due to the greater mass of the control animals. It is also possible that this late onset in peak activity in the controls represents chance variation in intensity. 4 of the 11 reserpine-pretreated rats receiving 10 mg/kg apomorphine failed to develop ASB. The incidence of non-responders, however, was not significantly greater than in controls and is in keeping with our previous work which has shown that a certain percentage of rats fail to develop ASB with this dose of apomorphine (Lal and Sourkes, 1973}. More recently, Jackson et al. {1975) have provided good evidence that treatment with a neuroleptic enhances dopamine-receptor sensitivity by their demonstration that the direct application of dopamine to the striatum of rats withdrawn from penfluridol treatment enhances the development of stereotyped behaviour.

BRAIN APOMORPHINE CONCENTRATIONS Acknowledgements This work was supported by grants from the Medical Research Council of Canada, le Conseil de la Recherche en Sant6 du Qu6bec, and the George W. Stairs Memorial Fund of McGill University. Additional support was received from Merck-Frosst Laboratories, Kirkland, Quebec. D. Tsang was a fellow o f the Conseil de la Recherche en Sant6 du Qu6bec during the course of this work. References Ettigi, P., N.P.V. Nair, S. Lal, P. Cervantes and H. Guyda, 1976, Effect of apomorphine on growth hormone and prolactin secretion in schizophrenic patients with or without oral dyskinesia withdrawn from chronic neuroleptic therapy, J. Neurol. Neurosurg. Psychiat. 3 9 , 8 7 0 . Gianutsos, G., R.B. Drawbaugh, M.P. Hynes and H. Lal, 1974, Behavioural evidence for dopaminergic supersensitivity after chronic haloperidol, Life Sci. 14,887. Jackson, D.M., N.-E. And6n, J. Engel and S. Liljequist, 1975, The effect of longterm penfluridol treatment on the sensitivity of the dopamine receptors in the nucleus accumbens and in the corpus striaturn, Psychopharmacologia 4 5 , 1 5 1 . Klawans, H.L. and R. Rubovits, 1972, An experimental model of tardive dyskinesia, J. Neural Transm. 33,235.

179 Lal, S. and T.L. Sourkes, 1973, Ontogeny of stereotyped behaviour induced by apomorphine and amphetamine in the rat, Arch. Intern. Pharmacodyn. Therap. 202, 171. McKenzie, G.M., 1971, Apomorphine-induced aggression in the rat, Brain Res. 34,323. Rotrosen, J., B.M. Angrist, M.B. Wallach and S. Gershon, 1972, Absence of serotonergic influence on apomorphine-induced stereotypy, European J. Pharmacol. 20,133. Smith, R.C. and J.M. Davis, 1975, Behavioral supersensitivity to apomorphine and amphetamine after chronic high dose haloperidol treatment, Psychopharmacol. Commun. 1 , 2 8 5 . Sourkes, T.L. and S. Lal, 1975, Apomorphine and its relation to dopamine in the nervous system, Advan. Neurochem. 1,247. Symes, A.L., S. Lal and T.L. Sourkes, 1975, Effect of catechol-O-methyltransferase inhibitors on brain apomorphine levels and stereotyped behaviour in the rat, J. Pharm. Pharmacol. 27,947. Tarsy, D. and R.J. Baldessarini, 1973, Pharmacologically induced behavioural supersensitivity to apomorphine, Nature (London) 245,262. Ungerstedt, U., 1971, Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigrostriatal dopamine system, Acta Physiol. Scand. Suppl. 367, 69. Von Voigtlander, P.F., E.G. Losey and H.J. Triezenberg, 1975, Increased sensitivity to dopaminergic agents after chronic neuroleptic treatment, J. Pharmacol. Exptl. Therap. 193, 88.