Original investigations

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003331589100210B

Psychopharmacology

Original investigations

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal common marmosets

Peter-A. L6schmann 2, Lance A. Smith 1, Klaus W. Lange 1, Peter Jaehnig 3, Peter Jenner 1, and C. David Marsden 1'*

1 Parkinson's Disease Society Experimental Research Laboratories, Pharmacology Group, Biomedical Sciences Division, King's College, Manresa Road, London SW3 6LX, UK

2 Research Laboratories of Schering AG, W-1000 Berlin 65, Federal Republic of Germany 3 AFB Comstat GmbH Berlin, Europacenter, W-1000 Berlin 15, Federal Republic of Germany Received October 15, 1990 / Final version April 12, 1991

Abstract. In normal common marmosets administration of the D-1/D-2 agonist apomorphine or the selective D-2 agonist quinpirole caused a dose-dependent increase in motor activity and induced stereotyped behaviour. Both the selective D-2 antagonist raclopride and the selective D-I antagonist SCH 23390 inhibited normal locomotor activity and induced catalepsy. Quinpirole- and apomorphine-induced motor activity were potently inhibited by pretreatment with raclopride. The effects of quinpirole, but not apomorphine, were weakly inhibited by SCH 23390. The selective D-1 partial agonist SKF 38393 decreased motor activity and did not induce grooming, oral movements or other behaviours. SKF 38393 inhibited motor activity induced by the administration of quinpirole but did not alter apomorphine-induced motor behaviour. Locomotor activity in normal common marmosets appears to be mediated mainly via D-2 systems.

In contrast to rodents, administration of SKF 38393 does not induce behavioural activation and there does not appear to be a facilitating effect of D-1 systems on D-2 function in the normal common marmoset. However, the ability of both SKF 38393 and SCH 23390 to inhibit quinpirole locomotor activity suggests some interaction between D-1 and D-2 systems to occur in this species.

Key words: D-1 receptors D-2 receptors Functional interaction - Locomotor activity - Common marmosets

Brain dopamine receptors are divided into D-1 adenylate cyclase linked sites and D-2 sites (Kebabian and Calne 1979); some of the latter are negatively linked to adenylate cyclase (Stoof and Kebabian 1981). Studies in rodents have shown specific behaviours related to each receptor population, but also indicate a functional linkage be-

* Present address: Department of Clinical Neurology, Institute of Neurology, The National Hospital, Queen Square, London WC1, UK

Offprint requests to." P. Jenner

tween the D-1 and D-2 sites in the intact animal (for review see Clark and White 1987; Waddington and O'Boyle 1987). For example, the D-2 agonist quinpirole and the mixed D-l/D-2 agonist apomorphine, but not the D-1 agonist SKF 38393, are able to induce locomotor hyperactivity and stereotypies in rats and mice. The administration of SKF 38393, however, does cause an increase in non-stereotyped grooming, sniffing and vacuous chewing (Molloy and Waddington 1984, 1987).

Also, administration of SKF 38393 potentiates the ability of D-2 agonists such as Ru 24296 (Mashurano and Waddington 1986) or bromocriptine (Jackson et al.

1988) to induce stereotypy. Stimulation of both D-1 and D-2 receptors appears necessary for the induction of some oral components of stereotypy such as licking and gnawing.

D-1 receptor activation in rodents may therefore play a facilitating or permissive role in D-2-mediated behaviours. A similar relationship can be observed using selective D-I and D-2 antagonist drugs. Thus, administration to rats of the D-1 antagonist SCH 23390 will induce catalepsy identical to that produced by selective D-2 antagonist drugs (Hoffman and Beninger 1985). In addition, both D-1 antagonists and D-2 antagonist drugs, like raclopride (Ogren et at. 1986), can inhibit stereotypy induced by D-2 agonists.

In normal rodents, D-2 receptors also manipulate D-l-mediated behaviours, but in a complex manner. For example, the grooming produced by SKF 38393 can be inhibited by both D-1 and D-2 antagonists (Murray and Waddington 1989a). In contrast, vacuous chewing induced by SKF 38393 is potentiated by selective D-2 antagonists such as sulpiride, presumably by reducing D-2 inhibitory tone (Murray and Waddington 1989b).

All these data point clearly to a mutual interaction between D-1 and D-2 receptors which can influence motor behaviours in rodents. The functional outcome of manipulating brain dopamine receptors appears to de- pend on the resulting balance between D-1 and D-2 systems. Such results may be of importance in designing new drug therapies for both neurological and psychotic

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d i s e a s e in m a n . H o w e v e r , it is u n k n o w n w h e t h e r a s i m i l a r r e l a t i o n s h i p exists b e t w e e n D-1 a n d D - 2 r e c e p t o r s i n m a n o r n o n - h u m a n p r i m a t e s , o r w h e t h e r selective D-1 o r D - 2 d r u g s p r o d u c e s i m i l a r b e h a v i o u r a l effects t o t h o s e o b - s e r v e d in r o d e n t s . C o n s e q u e n t l y , in this i n v e s t i g a t i o n w e h a v e s t u d i e d t h e effect o f m a n i p u l a t i n g D-1 a n d D - 2 r e c e p t o r s o n t h e m o t o r a c t i v i t y o f a p r i m a t e species, n a m e l y t h e c o m m o n m a r m o s e t , s e e k i n g t o u n d e r t a k e t h e s a m e series o f e x p e r i m e n t s o n w h i c h t h e r o l e s o f D - I a n d D - 2 sites in m o t o r b e h a v i o u r in r a t s w e r e e s t a b l i s h e d .

Materials and methods

Animals. Common marmosets (Callithrix jacchus) of either sex, weighing 280-420 g and aged 2-10 years at the beginning of the study, were used. The animals were housed either in pairs or alone under standard conditions at a temperature of 27 ° ( ± 1 o C) and 50 % relative humidity using a 12 h light-dark cycle (light on from 6.00 to 18.00 hours). The animals had free access to food pellets (Mazuri primate diet) and tap water, and in addition received a daily ration of fresh fruit and Mazuri marmoset jelly.

Measurement of locomotor activity. Locomotor activity was mea- sured simultaneously in four aluminium cages (50 x 60 x 70 cm) with stainless steel grid doors (50 x 70 cm) identical to the animals, home cage but equipped with eight horizontally orientated sets of infrared photocells. Across the cage three beams were located at floor level and one along each of the two perches. Other beams were directed from front to back of the cage at floor level and above each perch. The number of light beam interruptions due to the animal's movements were accumulated in 10-rain intervals and recorded for 120 min using a Commodore CBM 4032 computer. The animals were allowed to acclimatise to the test cage for a minimum of 30 rain prior to drug treatment.

Behavioural observations. In parallel to the automated recording of locomotor activity, the animals were observed through a one-way mirror. Motor behaviour was rated qualitatively to determine the presenced or absence of stereotypy, co-ordination of movement, the degree of stimulation or inhibition, incidence of head twitches, wet dog shakes or grooming, oral movements and other obvious motor signs in 5-min intervals for 75 min after drug administration. In addition, a video recording of one animal in each treatment group was taken to allow post-hoc assessment of alterations in motor behaviour.

Drug solutions. The following compounds were employed: SKF 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy- 1-phenyl- 1H-3-benzazepine hydrochloride; Research Biochemicals Inc., USA), SCH 23390 (2-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1 }t-3-benzazepine- 7-ol hemimaleate; Schering Corp., USA), apomorphine hydrochloride (Macfarlan Smith Ltd., UK), quinpirote (LY 171555;

tran s - ( - ) - 4aR - 4,4a, 5,6, 7, 8,8a, 9 - octahydro - 5 - propyl - 1H (or- 2H)- pyrazolo(3,4-g)quinoline monohydrochloride; Eli Lilly, USA), raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)methyl]- 2-hydroxy-6-methoxy-benzamide; Astra, Sweden) and domperidone (Janssen, Belgium). The solutions were prepared under sterile conditions. All compounds, except domperidone, were dis- solved in sterile physiological saline and administered in a final volume of 1 ml/kg body weight. Domperidone was suspended in a few drops of ethanol (70%) and diluted to volume (2 ml/kg body weight) with 10% sucrose/water solution and administered by oral gavage.

Dru9 treatments. Marmosets were randomly divided into groups of four and were subsequently treated with vehicle and the three doses of one test compound over the following weeks, allowing a 1-week

recovery period between experiments. Individual animals were max- imally employed in two such treatment groups with at least a 4-week period between experiments. A latin square design was used for the allocation of treatments within the groups.

Dose-response studies. Animals were pretreated with domperidone (2 mg/kg PO) 30 rain prior to the subcutaneous (SC) administration of apomorphine (0.18, 0.75, t. 5 mg/kg or vehicle) or intraperitoneal (IP) administration of quinpirole (0.15, 0.3, 0.6 mg/kg or vehicle) to prevent nausea or vomiting. Locomotor activity was recorded over the following 2-h period. The effects of SKF 38393 (1.25, 2.5, 5.0 mg/kg IP or vehicle), SCH 23390 (0.31, 1.25, 5.0 mg/kg IP or vehicle) or raclopride (1.25, 5.0, 20.0 mg/kg IP or vehicle) were examined in an identical manner, except that pretreatment with domperidone was not employed. To assess whether effects of SKF 38393 were affected by domperidone treatment, a group of four animals was treated with either vehicle or SKF 38393 (5 mg/kg IP) alone or pretreated with domperidone (2 mg/kg PO) 30 min prior to administration of SKF 38393 (5 mg/kg IP).

Interaction studies. Animals were pretreated with domperidone (2 mg/kg PO) 15 min prior to the administration of either SKF 38393 (1.25, 2.5, 5.0 mg/kg or vehicle IP) or SCH 23390 (0.31, 1.25, 5.0mg/kg IP). A further 15 min later apomorphine (1.5 and 0.75 mg/kg SC combined with SKF 38393) or quinpirole (0.6 mg/kg IP) were administered. Raclopride (0.31, 1.25, 5.0mg/kg IP or vehicle) was administered 15 rain prior to the administration of apomorphine (1.5 mg/kg SC) or quinpirole (0.6 mg/kg IP).

Data analysis. The mean ± SEM were calculated for time courses and accumulated locomotor counts of the different treatment groups. Statistical differences were calculated for accumulated locomotor counts by the non-parametric Page test for ordered alter- natives using exact distributions.

Results

Effects o f apomorphine and quinpirole on motor behaviour

A d m i n i s t r a t i o n o f a p o m o r p h i n e ( 0 . 1 8 - 1 . 5 m g / k g SC) o r q u i n p i r o t e ( 0 . 1 5 ~ 0 . 6 m g / k g I P ) d o s e - d e p e n d e n t l y in- c r e a s e d l o c o m o t o r a c t i v i t y in n o r m a l c o m m o n m a r - m o s e t s ( F i g s . 1 a n d 2). T h e effect o f a p o m o r p h i n e w a s m a x i m a l w i t h i n 10 m i n o f a d m i n i s t r a t i o n a n d l a s t e d f o r a b o u t 60 m i n . I n c r e a s i n g d o s e s d i d n o t a l t e r t h e d u r a t i o n o f a c t i o n b u t i n c r e a s e d t h e i n t e n s i t y o f m o t o r a c t i v i t y . Q u i n p i r o l e p r o d u c e d a m o r e s u s t a i n e d m o t o r effect, p a r - t i c u l a r l y a t t h e h i g h e r d o s e s e m p l o y e d . T h e effect o f b o t h a p o m o r p h i n e a n d q u i n p i r o l e w a s t o p r o d u c e a n i n c r e a s e in m o t o r b e h a v i o u r w h i c h t o o k t h e f o r m o f f a s t b u t c o n t r o l l e d m o v e m e n t s . I n the h i g h e s t d o s e s t e s t e d b o t h a p o m o r p h i n e a n d q u i n p i r o l e p r o d u c e d s o m e s t e r e o t y p e d m o v e m e n t s in t h e f o r m o f r e p e t i t i v e g r a s p i n g o r b o d y w a v i n g . A n i m a l s d i d n o t e x h i b i t d y s k i n e s i a o r d y s t o n i a a n d i n c r e a s e d g r o o m i n g w a s n o t o b s e r v e d .

Effects o f raclopride and S C H 23390 on motor behaviour

A d m i n i s t r a t i o n o f r a c l o p r i d e ( 1 . 2 5 - 2 0 m g / k g IP) to n o r - m a l c o m m o n m a r m o s e t s d e c r e a s e d l o c o m o t o r a c t i v i t y in a d o s e - d e p e n d e n t m a n n e r ( F i g . 3A). A n i m a l s b e c a m e

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Fig. 1A, B. The effect of apomorphine on motor activity in normal common marmosets. A Mean cumulative movement counts accumulated in 10-min intervals over 2 h (±SEM, n=4) of common marmosets pretreated with domperidone (2 mg/kg PO) 30 min prior to the subcutaneous administration of vehicle G o - - ) or 0.18 Go--), 0.75 G []-) or 1.5 G I - ) mg/kg apomorphine. Error bars for the lower doses of apomorphine are omitted for clarity but were in the same range as those shown for the vehicle and apomorphine 1.5 mg/kg SC treatment. B Mean cumulative movement counts accumulated over 2 h (±SEM, n=4) for the data shown in A.

Locomotor activity was increased (P<0.01, Page test, ordered alternative: vehicle < 0.18 < 0.75 < 1.5 mg/kg apomorphine)

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Fig. 2A, B. The effect of quinpirole on motor activity in normal common marmosets. A Mean cumulative movement counts accumulated in 10-min intervals over 2 h (:t:SEM, n=4) of common marmosets pretreated with domperidone (2 mg/kg PO) 30 min prior to the intraperitoneal administration of vehicle (--o--) or 0.15 (-o--), 0.3 ( [] ) or 0.6 G n - - ) mg/kg quinpirole, Error bars for the lower doses of quinpirole are omitted for clarity but were in the same range as those shown for the vehicle and quinpirole 0.6 mg/kg IP treatment. B Mean cumulative movement counts accumulated over 2 h (_k SEM, n=4) for the data shown in A. Locomotor activity was increased (P<0.01, Page test, ordered alternative:

vehicle < 0.15 < 0.3 < 0.6 mg/kg quinpirole)

sedated, cataleptic a n d akinetic after the administration o f raclopride. Similarly, S C H 23390 (0.31-5.0 m g / k g IP) also caused a dose-dependent decrease in l o c o m o t o r activity (Fig. 3B). Again, the effects o f S C H 23390 were qualitatively identical to those o f raclopride.

Effects of raclopride or S C H 23390 on motor behaviour induced by apomorphine or quinpirole

Quinpirole-induced l o c o m o t o r activity (0.6 m g / k g IP) as well as stereotyped m o v e m e n t s were dose-dependently inhibited by p r e t r e a t m e n t o f animals with S C H 23390 (1.25 5 . 0 m g / k g IP) or raclopride ( 0 . 3 1 - 5 . 0 m g / k g IP) (Fig. 4A). The effects o f raclopride and S C H 23390 were qualitatively similar, but raclopride h a d a m u c h m o r e m a r k e d effect and induced complete akinesia.

The increase in m o t o r activity and stereotypies produced by a p o m o r p h i n e (1.5 m g / k g SC) was abolished by p r e t r e a t m e n t with raclopride ( 0 . 3 1 - 5 . 0 m g / k g IP) (Fig. 4B). Indeed, t r e a t m e n t with raclopride p r o d u c e d complete akinesia and catalepsy. In contrast, the effect of a p o m o r p h i n e was not inhibited or qualitatively affect-

ed by the p r e t r e a t m e n t with S C H 23390 (1.25-5.0 m g / k g IP).

Effects of SKF 38393 on motor behaviour

Administration o f S K F 38393 ( 1 . 2 5 - 5 . 0 m g / k g SC) caused a dose-related decrease in l o c o m o t o r activity i n normal c o m m o n m a r m o s e t s (Fig. 5). The effect o f S K F 38393 was a p p a r e n t within 10 min and lasted for up to 120 rain. The effect o f S K F 38393 t o o k the f o r m of an inhibition o f l o c o m o t o r activity and reduced vigilance, but not catalepsy or complete akinesia. Animals did not exhibit stereotyped movements, purposeless chewing, dyskinesias, dystonia or g r o o m i n g behaviour.

S K F 38393 (5 m g / k g IP) administered alone (mean counts in 2 h 929 4-509) or in c o m b i n a t i o n with d o m - peridone (mean counts in 2 h 9 2 0 ± 4 1 5 ) reduced loco- m o t o r activity to the same extent c o m p a r e d to vehicle- treated animals (mean counts in 2 h t 9 4 2 ± 6 2 3 ) (P < 0.05). Again, the animals did not exhibit purposeless chewing, tongue protrusions or other oral movements. Retching, vomiting, sialorhea and other signs of gastrointestinal discomfort were not observed.

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Fig. 3A, B. The effect of raclopride or SCH 23390 on motor activity in normal common marmosets. Mean cumulative movement counts accumulated over 2 h (±SEM, n=4) for A vehicle, 1.25, 5.0 and 20 mg/kg raclopride IP and B vehicle, 0.31, 1.25 and 5.0 mg/kg SCH 23390 IP. Locomotor activity was decreased by raclopride and SCH 23390 (P < 0.05, Page test, ordered alternative:

vehicle > 0.125 > 5.0 > 20 mg/kg raclopride; P<0.05, Page test ordered alternative: vehicle > 0.31 > 1.25 > 5.0 mg/kg SCH 23390

Effect o f apomo~Thine or quinpirole in combination with S K F 38393 on motor behaviour

A d m i n i s t r a t i o n o f quinpirole (0.6 m g / k g IP) induced an increase in l o c o m o t o r activity (Fig. 6A). Stereotypies occasionally occurred in the g r o u p treated with quinpirole alone. P r e t r e a t m e n t with S K F 38393 (1.25-5.0 m g / kg IP) dose-dependently inhibited the effect o f quinpirole. N o stereotypies, dyskinesias, dystonia, p u r p o s e - less chewing or g r o o m i n g was observed.

A d m i n i s t r a t i o n o f a p o m o r p h i n e (1.5 and 0.75 m g / k g SC) also induced an increase in l o c o m o t o r activity (Fig. 6B), but again in animals treated with 1.5 m g / k g a p o m o r p h i n e alone stereotypies were seen occasionally.

Prior a d m i n i s t r a t i o n o f S K F 38393 (1.25-5.0 m g / k g IP) did not alter the l o c o m o t o r response p r o d u c e d by either dose o f a p o m o r p h i n e , but S K F 38393 seemed to suppress the occurrence o f stereotyped m o v e m e n t s . G r o o m i n g was seen occasionally, b u t purposeless chewing or other a b n o r m a l m o v e m e n t s were n o t observed.

Discussion

The evidence available f r o m rodent experiments clearly points to a reciprocal interaction between D-1 and D-2 systems in the initiation and control o f m o t o r function.

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Fig. 4A, B. The effect ofpretreatment with raclopride or SCH 23390 on locomotor activity induced by quinpirole or apomorphine in normal common marmosets. Mean cumulative movement counts accumulated over 2 h (± SEM, n= 4) for animals pretreated with 2 mg/kg domperidone PO 15 min prior to administration of vehicle or SCH 23390 (1.25, 2.5 and 5.0 mg/kg IP, hatched bars) or raclopride (0.3t, 1.25 and 5.0 mg/kg IP, grey bars) and challenged with 0.6 mg/kg quinpirole IP (A) or 1.5 mg/kg apomorphine SC (B) 15 min later. Locomotor stimulation induced by quinpirole was decreased by SCH 23390 (P<0.05 Page test, ordered alternative: vehicle> 1.25>2.5> 5.0 mg/kg SCH 23390) and ractopride (P<0.01 Page test, ordered alternative: vehicle>0.31>0.125>

5.0 mg/kg raclopride). Locomotor stimulation induced by apomorphine was decreased by raclopride (P<0.01, Page test, ordered alternative: vehicle > 1.25 > 2.5 > 5.0 mg/kg raclopride)

In particular, in n o r m a l animals D-1 systems act to facilitate D-2 initiated m o t o r behaviours. In the present study we have investigated using the same selective D-1 a n d D-2 drug c o m b i n a t i o n s whether a similar interaction occurs in a n o n - h u m a n p r i m a t e species, namely the c o m - m o n m a r m o s e t .

A d m i n i s t r a t i o n o f the mixed D - l / D - 2 agonist a p o - m o r p h i n e or the selective D - 2 agonist quinpirole caused an increase in controlled m o t o r activity, increased check- ing m o v e m e n t o f the head a n d in high doses stereotyped m o v e m e n t s o f the limbs or the whole body. These effects are identical to those previously reported in n o r m a l com- m o n m a r m o s e t s treated with a p o m o r p h i n e (Ridley et al.

1980) a n d other d o p a m i n e agonist drugs ( N o m o t o et al.

1987). T h e behavioural changes also c o r r e s p o n d to the effect o f D-2 and D - l / D - 2 agonists reported in rats, namely, increased l o c o m o t o r activity a n d stereotypy.

T h e administration o f the D-2 antagonist raclopride or the D-1 antagonist S C H 23390 p r o d u c e d a similar effect on m o t o r b e h a v i o u r in n o r m a l monkeys. Both drugs caused a p o t e n t inhibition o f all c o m p o n e n t s of l o c o m o t o r activity a n d in high doses catalepsy. This

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Fig. 5A, B. The effect of SKF 38393 on locomotor activity in normal common marmosets. A Mean cumulative movement counts accumulated in 10-rain intervals over 2 h (±SEM, n=4) of common marmosets following the intraperitoneal administration of vehicle

@o--) or 1.25 ( • ), 2.5 (~D--) or 5.0 (--I--) mg/kg SKF 38393.

Error bars for the lower doses of SKF 38393 are omitted for clarity but were in the same range as those shown for the vehicle and SKF 38393 5.0 mg/kg SC treatment. B Mean cumulative movement counts accumulated over 2 h (__+ SEM, n=4) for the data shown in A. Locomotor activity was decreased (P<0.01, Page test, ordered alternative: vehicle > 1.25 > 2.5 > 5.0 mg/kg SKF 38393)

parallels the ability of b o t h D-1 and D-2 antagonists to inhibit s p o n t a n e o u s l o c o m o t o r activity and to induce catalepsy in rodents (Christensen et al. 1984). The d a t a s u p p o r t a role for b o t h D-1 and D - 2 receptors in mediat- ing basal m o t o r activity in c o m m o n marmosets.

Both S C H 23390 and raclopride inhibited the m o t o r activity p r o d u c e d by quinpirole b u t the effect of raclopride was potent and that o f S C H 23390 partial and weak. This would suggest a p r e d o m i n a n t effect o f the D-2 system in producing l o c o m o t o r activity. Indeed, the actions o f a p o m o r p h i n e were potently a n d totally blocked by raclopride but there was no effect of S C H 23390. It therefore appears that D-1 systems play only a m i n o r role in the initiation and control of l o c o m o t i o n induced by these d o p a m i n e agonists in n o r m a l c o m m o n marmosets.

In contrast to a p o m o r p h i n e a n d quinpirole, the administration o f the selective D-1 partial agonist S K F 38393 did n o t stimulate m o t o r behaviour. Rather, the drug caused a partial inhibition o f n o r m a l m o t o r function without any qualitative changes in its c o m p o n e n t s or the induction o f catalepsy. These findings clearly contrast with the effects o f S K F 38393 in rats, where increased g r o o m i n g b u t no inhibition o f l o c o m o t o r activity is observed (Dall'Olio et al. t988). It is unlikely that gastrointestinal side effects, which have been reported

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Fig. 6A, B. The effect of apomorphine or quinpirole in combination with SKF 38393 on motor behaviour in normal comon marmosets.

A Mean cumulative movement counts accumulated over 2 h (~SEM, n=4) of common marmosets pretreated with domperidone (2 mg/kg PO) 30 rain prior to administration of quinpirole (0.6 mg/kg IP) alone or in combination with 1.25, 2.5 or 5.0 mg/kg IP SKF 38393 administered 15 rain previously. Locomotor activity was decreased (P<0.05, Page test, ordered alternative:

quinpirole> 1.25 > 2.5> 5.0 mg/kg SKF 38393). B Mean cumulative movement counts accumulated over 2 h (± SEM, n=4) of common marmosets pretreated with domperidone (2 mg/kg PO) 30 min prior to administration of apomorphine (1.5 mg/kg SC, hatched bars or 0.75 mg/kg SC, open bars) alone or in combination with 1.25, 2.5 or 5.0 mg/kg IP SKF 38393 administered 15 min previously. Locomotor activity was not altered by SKF 38393 administration

after higher doses (10 or 30 m g / k g SC) of S K F 38393 in squirrel m o n k e y s ( R u p n i a k et al. 1991), are responsible for the reduction o f l o c o m o t o r activity seen in our experiments. This a s s u m p t i o n is based on the observation that the degree o f inhibition o f l o c o m o t o r activity as well as the b e h a v i o u r were not altered by the peripheral D-2 antagonist domperidone, It thus a p p e a r s that using S K F 38393 to act on D-1 receptors in n o r m a l primates results in effects which differ f r o m those in rodents and which do not cause a behavioural activation.

The differences between the effects o f D-1 agonists in primates a n d in rodents were emphasised by the effects o f combinations o f S K F 38393 with quinpirole or apomorphine. S K F 38393 inhibited the stimulation o f m o t o r behaviour produced by quinpirole. This contrasts with the ability o f S K F 38393 to enhance and facilitate distinct c o m p o n e n t s o f m o t o r activity and stereotypy produced by the stimulation o f D - 2 receptors in rodents.

It is in agreement with the ability o f S K F 38393 to inhibit l o c o m o t o r activity ( N o m o t o et al. 1985, 1988) and rota- tional b e h a v i o u r (Barone et al. 1987) in a variety of

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p r i m a t e species exposed to the selective nigral neurotoxin 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP).

Interestingly, administration o f S K F 38393 did n o t qualitatively or quantitatively alter the m o t o r response to a p o m o r p h i n e . The reasons for this are not clear, but m a y relate to the p o t e n t D-1 receptor agonist activity o f apo- m o r p h i n e itself.

On the basis o f these results with S K F 38393, it appears that in p r i m a t e species D-1 receptor activation does not initiate m o t o r b e h a v i o u r a n d does not facilitate behaviours induced by D-2 receptor stimulation. Rather, D-1 receptor activation by S K F 38393 serves to depress spon- t a n e o u s m o t o r b e h a v i o u r a n d t h a t induced by the D - 2 agonist quinpirole in n o r m a l c o m m o n m a r m o s e t . The administration o f D-1 a n d D-2 agonist and antagonist drugs to c o m m o n m a r m o s e t s causes distinct behavioural effects, but these do n o t completely parallel those observed in rodents. A m a j o r difference lies in the effects o f S K F 38393 alone a n d in c o m b i n a t i o n with D-2 agonists. The present results can only be interpreted in terms o f the p h a r m a c o l o g i c a l actions o f S K F 38393, although it is feasible t h a t the drug m i g h t exert identical p h a r m a c o l o g i c a l effects in different species b u t which resulted in the initiation o f distinct behavioural responses. It m a y be that in primates S K F 38393 does n o t exert a selective D-1 d o p a m i n e agonist activity. S K F 38393 is a partial D-1 agonist a n d this m a y alter the response observed in primates and rodent species, since a high degree o f endogenous D- 1 tone m i g h t result in an antagonist action. Alternatively, S K F 38393 might be metabolised to a D-1 or D-2 antagonist c o m p o u n d in vivo. H o w e v e r , since its behavioural effects were distinct f r o m b o t h those o f S C H 23390 a n d ractopride in not inducing catalepsy, such explanations a p p e a r less likely.

Certainly in m a n S K F 38393 does not p r o d u c e the anti- p a r k i n s o n i a n activity t h a t its D-1 agonist effect in rodents would suggest (Braun et al. 1987). T h e uncer- tainty over S K F 38393 can only be resolved when further selective D-1 agonists b e c o m e available. However, in line with this concept are the results o b t a i n e d with the benzer- goline C Y 208-243, a c o m p o u n d which has also been characterised as a D-1 receptor partial agonist ( F o o t e et al. 1988). L o c o m o t o r activity o f the n o r m a l c o m m o n m a r m o s e t s is stimulated by this drug (Temlett et al.

1988a) a n d some patients with P a r k i n s o n ' s disease show- ed i m p r o v e m e n t (Temlett et al. 1988b). H o w e v e r , at this time it is not k n o w n whether the actions o f S K F 38393 or C Y 208-243 reflect the true effect o f D-1 agonist stimulation in a p r i m a t e species. Until a centrally active full D-1 agonist drug is available this situation will not be resolved.

An alternative explanation m a y involve a different p o p u l a t i o n o f D-1 receptors and the extent to which these are linked to D-2 receptors. There have already been suggestions for different D-1 receptor p o p u l a t i o n s f r o m in vitro ligand binding studies in rats (Wamsley et al.

1989). It remains unresolved whether the behavioural interaction between D-1 and D-2 receptors involves sites located on the s a m e neurones or indeed whether these are even in the same brain area.

Overall, a n d based on the use of S K F 38393, there

does not a p p e a r to be a behavioural activation occurring via D- 1 sites or a facilitating effect o f D- 1 systems on D-2 function in the n o r m a l c o m m o n m a r m o s e t . However, the weak inhibitory effects o f b o t h S K F 38393 and S C H 23390 on D-2 receptor-mediated effects might suggest some linkage between D-1 and D - 2 systems. Although no absolute conclusions can be d r a w n at present on the role o f D-1 systems in primates, it is clear that the effects observed in rodents c a n n o t be considered predictive o f events occurring in higher species.

Acknowledgements. This study was supported by the Wellcome Trust and the Parkinson's Disease Sodety. P-A L6schmann was a visiting research fellow.

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