Inhibition and potentiation of apomorphine-induced hypermotility in rats by neuroleptics

European Journal of Pharmacology, 36 (1976) 385--393

385

© North-Holland Publishing Company, Amsterdam -- Printed in The Netherlands

INHIBITION AND POTENTIATION OF APOMORPHINE-INDUCED HYPERMOTILITY IN RATS BY NEUROLEPTICS JORGEN BUUS LASSEN

Department of Pharmacology, A/S Ferrosan, Sydmarken 1--5, DK-2860 Soeborg, Denmark Received 10 October 1975, revised MS received 28 November 1975, accepted 16 December 1975

J. BUUS LASSEN, Inhibition and potentiation of apomorphine-induced hypermotility in rats by neuroleptics, European J. Pharmacol. 36 (1976) 385--393. The effect of apomorphine (ap) was investigated in rats kept in a familiar cage; 0.25--5 mg/kg s.c. produced a short-lasting, abnormal hypermotility consisting mainly of locomotion and sniffing without grooming. Ap was administered to rats pretreated s.c. with various drugs. Ap hypermotility was antagonized by 12 neuroleptics from different chemical groups. The ap inhibitory effect of 5 neuroleptics was decreased when the interval between pretreatment and ap administration was increased from 0.5 to 4 hr. Clozapine was the only neuroleptic showing no inhibition but potentiation at 4 hr. Mepazine, a phenothiazine lacking anti psychotic effects, as well as the NA receptor blockers aceperone and phenoxybenzamine, did not inhibit ap hypermotility. Ap was also given 24 hr after haloperidol and clozapine. At this time both neuroleptics showed ap potentiation. The ap inhibition and potentiation after a single administration of the neuroleptics is presumably due to selective blockade and subsequent supersensitivity of some DA receptors. Neuroleptics

Apomorphine

Dopamine

1. Introduction In rats apomorphine (ap) produces stereotyped licking and gnawing (Amsler, 1923; Janssen et at., 1960, 1965; Ernst, 1965, 1967), which probably is dependent on direct stimulation of dopamine (DA) receptors (Ernst and Smelik, 1966; Ernst, 1967; And~n et al., 1967). Most neuroleptics inhibit ap-induced gnawing (Janssen et al., 1965). The therapeutic antipsychotic effects of neuroleptics may also be dependent on DA receptor blockade (Munkvad et al., 1968; And~n et al., 1970). However, clozapine (Stille et al., 1971) and thioridazine (Janssen et al., 1965) do not inhibit ap gnawing. Both clozapine (Gross and Langener, 1966, 1970; Berewski et al., 1969; Angst et al., 1971a,b; De Maio, 1972; Ionescu et al., 1973) and thioridazine (Waldrup et al., 1961; Cole et al., 1964; Chien and DiMascio, 1961; Petrides et al., 1973; Bowers, 1975} have been reported to exert antipsychotic ef-

Hypermotility

fects with only minor extrapyramidal side effects. In this laboratory, a small dose of ap administered to rats kept in a familiar cage was found to produce an abnormal hypermotility, which was inhibited by some neuroleptics including clozapine (Buus Lassen, 1974a). Later it was found that this effect of ap was potentiated when ap was given 24 hr after the neuroleptics (Buus Lassen, 1975a). In the present communication the interaction between different neuroleptics and ap using various treatment intervals is described.

2. Materials and methods 2.1. Substances

Phenoxybenzamine, apomorphine and neuroleptics with the exception of clozapine, spiramide and pimozide were given as the

386

hydrochloride salts dissolved in physiological saline. Clozapine, spiramide and pimozide were dissolved by adding a few drops of hydrochloric acid, lactic acid and tartaric acid respectively (pH 3--5). The solutions were prepared just before administration, and were given s.c. in volumes of 1--5 ml/kg body weight. The doses refer to the forms mentioned.

2.2. Test procedure Using an Animex motimeter (Svensson and Thieme, 1969) the motility of rats kept in a familiar cage was measured as previously described in detail (Buus Lassen, 1974b). Female Wistar rats weighing 110--120 g were used. The behavior of the rats during the test period was observed. Each experimental group consisted of 4 rats. 4--20 identical experiments were performed with each treatment.

2. 3. Statistics Student's t-test was used for some comparisons. The activity of ap antagonists was evaluated using a regression line fitted to the points in a coordinate system, with log dose on the abscissa and the motility counts on the ordinate. This line was used for determination of the antagonist dose (EDs0), halving the difference between the motility of rats treated with saline alone and those treated with ap alone.

3. Results In a familiar cage the motility of rats in the daytime is very low. Injection of physiological saline induced a weak and transitory motility consisting of moderate locomotion, sniffing and various grooming movements. A qualitatively similar, but much more intense, behavioral pattern occurs when rats are transferred from a familiar to a novel cage. Ap 0.25 and 0.5 mg/kg produced a stronger, abnormal hypermotility, which was max-

J. B U U S L A S S E N c/30min

APOMORPHINE

4000

3000

t_!tt'

2000

1000

o.1 SAL I NE

o.2s

0.5

1~

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APOMORPHINE

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Fig. 1. Motility of rats after s.c. injection of physiological saline (10 groups) and ap (10 groups/dose). The columns indicate m o t i l i t y counts as mean -+ SD. The motility of ap-treated groups was c o m p a r e d with that of saline-treated controls, p values are shown at the b o t t o m of the columns.

imal during the first 30 min after the injection. A dose--response curve for this period is shown in fig. 1 : 0 . 1 mg/kg was inactive, 0.25--2 mg/kg induced a dose dependent increase in motility and 5 mg/kg produced no further increase above that produced by 2 mg/ kg. The ap-induced hypermotility consisted mainly of continuous rapid movements and sniffing on the b o t t o m of the cage with grooming totally absent. Occasionally, rearing on the hindlegs with simultaneous licking of the cage walls was observed more frequently at the highest doses. 30--40 min after the ap injection the .behavior changed. Periods of moderate locomotion and rest alternated, the sniffing became more varied and grooming spells appeared. After 60 min almost continuous rest was observed. The effect of ap was investigated after pretreatment with neurolpptics from several chemical groups. All the neuroleptics tested strongly inhibited the continuous, abnormal

INTERACTIONS OF NEUROLEPTICS WITH APOMORPHINE

387

between pretreatment and ap administration was increased from 0.5 to 4 hr. Clozapine was the only substance showing no inhibition but potentiation at 4 hr. Mepazine, a phenothiazine reported to have no antipsychotic effect, as well as the noradrenaline (NA) receptor blockers, aceperone and phenoxybenzamine, were inactive in doses up to 10 mg/kg. Both pharmacologically and clinically, haloperidol and clozapine are regarded as neuroleptics of quite different types (Bfirki et al.,

hypermotility during the first 30 min, whereas the more normal motility during the next 30 min was less affected. Table 1 shows doses (ED s 0 ) giving a 50% inhibition of hypermotility produced by 0.5 mg/kg ap. Phenothiazines, thiaxanthenes, butyrophenones, the diphenylbutylpiperidine pimozide and the dibenzoazepine clozapine antagonized ap hypermotility. 5 of the neuroleptics were given at various times before ap. The ap inhibition of these drugs decreased when the time interval

TABLE1 Antagonism of ap-induced hypermotility by different test drugs. Several doses of each drug (4 groups/dose) were administered 0.5, 2 or 4 hr before ap 0.5 mg/kg s.c. As described in Materials and methods, the motility count 0--30 rain after ap injection was used for determination of doses (EDs 0 ) giving 50% inhibition. Test drugs

Chlorpromazine Thioridazine Perphenazine Fluphenazine Trifluoperazine Chlorprotixen ~-Flupenthixol ~-Flupenthixol Haloperidol Melperone * Spiramide

EDs0 (95% confidence limits) (mg/kg) 0.5 hr

2 hr

4 hr

0.43 (0.25--0.71) 0.63 (0.43--0.91) 0.02 (0.012--0.033) 0.04 (0.03--0.06) 0.08 (0.034--0.19) 0.19 (0.16--0.24) 0.06 (0.03--0.11) 15.5 (7.7--31) 0.006 (0.005--0.008) 0.44 (0.35--0.55) 0.024 (0.015--0.039)

1.2 (0.9--1.6) 5.2 (3.1--8.6)

1.0 (0.6--1.4) 4.0 (2.5--6.5)

0.03 (0.02--0.05) 7.5 (2.2--26.1)

0.11 (0.075--0.16) 11.9 (7.4--18.9)

Pimozide Clozapine Mepazine Aceperone Phenoxybenzamine

2.3 (1.55--3.5) > 10 > 10

2.5 (1.5--3.5) > 10

* Previously methylperone. ** No inhibition but potentiation at 1, 2 and 5 mg/kg.

0.049 (0.032--0.075) >10 **

388

J. B U U S L A S S E N

1975). The interaction between these two neuroleptics and ap was studied using various doses of neuroleptic and ap (figs. 2, 3). Haloperidol 0.02--0.5 mg/kg and clozapine 2.5-10 mg/kg inhibited the hypermotility produced by ap 0.25--5 mg/kg. When the dose of ap was increased, a higher dose of neuroleptic was required to obtain inhibition. Haloperidol 0.5 mg/kg produced a more complete inhibition of ap than did clozapine 10 mg/kg, and clozapine 20 mg/kg produced no further inhibition. The effect of haloperidol (0.1 and 0.5 mg/

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Fig. 3. The effect o f ap alone and clozapine (cloz) + ap o n the m o t i l i t y o f rats. A p alone was given s.c. to 10 groups/dose. The same dose o f ap was administered to rats pretreated 30 rain before w i t h cloz 2 . 5 - - 2 0 m g / k g (4 groups/dose). The m e a n m o t i l i t y c o u n t s 0 - - 3 0 min after ap-injection are s h o w n in the figure. The m o t i l i t y o f groups receiving cloz + ap was c o m p a r e d w i t h the m o t i l i t y o f groups receiving the same dose o f ap alone. The p values were: cloz, 2.5 : 0.01 < p < 0.1; cloz, 5.0 : 0.001 < p < 0 . 1 ; c l o z , 10.0 : p < 0.001; cloz, 20.0 : p < 0.001.

HAL 0.5 ÷ AP

0.25

0.5

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Fig. 2. The effect o f ap alone and haloperidol (hal) + ap on t h e m o t i l i t y o f rats. A p alone was given s.c. to 10 groups/dose. The same dose o f ap was administered to rats pretreated 30 min before w i t h hal 0.02--0.5 m g / k g (4 groups/dose). The m e a n m o t i l i t y c o u n t s 0 - - 3 0 rain after ap injection are s h o w n in the figure. The m o t i l i t y o f groups receiving hal + ap was compared w i t h the m o t i l i t y o f groups receiving the same dose o f ap alone, p values were: Hal, 0.02 : 0.01 < p < 0 . 1 ; h a l , 0.05 : 0.001 < p < 0 . 1 ; h a l , 0.1 : 0.001 < p < 0.01; hal, 0.5 : p < 0.001.

kg) and of clozapine (10 and 20 mg/kg) alone was investigated in the same test situation by giving physiological saline instead of ap (fig. 4). Haloperidol decreased motility compared with saline-treated controls. At 0.5 mg/kg the rats were sitting quietly most of the time. Haloperidol-treated rats rested separated from each other in contrast to the saline-treated controls which rested together in one group. Clozapine did not alter motility, but the appearance of the rats was changed: clozapinetreated rats exhibited hunched back posture, abnormal tripping movements and a rather

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Fig. 4. T h e e f f e c t o f h a l o p e r i d o l a n d c l o z a p i n e a l o n e o n t h e m o t i l i t y o f rats. T h e m o t i l i t y was m e a s u r e d 0 - - 3 0 m i n a f t e r s.c. i n j e c t i o n o f saline ( 1 0 groups), h a l o p e r i d o l (4 g r o u p s / d o s e ) a n d c l o z a p i n e (4 g r o u p s / dose). T h e c o l u m n s i n d i c a t e m e a n -+ SD. T h e motilit y o f h a l o p e r i d o l - a n d c l o z a p i n e - t r e a t e d groups was c o m p a r e d w i t h t h e m o t i l i t y o f saline-treated c o n t r o l s . p values are s h o w n at t h e b o t t o m o f t h e c o l u m n s .

c/30min

i

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Fig. 6. T h e e f f e c t o f ap 0.5 m g / k g s.c. o n t h e m o t i l i t y of rats 24 h r a f t e r p r e t r e a t m e n t w i t h h a l o p e r i d o l 0 . 0 0 5 - - 2 . 0 m g / k g s.c. A p a l o n e was given to 10 g r o u p s a n d h a l o p e r i d o l to 4 g r o u p s / d o s e . T h e motilit y o f g r o u p s receiving h a l o p e r i d o l + ap was c o m p a r e d w i t h t h a t o f groups receiving ap alone, p values are s h o w n at t h e b o t t o m of t h e c o l u m n s .

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Fig. 5. T h e e f f e c t o f ap 0.1 m g / k g s.c. o n t h e m o t i l i t y of rats 24 h r a f t e r p r e t r e a t m e n t w i t h h a l o p e r i d o l 0 . 0 0 5 - - 2 . 0 m g / k g s.c. A p a l o n e was given t o 10 g r o u p s a n d h a l o p e r i d o l t o 4 g r o u p s / d o s e . T h e motilit y o f g r o u p s receiving h a l o p e r i d o l + ap was c o m p a r e d w i t h t h a t o f groups receiving a p alone, p values are shown at the bottom of the columns.

o., Apomorphine I mg/kg

Fig. 7. T h e e f f e c t o f ap 0.1 m g / k g s.c. o n t h e m o t i l i t y of rats 24 h r a f t e r p r e t r e a t m e n t w i t h clozapine 1.0-50.0 m g / k g s.c. A p a l o n e was given t o 10 g r o u p s a n d c l o z a p i n e t o 4 g r o u p s / d o s e . T h e m o t i l i t y of g r o u p s receiving c l o z a p i n e + ap was c o m p a r e d w i t h t h a t o f g r o u p s receiving a p alone, p values are s h o w n at t h e bottom of the columns.

390

J. B U U S L A S S E N

high frequency of grooming with forelegs but no grooming with the head and hindlegs, which was seen in the controls. Ap was also given 24 hr after haloperidol and clozapine. Ap, 0.1 mg/kg, which is inactive alone (fig. 1), produced hypermotility when administered 24 hr after haloperidol 0.005--1 mg/kg but not after haloperidol 2 mg/kg (fig. 5). The effect of ap, 0.5 mg/kg, which when given alone produced about half maximal hypermotility (fig. 1), was enhanced by haloperidol 0.02--2 mg/kg (fig. 6). Similar experiments were performed with clozapine and ap. Fig. 7 shows that clozapine 2.5--10 mg/kg but not 20--50 mg/kg potentiated ap (0.1 mg/kg). Ap, 0.5 mg/kg, was enhanced by clozapine 5--20 mg/kg but not by clozapine. 50 mg/kg (fig. 8).

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Fig. 8. T h e e f f e c t o f ap 0.5 m g / k g s.c. o n the motility o f rats 24 h r a f t e r p r e t r e a t m e n t w i t h c l o z a p i n e 1 . 0 - 50.0 m g / k g s.c. Ap a l o n e was given to 10 groups a n d c l o z a p i n e t o 4 g r o u p s / d o s e . T h e m o t i l i t y o f groups receiving c l o z a p i n e + ap was c o m p a r e d w i t h t h a t o f groups receiving a p alone, p values are s h o w n at the bottom of the columns.

4. Discussion The present investigation~clearly shows that various types of neuroleptics first inhibit and later increase ap-induced hypermotility in rats. The hypermotility produced by ap 0.5 mg was antagonized by 12 neuroleptics from different chemical groups but not by mepazine, a phenothiazine lacking antipsychotic effect, or by the NA-receptor blockers aceperone and phenoxybenzamine (Meek and Neff, 1973; Braestrup, 1973). Phenoxybenzamine has been found to partially antagonize the hypermotility produced by ap 1--1.25 mg/kg (Maj et al., 1974) indicating that higher doses of ap may influence noradrenergic systems. As in other tests for neuroleptics (MOiler Nielsen et al., 1973) a-flupenthixol was found to be much more active than ~-flupenthixol. Apinduced hypermotility in rats is not inhibited by reserpine or a-methyl-p-tyrosine (Maj et al., 1972, 1973) indicating that ap hypermotility like ap-induced gnawing, is dependent on direct stimulation of DA receptors. Clozapine and thioridazine inhibit ap hypermotility in rats (Maj et al., 1974; present results) but not ap gnawing in rats (Janssen et al., 1965; Stille et al., 1971) suggesting a selective blockade of one DA receptor type. The DA neurones in the zona compacta of the substantia nigra (A9) project to the caudate nucleus, while ventral tegmental DA neurones (A10) project to the nucleus accumbens, olfactory tubercles and other limbic forebrain structures (DahlstrSm and Fuxe, 1964; Ungerstedt, 1971; HSkfelt et al., 1974; Fuxe et al., 1974; Lindvall et al., 1974). Antipsychotic drugs producing a high incidence of extrapyramidal side effects (e.g. haloperidol, chlorpromazine and perphenazine) increase the baseline firing rate of A9 neurones while clozapine and thioridazine lack this effect. d-Amphetamine depresses the firing of DA neurones and this effect is reversed by neuroleptics including clozapine and thioridazine. It has been suggested that the antipsychotic effect of neuroleptics may be related to their

I N T E R A C T I O N S O F N E U R O L E P T I C S WITH A P O M O R P H I N E

effect on the A10 system and the extrapyramidal side effects to the action on A9 neurones (Bunney et al., 1973; Bunney and Aghajanian, 1974). Ap-induced hypermotility in rats may be mediated by a more selective activation of limbic DA receptors than those involved in the gnawing response. The locomotor stimulant effect of ap 0.1--1 mg/kg in rats was enhanced by a selective (6-hydroxydopamine) lesion of the nucleus accumbens presumably due to supersensitive mesolimbic DA receptors (Iversen et al., 1975). Injection of DA into the nucleus accumbens of nialamide-pretreated rats results in hypermotility (Pijnenburg et al., 1975), which can also be produced by the cyclic DA analogue, 2-amino-6,7-dihydroxy-l,2- 3,4-tetrahydronaphthalene (ADTN), injected bilaterally into the nucleus accumbens (Elkhawad and Woodruff, 1975). Withdrawal after prolonged treatment with various neuroleptics increased the sensitivity to ap-induced stereotyped gnawing (Schelkunov, 1967; Asper et al., 1973; M~ller Nielsen et al., 1974; Tarsy and Baldessarini, 1974; Gianutsos et al., 1974). This ap potentiation is presumably caused by supersensitivity of striatal DA receptors. However, withdrawal after 1 week of treatment with clozapine did not potentiate the ap-induced gnawing response or the turning response in rats with unilateral striatal lesions (Sayers et al., 1975). In the present experiments, potentiation of ap hypermotility was found both 4 and 24 hr after a single administration of clozapine. This apparent discrepancy may be due to the different ap-induced responses studied. The receptors involved in mediation of ap-induced hypermotility are blocked by clozapine and therefore supersensitivity appears subsequently. The gnawing and the circling responses were ]3either inhibited nor potentiated (Sayers et al., 1975) suggesting that supersensitivity can only arise after a receptor blockade. The ap potentiation by clozapine was dose dependent; after 4 hr it was observed at 1--5 mg/kg and after 24 hr of 2.5--20 mg/kg, higher doses did not potentiate ap. The substance 4,a
391

77/77) has been found to produce in rats a hypermotility characterized by locomotion and high grooming frequency. This behavioral effect of H 77/77 is antagonized by blockers of NA synthesis (FLA 63) and NA receptors (aceperone and phenoxybenzamine) as well as by very low doses of clozapine indicating that NA release is involved in the mediation of H 77/77-induced hypermotility and that clozapine is a potent NA receptor blocker (Buus Lassen, 1974c, 1975b). When H 77/77 was administered 24 hr after clozapine no enhanced hypermotility was found (unpublished results), therefore induction of supersensitive NA receptors does not seem to be involved in the enhanced ap-induced hypermotility found 24 hr after clozapine. Acknowledgements The helpful suggestions of Dr. R. Squires and the skilful technical assistance of Mrs. A.L. Svarer, Mrs. S. Bonde and Miss L. Rostrup are gratefully acknowledged. The author also wishes to thank Sandoz-Wander Ltd., Lundbeck & Co. Ltd., Janssen Pharmaceutica, Rhone-Poulenc and Smith, Kline & French for generous gifts of drugs.

References Amsler, C., 1923, Beitr~/ge zur Pharmakologie des Gehirns, Naunyn-Schmiedeb. Arch. Exptl. Pathol. Pharmakol. 97, 1. And6n, N.-E., A. Rubenson, K. Fuxe and T. H&kfelt, 1967, Evidence for doparnine receptor stimulation by apomorphine, J. Pharm. Pharmacol. 19, 627. And6n, N.-E., G. Bartholini, H. Corrodi, B. Csillik, E. De Robertis, A. Dresse, K. Fuxe, M.A. Gerebtzoff, J. Glowinski, E. Hansson, T. HSkfelt, J. Renson and B.E. Roos, 1970, Histological and molecular biochemistry. The neuroleptics, Mod. Probl. Pharmacopsychiat. 5, 1. Angst, J., U. Jaenieke, A. Padrutt and C. Scharfetter, 1971, Ergebnisse eines Doppelblindversuches yon HF 1854 (8-Chlor-ll-(4-met hyl-l-piperazinyl)5H-dibenzo(b,e)) (1,4(diazepin)) im Vergleich zu Levomepromazin, Pharmakopsychiat. 4, 192. Angst, J., D. Bente, P. Berner, H. Heimann, H. Helmchen and H. Hippius, 1971, Das klinische Wirkungsbild yon Clozapin, Pharmakopsychiat. 4, 201.

392 Asper, H., M. Baggiolini, H.R. Bfirki, H. Lauener, W. Rueh and G. Stille, 1973, Tolerance phenomena with neurolepties catalepsy, apomorphine stereotypies and striatal dopamine metabolism in the rat after single and repeated administration of loxapine and haloperidol, European J. Pharmaeol. 22, 287. Berzewski, H. yon, H. Helmchen, H. Hippius, H. Hoffmann and S. Kanowski, 1969, Das klinische Wirkungsspektrum eines neuen DibenzodiazepinDerivates, Arzneim. Forsch. 19, 495. Bowers, M.B., 1975, Thioridazine: Central dopamine turnover and clinical effects of antipsychotic drugs, Clin. Pharmacol. Therap. 17, 73. Braestrup, C., 1974, Effects of phenoxybenzamine aceperone and clonidine on the level of 3-methoxy-4-hydroxyphenylglycol (MOPEG) in rat brain, J. Pharm. Pharmacol. 26, 139. Bunney, B.S., J.R. Walters, R.H. Roth and G.K. Aghajanian, 1973, Dopaminergic neurons: Effect of antipsychotic drugs and amphetamine on single cell activity, J. Pharmacol. Exptl. Therap. 185, 560. Bunney, B.S. and G.K. Aghajanian, !974, Differentiation between neuroleptic antipsychotic properties and side effects by subgroups of dopaminergic neurons, Psychopharmacol. Bull. 10, 17. Buus Lassen, J., 1974a, Evidence for noradrenaline (NA)- and dopamine (DA)-receptor blockade by clozapine, J. Pharmacol. (Paris) 5, Suppl. 1, 14. Buus Lassen, J., 1974b, The effect of p-chloroamphetamine on motility in rats after inhibition of monoamine synthesis, storage, uptake and receptor interaction, Psychopharmacologia (Berlin) 34, 243. Buus Lassen, J., 1974c, Evidence for a noradrenergic and dopaminergic mechanism in the hyperactivity produced by 4,a-dimethyl-m-tyramine (H 77/77) in rats, Psychopharmacologia (Berlin) 37,331. Buus Lassen, J., 1975a, Interactions of haloperidol and clozapine with the dopamine (DA)-receptor stimulant apomorphine, 6. Internat. Congr. Pharmacol. 20.-25.7. 1975, abstract nr. 1146. Buus Lassen, J., 1975b, Inhibition of 4,c~-dimethylm-tyramine (H 77/77)-induced hypermotility in rats by single and repeated administration of chlorpromazine, haloperidol, clozapine and thioridazine, Psychopharmacologia (Berlin) 43, 25. Biirki, H.R., E. Eichenberger, A.C. Sayers and T.G. White, 1975, Clozapine and the dopamine hypothesis of schizophrenia, a critical appraisal, Pharmakopsychiat. 8, 115. Cole, J.O., 1964, Phenothiazine treatment in acute schizophrenia, Arch. Gen. Psychiat. 10, 246. DahlstrSm, A. and K. Fuxe, 1964, Evidence for the existence of monoamine-containing neurons in the central nervous system, Acta Physiol. Scand. 62, Suppl. 232, 1.

J. BUUS LASSEN De Maio, D., 1972, Clozapine, a novel major tranquilizer, Arzneim. Forsch. 22, 919. DiMascio, A., L.L. Havens and J.E. Snell, 1961, A comparison of four phenothiazine derivatives: A preliminary report on the'assessment of chlorpromazine, promethazine, perphenazine, and trifluoperazine, in: Recent advances in biological psychiatry, Vol. III, ed. J. Wortis (Grune & Stratton, New York) p. 68. Elkhawad, A.O. and G.N. Woodruff, 1975, Studies on the behavioural pharmacology of a cyclic analogue of dopamine following its injection into the brains of conscious rats, Brit. J. Pharmacol. 65, 107. Ernst, A.M., 1965, Relation between the :action o f dopamine and apomorphine and their O-methylated derivates upon the C.N.S., Psychopharmacologia (Berlin) 7,391. Ernst, A.M., P.G. Smetik, 1966, Site of action of dopamine and apomorphine on compulsive gnawing behaviour in rats, Experientia 22, 837. Ernst, A.M., 1967, Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats, Psychopharmacologia (Berlin) 10, 316. Fuxe, K., T. H6kfelt, O. Johansson, G. Jonsson, P. Lidbrink and ~. Ljungdahl, 1974, The origin of the dopamine nerve terminals in limbic and frontal cortex. Evidence for meso-cortico dopamine neurons, Brain Res. 82,349. Gianutsos, G., R.B. Drawbaugh, M.D. Hynes and H. Lal, 1974, Behavioral evidence for dopaminergic supersensitivity after chronic haloperidol, Life Sci. 14, 887. Gross, H. yon and E. Langner, 1966, Das Wirkungsprofil eines chemisch neuartigen Breitbandneuroleptikums der Dibenzodiazepingruppe, Wien. Med. Wschr. 40, 814. Gross, H. von and E. Langner, 1970, Das Neuroleptikum 100--129 HF-1854 (Clozapin) in der Psychiatrie, Intern. Pharmacopsychiat. 4, 220. HSkfelt, T., K. Fuxe, O. Johansson and A. Ljungdahl, 1974, Pharmaco-histochemical evidence of the existence of dopamine nerve terminals in the limbic cortex, European J. Pharmacol. 25, 108. Ionescu, R., S.U. Nica, L. Oproiu, A. Niturad and B. Tudorache, 1973, Double-blind study in psychopathic behavior disorders (clozapine and pericyazinc), Pharmakopsychiat. 6, 294. Iversen, S.D., P.H. Kelly, R.J. Miller and P. Seviour, 1975, Amphetamine and apomorphine responses in the rat after lesion of mesolimbic or striatal dopamine neurones, Brit. J. Pharmacol. 54, 244P. Janssen, P.A.J., C.J.E. Niemegeers and A.H.M. Jageneau, 1960, Apomorphine-antagonism in rats, Arzneim. Forsch. 10, 1003. Janssen, P.A.J., C.J.E. Niemegeers and K.H.L. Schellekens, 1965, Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Arzneim. Forsch. 15, 104.

INTERACTIONS OF NEUROLEPTICS WITH APOMORPHINE Lindvall, O., A. BjSrklund, R.Y. Moore and U. Stenevi, 1974, Mesencephalic dopamine neurons projecting to neocortex, Brain Res. 81,325. Maj, J., M. Grabowska and L. Gajda, 1972, Effect of apomorphine on motility in rats, European J. Pharmacol. 17,208. Maj, J., H. Sowinska and L. Baran, 1973, Effects of amantadine, amphetamine and apomorphine on the locomotor activity in rats, Life Sci. 12, Part 1, 511. Maj, J., H. Sowinska, L. Baran and Z. Kapturkiewicz, 1974, The effects of clozapine, thioridazine and phenoxybenzamine on the action of drugs stimulating the central catecholamine receptors, Pol. J. Pharmacol. Pharm. 26, 437. Meek, J.L. and N.H. Neff, 1972, The rate of formation of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate in brain as an estimate of the rate of formation of norepinephrine, J. Pharmacol. Exptl. Therap. 184, 570. Munkvad, I., 1970, Neuroleptics in the treatment of schizophrenia. The Neuroleptics, Mod. Probl. Pharmacopsychiat. 5, 1. M¢ller Nielsen, I., V. Pedersen, M. Nymark, K.F. Franck, V. Boeck, B. Fjalland and A.V. Christensen, 1973, The comparative pharmacology of flupenthixol and some reference neuroleptics, Acta Pharmacol. Toxicol. 33, 353. M¢ller Nielsen, I., B. Fjalland, V. Pedersen and M. Nymark, 1974, Pharmacology of neuroleptics upon repeated administration, Psychopharmacologia (Berlin) 34, 95. Petrides, A., 1973, Thioridazine for newly admitted psychiatric patients, Curr. Therap. Res. 15, 116. Pijnenburg, A.J.J., W.M.M. Honig and J.M. Van Ros-

393

sum, 197 5, Effects of antagonists upon locomotor stimulation induced by injection of dopamine and noradrenaline into the nucleus accumbens of nialamide-pretreated rats, Psychopharmacologia (Berlin) 41, 175. Sayers, A.C., H.R. BiJrki, W. Ruch and H. Asper, 1975, Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine, Psychopharmacologia (Berlin) 41, 97. Schelkunov, E.L., 1967, Adrenergic effects of chronic administration of neuroleptics, Nature 214, 1210. Stille, G., H. Lauener and E. Eichenberger, 1971, The pharmacology of 8-chloro-11-(4-methyl-l-piperazinyl)-5H-dibenzo(b.e.)(1,4)diazepine (clozapine), Farmaco, Ed.Prat. 26,603. Svensson, T.H. and G. Thieme, 1969, An investigation of a new instrument to measure motor activity of small animals, Psychopharmacologia (Berlin) 14, 157. Tarsy, D. and R.J. Baldessarini, 1974, Behavioral supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines, Neuropharmacol. 13,927. Ungerstedt, U., 1971, Stereotaxic mapping of the monoamine pathways in the rat brain, Acta Physiol. Scand. Suppl. 367, 1. Waldrop, F.N., R.H. Robertson and A. Vourlekis, 1961, A comparison of the therapeutic and toxic effects of thioridazine and chlorpromazine in chronic schizophrenic patients, Comprehens. Psychiat. 2, 96.