European Journal of Pharmacology, 33 (1975) 301--312 © North-Holland Publishing Company, Amsterdam -- Printed in The Netherlands

NEUROLEPTIC ANTAGONISM OF DYSKINETIC PHENOMENA BRENDA COSTALL and ROBERT J. NAYLOR

Postgraduate School of Studies in Pharmacology, University of Bradford, Bradford, England (Received 23 September 1974, revised MS received 9 January 1975, accepted 6 June 1975)

B. COSTALL and R.J. NAYLOR, Neuroleptic antagonism of dyskinetic phenomena, European J. Pharmacol. 33 (1975) 301--312. The bilateral intrastriatal administration of dopamine to guinea pigs pretreated with nialamide-induced dyskir,esias characterised by gnawing, biting and licking reactions, acute twisting of the head and neck, whole body or head and neck rocking movements, and a hyperactive state. Hyperactivity was inhibited by the peripheral administration of large doses of many neuroleptic agents, e.g. haloperidol, fluphenazine, but only pimozide and oxiperomide inhibited the other forms of dyskinetic movements. This was not due to a peculiar depressant effect of these agents in the guinea pig since haloperidol was shown to be equipotent to oxiperomide and of greater potency than pimozide both in causing catalepsy and antagonising amphetamine stereotypy. The specificity of the antidyskinetic abilities of oxiperomide and pimozide was emphasised by the inactivity of a large number of typical neuroleptics (AHR2277, AHR2244, benperidol, clothiapine, fluphenazine, methiothepin, oxypertine, perphenazine, tetrabenazine), atypical neuroleptics (chlorprothixine, clozapine, sulpiride, thioridazine), m o t o r depressant agents (AY22,214, IB503, NPL82, YG19,256, phencyclidine, metoclopramide, sodium pentobarbitone), adrenergic blocking agents (aceperone, piperoxan, propranolol) and dopaminergic agonists (D-amphetamine, D145, methylphenidate, nomifensine, piribedil). Apomorphine was shown to reduce the intensity of the dyskinetic phenomena but the dosage was found to be critical. Results are interpreted in terms of two neostriatal dopaminergic mechanisms and discussed in relationship to clinical dyskinesias. Dyskinesias

Dopamine

Striatum

Neuroleptic agents

1. Introduction Tardive dyskinesias or persistent oral dyskinesias have emerged as a highly undesirable long-term effect of neuroleptic therapy (Uhrbrand and Faurbye, 1960; Crane, 1968). More recently, similar abnormal movements have been reported after L-dopa therapy (Barbeau et al., 1971). The treatment of these dyskinesias has remained empirical for the most effective amelioration is observed after neuroleptic treatment (Curran, 1973; Klawans, 1973; Gerlach et al., 1974). The experimental model of tardive dyskinesias suggested by Klawans and Rubovitz (1972) emphasises the basic contradiction: drug-induced (amphetamine) 'dyskinetic' phenomena can be specifically antagonised by

neuroleptic agents which in themselves can induce dyskinesias. However, using the intrastriatal injection technique we have recently demonstrated the importance of neostriatal dopaminergic systems for the mediation of abnormal involuntary movements in the rat and guinea pig (Costall et al., 1974, 1975). Of the dyskinesias which develop in these species, the gnawing, biting and licking reactions appear to be superficially very similar to the oro-bucco-lingual dyskinesias which are highly characteristic of drug-induced dyskinesias in man (Marsden et al., 1974). The present study was designed to use these abnormal involuntary movements induced by intrastriatal dopamine as a model for investigating any action on abnormal movements.

302

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2. Materials and methods

2.1. Animals All studies utilised male Dunkin--Hartley (DHP/Lac) guinea pigs. These weighed 250-300 g for peripheral studies and 350--500 g at the time of operation.

2.2. Behavioural observations following peripheral drug administrations For observation and measurement of catalepsy guinea pigs were placed in individual perspex cages (25 cm × 15 cm and 15 cm high), equipped with a 10 cm high horizontal bar, in a sound-proofed, diffusely illuminated room maintained at a temperature of 21 + 1 ° C. Animals were placed in the observation/ testing cages 30 min before drug treatment to allow adaptation to the new environment. All observations were made between 08.00 am and 0.800 pm. Animals were tested for the presence of catalepsy by placing both front limbs over the horizontal bar, a cataleptic animal maintaining this position for a period of time dependent upon the degree of catalepsy. Animals were tested frequently after drug administration to determine the onset of catalepsy and the intensity of catalepsy was then measured at 15--30 min intervals t h r o u g h o u t the duration of the drug effect. In order to account for animals maintaining the imposed position for an infinite period of time the scoring

TABLE 1 Scoring system used for assessment of the intensity of catalepsy. Intensity (min)

Score

0 0.1-2.5 2.6-5.0 5.1-10.0 10.1-20.0 20.1-~

0 1 2 3 4 5

system shown in table 1 was adopted for estimation of the intensity of catalepsy. The stereotyped behaviour patterns induced in the guinea pig were found to be characterised almost exclusively by biting, gnawing or licking; generally, the low intensity components of stereotypy o b s e ~ e d in the rat (sniffing and repetitive head and limb movements) were n o t induced in the guinea pig. Stereotypy was, therefore, assessed on a simple system of 0 -- no biting, gnawing or licking; 1 -- periodic biting, gnawing or licking; 2 -- continuous biting, gnawing or licking. Assessments were made at 15 min intervals t h r o u g h o u t the duration of a drug effect. Values obtained both in the catalepsy and stereotypy tests were found to be sufficiently close to normal to allow the application of parametric statistics. The significance of druginduced changes in stereotypic and cataleptic intensity was assessed using the Student's ttest.

2.3. Intracerebral injection technique Stainless steel guide cannulae were constructed and implanted in the caudate--putamen as previously described for the rat (Costall and Naylor, 1974) excepting that the guinea pigs were anaesthetised with sodium pentobarbitone, 30 mg/kg i.p. Guide cannulae were implanted with the tips at a coordinate of Ant. 10.25, Vert. +5.6, Lat. +3.5 determined with respect to the zero of the Kopf stereotaxic instrument and with the incisor bar raised 5 mm. Injection cannulae were constructed to extend 1.5 mm b e y o n d the tip of the guide. Animals, first used 2--3 weeks after the operation, were manually restrained during the injection procedure in which dopamine, 100 pg, was administered intrastriatally in a volume of 1 pl over a 5 sec period from an Agla micrometer syringe. 55 sec were allowed for deposition of drug. Each guinea pig was used on a maximum of 5 occasions with 14 days allowed for recovery between each drug administration. The location of the guide cannulae was confirmed histologically upon

NEUROLEPTIC ANTAGONISMOF DYSKINESIAS

303

completion of the studies and found to be indistinguishable from those previously reported (Costall et al., 1975).

was prepared for intrastriatal administration immediately before use in nitrogen-bubbled distilled water neutralised with sodium bicarbonate. All other agents were administered by a peripheral route, apomorphine s.c. and the other drugs i.p. Doses were calculated as the base and administered in a volume of 1 ml/kg.

2.4. Assessment o f dyskinetic phenomena Dyskinesias were induced in nialamide pretreated guinea pigs (75 mg/kg i.p. 2 hr) by bilateral intrastriatal dopamine (100 pg in 1 gl). Characteristically, these involved gnawing/ biting reactions with occasional protrusion of the tongue with or without licking movements, and marked hyperactivity. Less frequently, acute twisting of the head and neck was periodically observed. These dyskinesias have been shown to be highly specific for dopamine and dopamine-like drugs (Costall et al., 1975). In addition, whole body rocking movements or head and neck jerks were apparent in some animals; these abnormal movements have been shown to represent nonspecific effects (Costall et al., 1975). More detailed and comprehensive descriptions are given in the text quoted. Generally, dyskinesias developed within 60--120 min of the dopamine administration and lasted for at least 6 hr. Experiments to determine the ability of various agents to antagonise the dyskinesias were carried out 3 hr after the dopamine injection. Visual observations of the effect of the drugs on the dyskinesias were classed as all or none. However, certain drug effects were selected for further quantification: the presence of the dyskinesias was assessed by placing the guinea pigs in perspex cages whose movements on rubber supports could be transmitted via a phonocartridge to a grass polygraph (Model 7B) recorder. The technique was essentially as described by Kelly and Naylor (1974) for the assessment of tremor. Further quantification of the hyperactivity was obtained by recording the number of interruptions of a light beam from a photocell attached to the perspex cage.

2.5. Drugs 2. 5.1. General Dopamine hydrochloride

(Koch--Light)

2.5.2. Neuroleptic agents AHR2277 [ 4 4p-fluorobenzoyl)-l-(3-[p-fluorobenzoyl]-propyl)-piperazinehydrochloride] (A.H. Robins), AHR2244[1-(3-p-acetyl-[omethoxyphenoxyl]-propyl)-4-(p-fluorobenzoyl)-piperidine hydrochloride] (A.H. Robins), benperidol (Janssen), methiothepin (R086837) (Roche), oxiperomide (Janssen), oxypertine (Sterling--Winthrop) and tetrabenazine (Roche) were dissolved in a minimum quantity of ascorbic acid made up to volume with distilled water, clothiapine (Wander), clozapine (Wander), perphenazine (Allen and Hanbury's) and sulpiride (Delagrange) in a minimum quantity of hydrochloric acid made up to volume with distilled water, haloperidol (Janssen) in 1% lactic acid, fluphenazine (Squibb) and thioridazine (Sandoz) in distilled water and chlorprothixene (Roche) and pimozide (Janssen) were prepared as aqueous suspensions in 2% carboxymethylcellulose. 2.5.3. Motor depressants AY22,214[(+)-(4a,13b-trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo(6,7)cyclohepta(1,2,3-de)pyrido(2,1-a)isoquinoline~hydrochloride] (Ayerst), 1B503 [4~3dimethylaminopropyliden-1)-9,10-dihydro-4H-benzo(4,5)cyclohepta( 1,2-b)thiophen hydrogen maleate] (Sandoz), metoclopramide monohydrochloride (Beechams), phencyclidine hydrochloride (Parke Davis) and YG1925614~l,2,3,4,9b,~etrahydro- 5-methyl-2H-indeno(1,2-c)pyridin-2butan0n mesilate] (Sandoz) were dissolved-in distilled water and NPL8216-chloro-4-(3-dimethylaminopropylidene)-2,3,9,1(~tetrahydro4H-benzo(4,5)cyclohepta(1,2-b)thiophen] (Sandoz) was prepared as an aqueous suspension in 2% carboxymethylcellulose. Sodium pentobarbitone was used in the injection form

304

B. C O S T A L L , R.J. N A Y L O R

prepared by the manufacturer (Abbott nembutal).

2.5.4. Adrenergic blocking agents Aceperone (Janssen) was dissolved in a minimum quantity of glacial acetic acid made up to volume with distilled water and piperoxan (Roche) and propranolol hydrochloride (I.C.I.) in distilled water.

methylphenidate hydrochloride (Ciba--Geigy), and piribedil [ET495, 1-(2"-pyrimidyl)-4-piperonyl-piperazine monomethanesulphonate ] (Servier) were dissolved in distilled water. Nomifensine (Hoe 984, 8-amino-2-methyl-4phenyl-l,2,3,4,-tetrahydroisoquinoline hydrogen maleate) was prepared in a minimum quantity of hydrochloric acid made up to volume with distilled water and apomorphine hydrochloride (Macfarlem Smith) in distilled water containing 0.1% sodium metabisulphite.

2.5.5. Minor tranquillisers Chlordiazepoxide hydrochloride (Roche) and Sch12679 (N-methyl-l-phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-3-benzazepine maleate) (Schering) were dissolved in distilled water and diazepam (Roche) was prepared as an aqueous suspension in 2% carboxymethylcellulose.

3.1. The induction of stereotyped behaviour by dopaminergic agonists

2.5.6. Dopam inergic agonists D 14 5 ( 1,3 - d i m e t hyl- 5-aminoadamantan) (Merz), D-amphetamine sulphate (Sigma),

Apomorphine, D-amphetamine, piribedil, methylphenidate and nomifensine each induced stereotyped biting, chewing or licking

3. Results

TABLE 2 S t e r e o t y p e d b e h a v i o u r i n d u c e d by d o p a m i n e r g i c agonists in t h e guinea pig. S t e r e o t y p e d b e h a v i o u r was assessed as 0 - - a b s e n t , 1 - - p e r i o d i c biting/gnawing/licking, 2 - - c o n t i n u o u s biting/ gnawing/licking. The d e v e l o p m e n t o f ataxia p r e c l u d e d t h e use o f higher doses o f D145. D o p a m i n e r g i c agonist

Apomorphine

D-amphetamine

Piribedil

Methylphenidate

Nomifensine

D145

Dose (mg/kg)

Stereotyped behaviour No. o f animals responding

Onset (min)

Intensity

Duration (min)

0.5 1 2 4 2.5 5 10 20 50 100 200 50 100 200 50 100 200 50

2/6 6/6 6/6 6/6 0/6 2/6 6/6 6/6 0/6 3/6 6/6 1/6 2/6 6/6 0/6 0/6 6/6 0/6

12--16 6--9 3--5 3--6 -36--49 30--45 20--22 -27--34 22--30 22 12--18 3--7 --11--21 --

1 1 2 2 0 1 1 2 0 1 1 1 2 2 0 0 2 0

21--38 31--36 32--44 39--54 -120+ 120+ 120+ -56--72 83--114 67 80--96 120+ --120+ --

I00

0/6

--

0

--

NEUROLEPTIC ANTAGONISM OF DYSKINESIAS Haloperidol

Oxiperomide

.125-25 "5 1

Fig. 1. treated scoring 16% of

2

-5

.125"25 "5 1

305

Pimozide

2

4

8

'5

1

2

4

8

16 32 4 m g / k g

Catalepsy induced by haloperidol, o x i p e r o m i d e and p i m o z i d e in normal guinea pigs [] and guinea pigs 2 hr previously with nialamide, 75 mg/kg i.p. ~. The intensity of catalepsy was assessed according to the system s h o w n in table 1. Each value is the mean of at least 6 determinations. Standard errors are less than the means.

by the neuroleptic agents in a dose-dependent manner, lower doses reducing the frequency of the biting responses whilst larger doses virtually abolished this response. Again, haloperidol and oxiperomide were shown to be approximately equipotent and more potent than pimozide (fig. 2). Pretreatment with nialamide reduced the antistereotypic effectiveness of all neuroleptic agents (p < 0.001). This pretreatment also enhanced the duration of the amphetamine effect.

in the guinea pig at doses indicated on table 2. D145, in doses up to 100 mg/kg, was without effect. It was noticeable that only D-amphetamine also caused marked hyperactivity.

3.2. Catalepsy and antagonism of stereotyped behaviour by neuroleptic agents Haloperidol, oxiperomide and pimozide each induced a dose-dependent cataleptic behaviour in the guinea pig. Haloperidol and oxiperomide were shown to be approximately equipotent, causing catalepsy at doses greater than 0.1 mg/kg. Pimozide was a less potent cataleptigen, the threshold being at 1 mg/kg. Pretreatment with nialamide enhanced the cataleptic abilities of haloperidol and pimozide (p < 0.01) but reduced that of oxiperomide (p < 0.001) (fig. 1). The continuous stereotyped biting response to 20 mg/kg D-amphetamine was antagonised Haloperidol

O "5 1

2

Oxiperomide

1

0

'5

1

2

3.3. Modification of dyskinetic phenomena by neuroleptic agents The oro-bucco-lingual (gnawing, biting, licking) and cervical (acute twisting of the head and neck) dyskinesias and the whole body or head and neck rocking movements induced by bilateral intrastriatal dopamine, 100 pg, were not modified by the peripheral Pimozide

1

O 4

8 16 32 m g / k g

Fig. 2. Antagonism by haloperidol, o x i p e r o m i d e and pimozide of the stereotyped behaviour induced by 20 mg/kg i.p. D - a m p h e t a m i n e in normal guinea pigs o and guinea pigs treated 2 hr previously with nialamide, 75 m g / k g i.p. , . The neuroleptic agents were administered 30 m i n before the amphetamine. S t e r e o t y p y is expressed as the % inhibition m a x i m u m score as assessed according to the system 0 -- no stereotypy, 1 - - periodic gnawing/bltlng/licking, 2 - - c o n t i n u o u s gnawing/biting/licking. Each value is the m e a n of at least 8 determinations. Standard errors are less than 21% of the means.

306

B. COSTALL, R.J. NAYLOR

TABLE 3 Modification of dyskinetic phenomena by neuroleptic agents. Oro-bucco-lingual (biting/gnawing/licking) and cervical (acute twisting of the head and neck) dyskinesias and dyskinesias characterised by whole body or head and neck rocking movements were induced by the bilateral intrastriatal administration of 100 pg (1 pl) dopamine to guinea pigs treated 2 hr previously with 75 mg/kg i.p. nialamide. The neuroleptic agents were administered 3 hr after the intrastriatal dopamine when dyskinesias were established. Neuroleptic agent

Dose (mg/kg i.p.)

Inhibition of dyskinesias No. of animals inhibited

Haloperidol Pimozide Oxiperomide

4 8 16 4

0/8 0/8 0/8 0/8

8

0/8

16

8/8

0.5 1 2 4

0/8 8/8 8/8 8/8

administration o f haloperidol even at doses representing eight times its m a x i m u m cataleptic p o t e n c y . However, b o t h pimozide and o x i p e r o m i d e inhibited all forms o f dyskinesia at doses approaching those which cause a m a x i m u m intensity catalepsy (table 3, fig. 1). The inability of haloperidol to inhibit the dyskinesias was e x t e n d e d to a large n u m b e r of other neuroleptic agents: A H R 2 2 7 7 , AHR2244, benperidol, clothiapine, fluphenazine, fluspirilene, m e t h i o t h e p i n , perphenazine (4-16 mg/kg i.p.), chl or pr ot hi xe ne , clozapine, o x y p e r t i n e , thioridazine (20--40 mg/kg), sulpiride (50--100 mg/kg) and tetrabenazine (16--64 mg/kg). However, larger doses of all these neuroleptic agents, including haloperidol, ox ip er o mid e and pimozide, invariably reduced or abolished the hyperactivity induced by intrastriatal d o p a m i ne (fig. 3).

3.4. Modification of dyskinetic phenomena by dopaminergic agonists S t e r e o t y p i c doses of D-amphetamine, piribedil, m e t h y l p h e n i d a t e and nomifensine failed to m o d i f y the dyskinesias induced by in-

Onset (min)

Duration (min)

-----

-----

-20--55

-3--5 3--7 5--8

-180+

-14--32 31--44 25--40

trastriatal dopamine. Using apom orphi ne, doses of 1--4 mg/kg s.c. were consistently shown to be ineffective against the dyskinesias although at 8 mg/kg the dyskinesias were reduced in intensity or abolished in 11/16 guinea pigs. These animals showed little or no biting and most became very quiet. However, the dose of a p o m o r p h i n e appeared very critical since the dyskinesias were inhibited in only 2/16 guinea pigs at 16 mg/kg s.c. apom orphi ne and, at this dose, the guinea pigs exhibited vigorous biting behaviour {fig. 4, see p. 3O8).

3.5. Modification of dyskinetic phenomena by motor depressants, minor tranquillisers and adrenergic blocking agents The dyskinesias induced by intrastriatal dopamine, with the e x c e p t i o n of hyperactivity, persisted in the presence of agents which depress m o t o r funct i on (IB503, Y G 19256, NPL82). Hyperactivity was inhibited at doses of 40 mg/kg i.p. Similarly, guinea pigs treated with 16 mg/kg phencyclidine or 10 mg/kg sodium p e n t o b a r b i t o n e became markedly depressed and even ataxic but cont i nued to

NEUROLEPTIC ANTAGONISM 200-

ments, but a t high doses all agents reduced or inhibited hyperactivity.

B,

s..

307

O F DYSKINESIAS

),150 -

| o

2

4

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IDo 0

2

4

8

4. Discussion

0

2

4

8 rng/kg halop,

5 tO IS 30 35 N $

Fig. 3. Effect of haloperidol on the hyperactivity induced by the bilateral intrastriatal administration of dopamine, 100 /~g to animals treated 2 hr previously with 75 mg/kg i.p. nialamide. Haloperidol was administered 3 hr after intrastriatal dopamine when hyperactivity was established. Hyperactivity was measured as the number of interruptions of a beam from a photocell attached to the observation cage and is expressed as the total number of counts during a 10 rain period. A. 0--10 rain, B. 10--20 rain and C. 170--180 min following the haloperidol !njection. Traces corresponding to each group of histograms are those obtained from a typical animal treated with 8 mg/kg haloperidol where hyperactivity is inhibited but other dyskinesias (oro-bucco-lingual/cervical/ whole body or head and neck r o c k i n g ) c o n t i n u e . Each dyskinetic movement was transmitted from an observation cage on rubber supports via a phonocartridge attached to the cage and connected to a Grass polygraph recorder.

demonstrate the oro-bucco-lingual and cervical dyskinesias and the whole body or head and neck rocking movements. Only when a guinea pig was anaesthetised with 15 mg/kg sodium pentobarbitone were the dyskinesias inhibited. The minor tranquillisers chlordiazepoxide, diazepam (10 mg/kg) or Sch 12679 (40 mg/kg), the a-blockers aceperone (20 mg/kg) and piperoxan (20 and 40 mg/kg) or the fl-blocker propranolol (20 and 40 mg/kg) all failed to reduce the intensity of the orobucco-lingual and cervical dyskinesias and the whole body or head and neck rocking move-

The induction of stereotyped behaviour and catalepsy in animals or the developement of oro-bucco-lingual dyskinesias or hypokinetic Parkinson-like effects in man have all been interpreted in terms of a modification of striatal dopaminergic activity (see reviews by Fog, 1972; Korczyn, 1972). Almost without exception it has been implicit in these interpretations that one is considering a single type of dopaminergic mechanism, stimulation producing the stereotypy/oro-bucco-lingual dyskinesias whereas a blockade will result in catalepsy/Parkinson-like effects. However, an important clinical observation made by Klawans (1973} is that drug-induced dyskinesias can develop in patients who have no evidence of drug-induced Parkinsonism. He hypothesised the existence of two types o f dopamine receptor to mediate the two effects and suggested that they are not equally susceptible to neuroleptic blockade. The present studies provide the first experimental evidence in support of this hypothesis. We have recently demonstrated that the abnormal involuntary movements of gnawing/ biting/licking and severe head and neck twisting, and the marked hyperactivity observed after the intrastriatal injection of dopamine are very specific for dopamine and dopaminelike agents (Costall et al., 1974, 1975). These effects are not observed after the injection of dopamine into areas around the striatum. Thus although the onset of the abnormal involuntary movements is delayed for approximately 60--90 min following intrastriatal injection, it is unlikely that this reflects the necessity to diffuse to tissue adjacent to the striatum. (We would emphasise that these studies do not, however, indicate that other dopamine mechanisms in other areas of the brain are ineffective to influence motor function.) The only abnormal involun-

A

B

C

i

+

5 min

10 min

N

15 rain

+:.++

,....

!+

~+, ~+, r~I1+T *

20 ~ n

5

10 15 20 25 30s

Fig. 4. E f f e c t o f a p o m o r p h i n e o n t h e dyskinesias i n d u c e d b y t h e bilateral i n t r a s t r i a t a l a d m i n i s t r a t i o n of d o p a m i n e , 100 pg t o a n i m a l s t r e a t e d 2 h r previously w i t h 75 m g / k g i.p. nialamide. A p o m o r p h i n e was a d m i n i s t e r e d 3 h r a f t e r i n t r a s t r i a t a l d o p a m i n e w h e n t h e dyskinesias were established. A, E f f e c t o f s o l v e n t , B, 8 m g / k g s.c. a p o m o r p h i n e causing a r e d u c t i o n in d y s k i n e t i c b e h a v i o u r or C, a b o l i s h i n g dyskinesias. E x a m p l e r e c o r d i n g s are s h o w n for effects o c c u r r i n g 5, 10, 15 a n d 20 rain a f t e r t h e a p o m o r p h i n e injection. R e c o r d i n g s were m a d e o n a Grass p o l y g r a p h c o n n e c t e d via a p h o n o c a r t r i d g e a t t a c h e d t o t h e a n i m a l cage o n r u b b e r s u p p o r t s . Generally, t h e high a m p l i t u d e r e s p o n s e s r e p r e s e n t e d w h o l e b o d y or h e a d a n d n e c k r o c k i n g m o v e m e n t s whilst t h e o r o - b u c c o lingual a n d cervical dyskinesias c o n s t i t u t e d t h e low i n t e n s i t y responses.

NEUROLEPTIC ANTAGONISM OF DYSKINESIAS tary movements shown in the above study to be induced at both striatal and extrastriatal sites of action were whole b o d y or head and neck rocking movements. These were of minor interest to the present study. Nevertheless, it is difficult to reconcile a latency of onset of 60--90 min with a hypothesis of a rapid and direct dopamine receptor stimulating effect, a problem c o m p o u n d e d by the essential prerequisite of a monoamine oxidase inhibitory pretreatment regime. Together, these two factors would suggest that intrastriatally administered dopamine must partially influence presynaptic mechanisms to induce abnormal involuntary movements. Within the obvious limits by which experimental data from small laboratory animals can be extrapolated to man, it is suggested that the gnawing/biting/licking reactions and the abnormal cervical movements induced b y intrastriatal dopamine in the guinea pig may result from the activation of a mechanism very similar to that involved with drug-induced oro-bucco-lingual dyskinesias observed in the clinic. The present studies show that neuroleptic agents can inhibit the d0pamineinduced hyperactivity in doses having no effect on either the oro-bucco-lingual or cervical dyskinesias. It is hypothesised that the dopaminergic mechanism mediating the hyperactivity in the guinea pig is analogous to the system normally opposing to akinesia in man and whose inhibition by neuroleptic agents results in a Parkinson-like syndrome (DA-1); a second mechanism (DA-2) mediates the orobucco-lingual dyskinesias in man and the gnawing etc. in the guinea pig and is shown to be more resistant to neuroleptic treatment. The acceptance of two different dopaminergic mechanisms would facilitate an understanding of clinical drug induced dyskinetic phenomena as follows. Many experienced clinicians have commented on the many similarities between the acute dyskinesias induced by L-dopa and the tardive dyskinesias induced by the neuroleptic drugs (see review by Marsden, 1974). We suggest that the dyskinesias induced by L-dopa

309 (Barbeau et al., 1971) or the recently introduced dopaminergic agonist piribedil (Chase, 1975; Emile et al., 1975; McDowell and Sweet, 1975) are due to an excessive stimulation of DA-2 mechanisms and that the tardive dyskinesias induced by neuroleptic agents (Klawans, 1973; Villeneuve et al., 1973; Marsden, 1974) are indirectly due to an activation of the same mechanism. After neuroleptic treatment there is a marked increase in the synthesis and release of dopamine. This may be attributed to an activation of feed back mechanisms resulting from pre- and/or postsynaptic dopamine receptor blockade (And~n et al., 1970; Sedvall, 1975), with an important effect on the DA-1 mechanism. The abnormal increase i n synthesis and release of dopamine may then influence the DA-2 mechanisms which are not normally subject to such a degree of stimulation and which are relatively resistant to neuroleptic blockade. Three further points must be considered. Firstly, it is a frequent clinical observation that withdrawal of neuroleptic therapy may precipitate or exacerbate dyskinesias (Klawans et al., 1970; Curran, 1973; Marsden, 1974). This indicates that neuroleptic agents must also exert some inhibitory activity on dyskinztic phenomena which may be a weak inhibitory effect on the DA-2 system or a more powerful antagonism of the DA-1 system, for removal of a neuroleptic effect from either system could reasonably be expected to exacerbate dyskinesias. Secondly the reduction in L-dopa or neuroleptic-induced tardive dyskinesias by increasing dosage of neuroleptic agent (Yahr, 1970, Kazametsuri et al., 1972; Marsden, 1974) may be attributed to a rather non-specific blockade of all dopamine systems including an inhibition of the DA-2 mechanism. Thirdly, it may be expected that stereotypic agents should exacerbate dyskinesias and this has been shown in the clinic (Fann et al., 1973) although some reports indicate that apomorphine and piribedil may reduce dyskinesias (Gessa et al., 1972; Chase, 1975). In the present model piribedil was without effect. Although an intermediate

310 dose of apomorphine reduced or abolished the dyskinesias, lower or higher doses were ineffective. It is conceivable that at a particular dose level the ability of apomorphine to decrease the synthesis of dopamine (Kehr, 1975) may contribute to an anti-dyskinetic effect although at higher doses the dopaminelike stimulant action predominates. The dyskinesias which persist in the absence of drug treatment indicate a basic functional change in dopaminergic p r e - o r postsynaptic activity or in the systems modulating dopaminergic activity. This may finally involve changes attributed to pathophysiological and/or pharmacological 'denervation'. Also, it is conceivable that structural changes may be a complication after years of drug treatment (Gross and Klatenback, 1969; Christensen et al., 1970). It is clear that a drug which is able to selectively block the DA-2 mechanism would be of considerable experimental and clinical interest. It is possible that pimozide may be one such agent for this drug has particular value in suppressing dyskinetic phenomena in the clinic (Fog and Pakkenberg, 1970; Calne,. personal communication) and suppressed all dyskinetic activity in the present study. The possibility of further antidyskinetic drugs is shown by the results obtained using oxiperomide which rapidly and completely controlled all dyskinesias. Oxiperomide is a potent neuroleptic agent (Costall and Naylor, 1974b) and was considerably more active than pimozide although the duration of its effect was short. The specificity of the actions of pimozide and oxiperomide was shown by the inability of a wide range of phenothiazine, butyrophenone, diphenylbutylamine, indole, benzoquinolizine and dibenzazepine neuroleptic drugs to reduce the dyskinesias. It is highly improbable that this simply reflects a peculiar sensitivity of the guinea pig to the depressant effects of pimozide and oxiperomide since haloperidol was shown to be equally potent to oxiperomide and more potent than pimozide as a cataleptic agent. Also, it is equally

B. COSTALL, R.J. NAYLOR improbable that the nialamide pretreatment selectively reduced the depressant effects of haloperidol since preliminary studies showed that the cataleptic activity of both haloperidol and pimozide was enhanced whilst that of oxiperomide was reduced by such pretreatment. Furthermore, although the antistereotypic activity (amphetamine) of haloperidol was reduced by nialamide pretreatment, similar results were obtained using oxiperomide and pimozide. The specificity of the antidyskinetic effects of pimozide and oxiperomide was also emphasised by the inactivity of atypical 'neuroleptics', chlorprothixene, thioridazine, ctozapine and sulpiride, and agents with motor depressant actions, an indenopyridine derivative YG19256 (Roubicek et al., 1972), a pentacyclicamine AY22,214 (Voith and Herr, 1972), thieno benzothiazine derivatives IB503 and NPL82 (Boissier et al., 1969; Loew, 1970} and phencyclidine and metoclopramide. Minor tranquillisers, diazepam, chlordiazepoxide and Sch12679 (Barnett et al., 1972) and a- and fl-adrenergic blocking agents aceperone, piperoxan and propranolol were also ineffective against the oro-bucco-lingual and cervical dyskinesias and the whole body/ head and neck rocking movements. The drugs with depressant effects on motor function invariably reduced or abolished the hyperactivity, especially using larger doses, although guinea pigs continued to exhibit other dyskinesias even after ataxic doses of pentobarbitone, only anaesthetisation abolishing the dyskinesias. Thus, the reduction or abolition of the oro-bucco-lingual and cervical dyskinesias and the whole body or head and neck rocking by pimozide and oxiperomide is indicated as specific for these drugs, although the hyperactivity can be reduced or abolished by many agents, albeit in relatively large doses. It may be noted here that although the orobucco-lingual and cervical dyskinesias, and the hyperactivity, were shown to be specific for dopamine in the striatum and the whole body or head and neck rocking movements appear to be non-specific for the striatum (Costall et

NEUROLEPTIC

ANTAGONISM

OF DYSKINESIAS

al., 1974, 1975), the present studies indicate that all these forms of dyskinetic movements can be inhibited by neuroleptic agents and are thus dependent upon dopaminergic mechanisms. The present study has considered dyskinesias in terms of dopaminergic mechanisms but it must be emphasised that other systems, for example, cholinergic, gabaminergic, serotonergic, may all contribute to the regulation of normal m o t o r function (Marsden, 1974; Marsden et al., !974). Although our conceptual framework of dyskinetic--~ntidyskinetic activity is over-simplistic it remains a realistic approach. It is important to emphasise that the present studies show an involvement of neostriatal dopamine with the induction of dyskinesias and indicate the value of interpreting these effects in terms of more than one dopaminergic mechanism. Whilst all neuroleptics are able to reduce or abolish hyperactivity other forms of dyskinesia are specifically inhibited by only two of the m a n y neuroleptic agents tested, pimozide and oxiperomide. This finding may be relevant to the clinical state which is generally refractory to drug treatment and may form the basis of a valuable test procedure for the detection of antidyskinetic agents.

Acknowledgements This work was supported by the Medical Research Council. The authors are grateful for gifts of drugs from Allen and Hanbury's Ltd., Ayerst Research Labs., Beecham Research Labs., Ciba--Geigy, Labs. Delagrange, Hoechst Pharmaceuticals, I.C.I. Ltd., Janssen Pharmaceutica, Merz and Co., Parke Davis and Co., A.H. Robins Co. Ltd., Roche Products Ltd., Sandoz Products Ltd., Servier Labs. Ltd., Sterling-Winthrop Research Institute, E.R. Squibb and Sons Ltd. and A. Wander Ltd.

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