Terguride stimulates locomotor activity at 2 months but not 10 months after l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine treatment of common marmosets

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(c~ 1992 Elsevier Science Publishers B.V. All rights rcscrvcd 0014-2999/92/$05.00

EJP 52334

Terguride stimulates locomotor activity at 2 m o n t h s but not 10 m o n t h s after l - m e t h y l - 4 - p h e n y l - l , 2 , 3 , 6 - t e t r a h y d r o p y r i d i n e treatment of c o m m o n m a r m o s e t s

K l a u s W. L a n g c , P e t e r - A . L 6 s c h m a n n '~, I t c l m u t W a c h t c l ~, R e i n h a r d H o r o w s k i '~, P e t e r JS.hnig ~, P e t e r J e n n e r a n d C. D a v i d M a r s d c n b

Parkinson ~ Disease Society Experimental Research Laboratories, Pharmacology Group, Biomedical Sciences Dit'ision, King's College, Manresa Road, l.ondon S W3, U.K., ~ Research Laboratories o f Schering A G, D- 1000 Berlin 6.5, I': R.G., t, Unit ersity Department o f Clinical Neurolog3', Institute o/"

Neurology, The National llo.spital, Queen Square, l.ondon WC1, U.K. and ~ A 1" B Comstat GmbH Berlin, Europacenter, D-IO00 Berlin 30, b:R.G.

Received 27 June 1991, revised MS received 16 October 1991, accepted 17 December 1991

The mixed dopaminc (DA) agonist/antagonist tcrguridc acts as a I)A antagonist on normosensitivc receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinson's disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmoscts with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridinc (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Tcrguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced bchavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguridc has anti-akinetic efficacy in this primate model of Parkinson's disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species.

MPTP (1-methyl-4-phcnyl-l,2,3,6-tetrahydropyridinc); Parkinsonism; Tcrguride;

Dopamine D 2 receptors (mixed agonist/antagonist); (Common marmoset)

I. I n t r o d u c t i o n

T h e current t r e a t m e n t of Parkinson's disease with indirect or direct d o p a m i n e (DA) agonists (i.e., L-Dopa, lisuride, pergolide or bromocriptinc) is limited by side effects. W h e r e a s somc initial adverse reactions such as nausea and vomiting usually disappear due to rapid tolerance, the incidence of others such as fluctuations in m o t o r p e r f o r m a n c e and involuntary m o v e m e n t s in- creases after long-term t r e a t m e n t with L - D o p a (Mars- den and Parkcs, 1976). Psychosis is a n o t h e r limiting side effect of all dopaminergic therapies, especially in elderly patients. A balanced stimulation of D A recep- tc.rs, taking into account the differential status of D A receptor sensitivity in the course of the disease, could lead to a more specific therapeutic effect and reduction of side effects.

Correspondence to: P.-A. lJJschmann, Schcring AG, Ncuropsy- chopharmacology, Postfach 65 03 11, D-1000 Berlin 65, F.R.G. Tel.

49.30.468 2162, fax 49.30.4691 6738.

Mixed D A agonists/antagonists, with terguridc be- ing the prototype compound, are promising for such an approach. Tcrguride, a derivative of the dopaminergic ergolinc lisuride, binds with high affinity to rat striatal D A 1) 2 and to a lesser extent to D A D~ binding sites (Valchfir ct al., 1987). The c o m p o u n d acts as a D A antagonist in normal rats but shows D A agonistic properties in reserpine-treated rodents (Wachtcl and Dorow, 1983). In naive rats, terguride dose dependently inhibits locomotor activity. However, stimulation occurs after subchronic p r c t r e a t m e n t with reserpine.

Similarly, terguride does not induce stereotypies in rats treated acutely with reserpine, but does so after subchronic treatment with reserpine (Wachtel ct al., 1984).

F u r t h e r m o r e , and in c o m m o n with classical D A agonists, terguridc suppresses hyperprolactinaemia in fe- male rats p r e t r e a t e d with reserpine and induces con- tralateral rotations in rats injected unilaterally with 6-hydroxydopaminc into the substantia nigra (Dlab~c and Krej(:i, 1980; lJSschmann et al., 1991a).

Administration of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) to man or non-human primates

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(Davis et al., 1979; Langston et al., 1983; Burns et al., 1983) including common marmosets (Jenner ct al., 19841 induccs a parkinsonian syndromc duc to the selective destruction of nigrostriatal neurones, which causes a substantial decrease in the DA content of the caudate nucleus and putamen and a corresponding decrease in [~H]DA uptake (Jenner el al., 1984). The deficits in motor p e r f o r m a n c e produced by M P T P trcatmcnt of common marmosets respond to classical anti-parkinsonian drugs such as L - D o p a in combina- tion with a peripheral decarboxylase inhibitor (Jenner et al., 1984), or D A rcccptor agonists such as ( + ) - P H N O ( N o m o t o et al., 19871, N-0437 (l.6schmann ct al., 1989) or the ergoline derivative lisuridc (L6sch- mann ct al., 1991b). T h e M P T P - t r e a t e d monkey ap- pears to be the most suitable pharmacological model of Parkinson's disease currently available.

C o m m o n marmosets recover from the initial symptoms induced by M P T P treatment over a period of several months. This bchavioural recovery, is associated with increased D A turnover in the c a u d a t c - p u t a m c n (Jenner et al., 1984; Rose ct al., 19891 and is not reverscd by further treatment with M P T P (Ueki et al., 19891. The present study was designed to test the hypothesis that the behavioural recovery in common marmosets after M P T P treatment would be associated with a change in their behavioural response to a mixcd D A agonist/antagonist. Wc therefore c o m p a r e d the actions of terguride in naive common marmosets to its effects in groups of animals exposed to M P T P either 2 months or 10 months prior to the administration of terguride. The results obtained under these conditions are discussed in view of the pharmacological effects of tcrguride in patients.

2. Materials and methods 2.1. Animals

C o m m o n marmosets (Callithrix jacchus) of either sex weighing 280-420 g and aged 6 - 1 0 years at the beginning of the study were used. The animals were housed in pairs or alone under standard conditions at a t e m p e r a t u r e of 27°C ( + I°C) and 50% relative humid- ity with a 12-h light-dark cycle (light on from 6:00 to 18:00 h). 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. During M P T P treatment and throughout the following weeks the animals were hand-fed with Mazuri marmoset jelly and fresh fruit puree until they were able to maintain themselves. Electrolyte, nutrient and fluid balance were maintained by s.c. infusion of an electrolyte, amino acid and vitamin solution (Duphalyte, Duphar, UK) when necessary.

2.2. Measurement of locomotor actit:ity

Ix)comotor activity was measured simultaneously in four aluminium cages (50 × 60 × 70 cm) with stainless steel grid doors (50 × 70 cm) identical to thc animals' home cages but equipped with eight horizontally orien- tated sets of infrared photocells. Across the cage three beams wcrc located at floor level and one along each of the two pcrchcs. O t h e r beams were directed from front-to-back of the cage at floor level and abc~ve each pcrch. The n u m b e r of light b e a m interruptions due to the animal's movements were accumulated in 10-min intervals and recorded for 360 rain, using a Com- modore CBM 4032 computer. The animals were al- lowed to acclimatize to the test cage for a minimum of 30 rain prior to drug treatment.

2.3. Behat:ioural obsercations

In parallcl to the automated recording of locomotor activity the animals were observed under blinded conditions through a one-way mirror. Motor behaviour was rated qualitatively to determine the presence or ab- sence of stereotypy, head twitches, wet-dog shakes or grooming, oral movements, co-ordination of m o v e m e n t ( g o o d / i m p a i r e d ) and other obvious motor signs in 5- min intervals for 360 rain after drug administration.

The maximal score for each item was 72.

2.4. Drugs and solutions

The following compounds were used: M P T P (l- methyl-4-phenyl- 1,2,3,6-tetrahydropyridine hydrochlo- ride; Schering A G ) and tcrguride (Sobering AG). M P T P was dissolved in sterile physiological saline and tcrguridc was suspended in sterile physiological saline containing 10(I g/1 polycthoxylated castor oil (Cremo- phor EL, BASF, FRG). All solutions were p r e p a r e d immediately before administration.

2.5. MPTP treatment

The animals were treated with M P T P in doses of 2 m g / k g s.c. daily for up to 6 days. Since the response of individual animals differed markedly, variable dose regimes were applied to obtain comparable initial motor deficits. I m p a i r m e n t of motor function was quanti- fied daily with a rating scale (L/ischmann c t a l . , 1989).

T h e animals were treated until they reached a maximal disability score of 18 24 h after the last M P T P injection. The cumulative doses administered ranged from 8 to 12 m g / k g . After M P T P treatment the animals recovered from acute effects over a period of some weeks. During the following months a further gradual recovery, from the M P T P effects was obscrvcd. One group of three animals was tested 2 months (group A)

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aad a second group of thrcc animals 10 months (group B) after exposure to MPTP.

2.6. Drug treatments

A group of four marmosets was treated with vehicle a a d one of the three doses of tcrguridc (4.0, 8.0 or 12.0 m g / k g i.p.) ovcr the following weeks, allowing 1 week recovery between experiments. T r e a t m e n t s wcrc ran- d~mizcd within the group. M P T P - t r c a t c d marmosets were tested either 2 months (group A, N = 3) or 10 months (group B, N = 3) after M P T P treatment with vehicle or one of the three doses of tcrguride (4.0, 8.0 or 12.0 m g / k g i.p.) in a identical design. All experiments started at 11:00 a.m. and finished at 5:00 p.m.

2. Z Data analysis

T h e means _+ S.E.M. wcrc calculated for time courses and accumulated locomotor counts of the different treatment groups. Statistical differences were calculated for accumulated locomotor counts by the n o n - p a r a m e t r i c Page test for non-independent data.

lntraindividual m o n o t o n e trends of treatment effects were detected using the o r d e r e d alternative: vehicle <

4.0 < 8.0 < 12 m g / k g , using exact distributions followed by sequential tests against two alternative hy- potheses (vehicle < 4.0 < 8.0 m g / k g ) or (vehicle < 4.0 and 8.0 < 12.(I m g / k g ) when appropriate.

3. Results

When a d a p t e d to the environment of the test cages, naive c o m m o n m a r m o s e t s showed very little locomotor activity when not disturbed. Injection of vehicle was followed by a 30-min period of exploratory activity but,

~ 300 , ~ z 260 ] 0 ~

2 ~ 4 o - 1 , lr

~ "[ 00 E 60

~ 20

~ -20

~0

TTLI ~I

60 120 180 240 300 360

Time (rain)

Fig. 1. Mean l o c o m o t o r activity counts ( + S . E . M . . N = 4) accumu- ]aled in 10-rain intervals for 180 rain of naive c o m m o n m a r m o s e t s treated with vehicle (.~) or 4.0 (e), 8.0 (/~) and 12.0 ( • ) m g / k g of tc:guride, respectively. E r r o r bars for the t r e a t m e n t g r o u p s are omilted for clarity but were within the same range as those s h o w n for

the vehicle group.

T A B L E 1

Median stereotypy scores with the range in p a r e n t h e s e s over 360 rain after t r e a t m e n t of c o m m o n m a r m o s e t s with terguridc.

T r e a t m e n t N o r m a l 2 m o n t h s 10 m o n t h s post M P T P post M P T P

Vehicle 0 (0) 0 (0) 0 (0)

4 m g / k g 0 (0) 4 (5) 3 (3)

8 m g / k g 0 (0) 7 (5) 2 (3)

12 m g / k B 0 (0) 21 (14) 4 (1)

thereafter, little or no activity for up to 180 min. This exploratory activity was dose dependently reduced by terguride 4.0, 8.0 and 12.0 m g / k g i.p. (figs. 1 and 4). At later times vehicle-treated animals were more active whereas terguride-treated animals showed almost com- plete akinesia.

Prior to behavioural testing, all animals of group A (treatment with M P T P 2 months before the experiment) showed a reduction in basal locomotor activity and exhibited slower and less coordinated movements, reduced checking m o v e m e n t s of the head and eye- blinks as well as abnormal postures of some parts of the body. T h e behavioural deficits were different in group B (treatment with M P T P 10 months before testing). Locomotor activity was still reduced in one of these animals whereas a n o t h e r showed signs of hyper- excitability and unrest. The behaviour of the third animal was not different from that of controls.

Animals treated with M P T P 2 months prior to the experiment (group A) showed reduced locomotor activity when exposed to vehicle. Terguridc stimulated locomotor activity in the first I80 min after administration.

Because stereotyped movements were elicited by the higher doses tested, 4.0 m g / k g of tcrguride was most effective (fig. 4 and table 1). T h e stimulatory effect of tcrguride was more pronounced during the last 3 h of

~" 900

|

Z o 780

,~

L M

~ 660

--~ 540

~

~ ~ 2 0

~ 300 E 180

~ so

:~ -60

T

. . ,

10 60 120 180 240 300 360

Time (rain)

Fig. 2. Mean locomotor activity counts (_,'. S.E.M., N = 3) accumu- laled in 10-min inlcrvals for 360 rain of c o m m o n m a r m o s e t s pre- treated with M P T P 2 m o n t h s prior to the adminislration of vehicle ( o ) or 4.0 (e), 8.0 ( ,~ ) and 12.0 ( • ) m g / k g of terguride, respectively.

E r r o r bars for the higher doses are omitted for clarity but were within the same range as those s h o w n for 8.0 m g / k g or vehicle i.p.

(note the difference in scale to fig. 1).

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~ 900 r ]

.

'~z" 780 l tu ~ 660 ] .EE 540 i

~° 420 T

~ ~ T~,~. '

~ 8°°t~ ' ~ , ~ ~ '

E _{, 8 0}

8 ~ o j] i ~ ~ . ~ , - ~ i ~ " - ,

~ -~o ~ ... ~ J

10 60 120 180 240 300 360

Time (min)

Fig. 3. Mean locomotor activity counts ( + S.E.M., N 3) accumulated in 10-min intc~,als for 360 min of common marmosets pro- treated with MPTP 10 months prior to the administration of vehicle (o) or 4.0 (~), 8.0 ( ~ ) and 12.0 ( ~ ) mg/kg of terguridc, respccti~ ely.

Error bars for the higher doses are omitted lbr clarity but wcrc within the same range as those shown for 8.13 mg/kg or vehicle i.p.

the o b s e r v a t i o n p e r i o d (fig. 2). V e h i c l e - t r e a t e d a n i m a l s showed some activity at this time of day, w h e n they are usually fed. M a r m o s e t s t r e a t e d with 4.0 a n d 8.0 m g / k g of t e r g u r i d e were clearly s t i m u l a t e d . T h e p r e s e n c e of stcrcotypics (table 11 resulted in a s m a l l e r s t i m u l a t i o n o f l o c o m o t i o n after a d m i n i s t r a t i o n of 12 m g / k g of t c r g u r i d c i.p. (fig. 5).

T h e basal l o c o m o t o r activity of c o m m o n m a r m o s e t s t r e a t e d with M P T P 10 m o n t h s prior to the e x p e r i m e n t (group B) was variable, l e a d i n g to s o m e w h a t h i g h e r activity c o u n t s after vehicle t r e a t m e n t as c o m p a r e d with controls a n d a n i m a l s of group A (figs. 3 a n d 4).

T r e a t m e n t with t e r g u r i d e r e d u c e d l o c o m o t o r activity at

~ 1500

,000 . i_i l

8 8

~ 0 " ' '

~ Normal MPTP 2 MPTP 10

Fig. 4. Mcau locomotor activity counts ( = S.E.M.) accumulated over 180 in for the data shown in figs. 1-3. All groups of common marmosets wcrc treated with vehicle (open columns), 4.0 (dense hatched columns), 8.11 (hatched columns) and 12.0 (crossed columns) mg/kg of terguride. In naive animals tcrguridc dose dependently reduced locomotor activity (P < 13.01, Page test, ordered alternative:

vehicle > 4.0 > 8.13 > 12i1 mg/kg of tcrguride). In common marmoscts treated with MIrTP 2 months prior to the experiment, tel'- guride stimulated locomotor activity at the lowest dose tested (4.0 mg/kg i.p., P < 0.05, Page test; ordered alternative: vehicle < 4.0 and 8.0 < 12.0 mg/kg of terguridc). In animals exposed to MPTP 113 months prior to the experiment, terguride rednccd locomotor actMty up the highest dose tested allhough the effect was not significant.

~

^" ⁸⁰⁰⁰

z

6000 1

c ~/×"

~ 4000

~ 2000

~ 0 -

Normal MPTP 2 MPTP 1

Fig. 5. Mean locomotor activity counts ( ~ S . E . M . , N = 31 accnmu- lated over 360 min for the data shown in figs. 2 aud 3. Both groups of common marmosets wcrc treated with vehicle (open columns), 4.0 (dense hatched columns). 8.0 (hatched colunms) and 12.0 (crossed colunms) mg/kg of tcrguride. In animals treated with MPTP 2 months prior to the experiment, tcrguridc clearly stimulated locomotor activity at ~he lower doses tested (4.0 and 8.0 mg/kg i.p.).

Ilowcvcr, due to the variability of iudividual animal responses, this effect was not statistically significant. In common marmosets exposed to MPTP 10 months prior to the experiment, terguridc had no effect

upon locomotor activity.

all doses tested, a l t h o u g h the effect did n o t seem to be d o s e - d e p e n d e n t . D u r i n g the s e c o n d 3-h period, ter- g u r i d e showed a t e n d e n c y to s t i m u l a t e l o c o m o t o r activity. A g a i n , this effect was n o t significant (figs. 3 a n d 5) for the 6-h o b s e r v a t i o n period. N o n e of the doses of t e r g u r i d e tested i n d u c e d p r o n o u n c e d s t e r e o t y p e d m o v e m e n t s in this g r o u p of a n i m a l s (table 1).

4. D i s c u s s i o n

In r o d e n t s w i t h o u t lesions, t e r g u r i d e has D A a n t a g - onistic p r o p e r t i e s , r e s u l t i n g in a r e d u c t i o n of l o c o m o t o r activity a n d in catalepsy w h e n higher doses are a d m i n - istered. In line with these findings, the c o m p o u n d r e d u c e s exploratory l o c o m o t o r activity of n o r m a l com- m o n m a r m o s e t s . This d e p r e s s a n t effect Iasts up to 6 h.

D A agonistic p r o p e r t i e s arc u n m a s k e d in r o d e n t s pre- t r e a t e d s u b c h r o n i c a l l y with r e s e r p i n e ( W a c h t e l et al., 1984). It is likely that the d e p l e t i o n of m o n o a m i n e r g i c t e r m i n a l s may lead to a n i n c r e a s e d sensitivity of postsy- n a p t i c receptors. T h e a n t i - p a r k i n s o n i a n activity of ter- g u r i d e in the M P T P - t r e a t e d p r i m a t e , the most reliablc m o d e l fl)r P a r k i n s o n ' s disease at p r e s e n t available, has b e e n shown previously. T h e c o m p o u n d i n d u c e s rotations in m o n k e y s r e n d e r e d h c m i p a r k i n s o n i a n by intrac- arotid i n f u s i o n of M P T P (Brihckc et al., 1988). In accord with these findings, o u r data indicate that D A agonistic effects in the M P T P - t r c a t c d c o m m o n mar- m o s e t arc also critically d e p e n d e n t o n the r e c e p t o r status. A clear s t i m u l a t o r y effect was only seen in a n i m a l s t r e a t e d 2 m o n t h s previously with M P T P w h e n they had not recovered b c h a v i o u r a l l y from the M l r f P t r e a t m e n t . I n the first 3 h, 4 m g / k g of t e r g u r i d e

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produced the greatest response (fig. 4) whereas in the 6-h period 4 and 8 m g / k g stimulated locomotor activ- il.y (fig. 5). In animals that had recovered from M P T P treatment given 10 months previously, tcrguride inhib- i,.cd locomotor activity in the first 3 h, as it did in f o r m a l marmosets, although this effect was not statistically significant, llowever, in the 6-h period, all doses tested slightly stimulated locomotor activity, a response consistent with the weak DA agonistic effects of tcrguride under these conditions. We hypothesize that the bchavioural recovery of common marmosets is accom- panied by a normalization of receptor sensitivity duc to changes in either the binding affinity or the coupling of receptors to second messenger systems. Thus, in ani- raals recovered from prior M P T P treatment, the increased I)A turnover (Rose et al., 1989) could lead to a higher availability of DA and subsequent normalization of the sensitivity of presynaptic autoreceptors. Under these conditions tcrguride would act as autoreceptor agonist, resulting in a reduced I)A release and inhibition of locomotor activity during the initial 3-h period.

In the second 3-h period, tcrguridc would exert weak DA agonistic properties at postsynaptic receptors.

An alternative explanation involves the partial DA agonistic properties of terguride. Thus, the increased DA turnover could lead to a higher availability of DA, with terguride antagonizing the effects of endogenous I)A. The initial inhibition of locomotor activity could be explained by such a phenomenon. Since terguridc did not reduce but slightly increased locomotor activity in recovered common marmosets over the 6-h period, the latter hypothesis seems less likely.

Two faccts of the effects of tcrguridc arc of interest when compared with the effects of direct DA agonists such as ( + ) - P H N O (Nomoto et al., 1987) in this animal raodcl. First, tcrguridc did not cause a rapid and sustained locomotor hyperactivity even with the rela- tively high doses used. Second, the normal diurnal pattern of locomotor activity was preserved. Increased activity after treatment with terguride was seen during periods of higher basal locomotor activity nnder con- trol conditions. Both observations contrast with the stimulatory effect on locomotor activity seen in reser- pinizcd-rodents and are compatible with the idea that terguride 'enables' voluntary locomotion in the MPTP-treated marmoset rather than causes hyperstim- ulation. This atypical pharmacological profile, in which DA agonistic and D A antagonistic properties arc combined in one molecule, has been described as mixed DA agonism/antagonism in rodents. Our data show similar effects of terguride in a primate species.

The unique pharmacological profile of terguridc suggests an interesting range of possible indications, some of which have already been tested in clinical trials. Like classical DA agonists, single doses of tcrguride ranging from 0.25 to 1.0 mg lower prolactin

levels in humans and produce endocrine effects identical to those seen with bromocriptinc, but with less side effects. In a double-blind cross-over study, subjects could not distinguish the lower tcrguridc doses from placebo and 1 mg of tcrguridc was always preferred to 2.5 mg bromocriptinc (Ciccarclli et al., 1988). Clinical observations confirm that terguride is useful in the treatment of hyperprolactinaemic conditions including prolactinomas (Dallabonzana et al., 1986). Antiparkin- sonian effects have been reported when terguride was used as monotherapy or combined with L-Dopa in advanced disease (Corsini et al., 1985). In open clinical trials in paticnts with Parkinson's disease, especially in elderly patients (Briicke et al., 1986), there was a low frequency of typical dopamincrgic side effects such as nausea, cmcsis or orthostatic hypotension. However, in a double-blind study in dc now) patients terguride was better tolerated but less active than lisuride after 3 months of therapy and its possible long-term effects are still trader investigation (U.K. Rinnc, personal communication). In placebo-controlled double-blind studies in patients with motor fluctuations, terguridc added to L-Dopa had a significant effect on disability and also improved wearing off and dyskinesias (E.

Martignoni and G. Nappi, personal communication).

In these studies antidyskinetic and anti-akinctic effects of terguridc wcrc obse~'ed in the same patients. Tcr- guridc had very pronounced anti-dyskinetic effects without interference with the anti-akinctic effects of L-Dopa in parkinsonian patients with motor fluctuations as shown in a double-blind placebo-controlled study (Baronti et al., 1989 and submitted for publica- tion). Tcrguridc has positive effects on tardive dyskincsia even in the presence of ncurolcptic drugs (Silk6 ct al., 1987). Finally, in an open clinical trial, including 11 patients with chronic schizophrenia and marked negative symptoms, tcrguride improved symptomatology in eight patients on the scale for assessment of negative symptoms (SANS). In none of the patients were psy- chotic symptoms elicited and the compound was well tolerated (Olbrich and Schanz, 1988).

Mixed DA agonist/antagonists may have good antiparkinsonian actions with fewer side effects, especially in patients susceptible to motor fluctuations, dyskinesias, psychosis or e n h a n c e d sensitivity towards dopamincrgic drugs.

In conclusion, the MPTP-treated common marmoset offers a useful pharmacological model and is of predictive value for the characterization of not only classical direct D A agonists but also mixed DA agonist/antagonists. Tcrguride can be used in a pharmacological in vivo test for the assessment of the sensitivity status of central DA receptors in MPTP-trcated primates. Tcrguride could also be valuable for the assessment of the function of dopaminergic cell trans- plants.

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Acka~owledgements

K.W. Lange was supported by the European Science Foundation and the European Medical Research Council. P.A. ISSschmann was a visiting research fellow at the University I)epartment of Clinical Neurology, Institute of Neurology, The National Hospital, Queen Square, London.

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