Functional interaction between dopamine D1 and D2 receptors in ‘MPTP’ monkeys

ELSEVIER

European Journal of Pharmacology 253 (1994) 215-224

Functional interaction between dopamine D 1 and in 'MPTP' monkeys

D 2

receptors

M. Rosario Luquin *, Javier Guill6n, Eduardo Martinez-Vila, Janet Laguna, J. Manuel Martfnez-Lage Department of Neurology, Clinica Universitaria, University of Navarra, 31080 Pamplona, Spain (Received 5 July 1993; accepted 24 November 1993)

Abstract

We have studied the motor response induced by independent administration of 4 different doses of a dopamine D 2 [(+)-PHNO] and a dopamine D 1 (CY 208-243) receptor agonist in 5 MPTP (1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine) monkeys. Both drugs had similar antiparkinsonian effects and both elicited choreic dyskinesias. Simultaneous administration of (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine] and CY 208-243 [(-)4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3a-b] phenanthyxidine] did not result in modification of the dose-response curve induced by each dopamine receptor agonist given alone. Pretreatment with the dopamine D~ receptor antagonist SCH 23390 (0.8 mg/kg) and the dopamine D 2 receptor antagonist sulpiride (60 mg/kg) reduced the magnitude and the duration of the motor response induced by (+)-PHNO and CY 208-243, respectively, but did not modify the intensity and characteristics of choreic dyskinesias. These results demonstrate that the motor effects and the dyskinesias cannot be dissociated by selective dopamine D~ and D 2 receptor stimulation. It appears that stimulation of dopamine D 1 and D 2 receptors by endogenous dopamine is required to obtain the full motor response induced by selective dopamine receptor agonists as demonstrated by the reduction of the motor improvement found after pretreatment with SCH 23390 and sulpiride. Key words: MPTP (1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine); MPTP monkeys; (+)-PHNO ((+)-4-propyl-9-hydroxynaphthoxazine); CY 208-243 ((-)4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3a-b]phenanthyxidine); Dopamine D 1 receptor; Dopamine D z receptor; SCH 23390; Sulpiride; Dopamine D1/D 2 interaction

1. Introduction

Abundant evidence has accumulated in the past suggesting a functional interaction between dopamine D a and D 2 receptors in dopamine-mediated behaviour (Robertson and Robertson, 1986; Clark and White, 1987; Sonsalla et al., 1988; Morelli et al., 1991). The role of other recently described dopamine receptors (D3, D4, D s) in motor function remains to be elucidated (Schwartz et al., 1992). In normal rodents, selective stimulation of dopamine D 1 and D 2 receptors produces different patterns of behaviour. The dopamine D 2 receptor agonist quinpirole and the mixed agonist apomorphine elicit hyperactivity and stereotyped behaviour while dopamine D 1 receptor agonists such

* Corresponding author. 0014-2999/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0 0 l 4 - 2 9 9 9 ( 9 3 ) E 0 8 6 7 - R

as SKF 38393 (2,3,4,5-tetrahydro-7,8-dihydroxyl-1phenyl-lH-3-benzazepine hydrochloride) and CY 208243 ((-)4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3ab]phenanthyxidine) produce non-stereotyped oral movements (grooming, sniffing and vacuous chewing) but fail to induce hyperactivity (Braun and Chase, 1986; Waddington and O'Boyle, 1987; Markstein et al., 1988). However, a complex functional interaction between these two subtypes of receptors seems to occur in the striatum of normal rodents. Co-administration of SKF 38393 with a D z agonist like quinpirole, bromocriptine or R U 24213 induces more intense stereotypes than each drug given alone (Arnt et al., 1987; Mashurano and Waddington, 1986; Jackson et al., 1988). Similarly, in mice rendered hypokinetic by reserpine, selective D z agonists such as LY 141865 (trans-(+)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-2 Hpyrazolo(3,4-g)quinoline dihydrochloride), quinpirole

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M.R. Luquin et al. / European Journal of Pharmacology 253 (1994) 215 224

and bromocriptine only induce locomotor stimulation when combined with SKF 38393, even with subthreshold doses (Jackson and Hashimuze, 1986; Carlsson et al., 1988; Gershanik et al., 1983). In addition, in intact rats selective dopamine D~ and D 2 receptor antagonists (SCH 23390 and sulpiride) can block stereotypes induced by dopamine D 2 receptor agonists and either antagonist can independently inhibit the hypermotility induced by apomorphine (Murray and Waddington, 1989; Hess et al., 1986; Ogren et aI., 1986). This functional |inkage between D1 and D 2 dopamine receptors is lost to some extent in the denervated striatum. In rats with 6-OHDA (6-hydroxydopamine)elicited nigrostriatal lesions, both D~ and D 2 dopamine agonists elicit circling behaviour and this motor response is specifically inhibited by selective dopamine D~ and D 2 receptor antagonists respectively (Barone et al., 1986; Clark and White, 1987). On the other hand, the ability of different dopamine D 2 receptor agonists to produce circling behaviour is dramatically attenuated by pretreating animals with a-methyl paratyrosine or the selective dopamine D1 receptor antagonist SCH 23390, suggesting that dopamine D~ receptor stimulation is absolutely essential for the activity of dopamine D 2 receptor agonists (Hess et al., 1986; Barone et al., 1986). In the same model, co-administration of ineffective doses of SKF 38393 and dopamine D 2 receptor agonists, produces contralateral turning behaviour, indicating a synergistic effect between these two subtypes of dopamine receptors (Robertson and Robertson, 1986; Dall'Olio et al., 1988). Taking all these findings together, it appears that, in normal and denervated striatum of rodents, dopamine D x receptor stimulation exerts a facilitating role on D2-mediated motor response but there is no consistent evidence indicating a modulatory role of dopamine D 2 receptors in the expression of Dl-mediated behaviour. A more complex functional interaction between these two dopamine receptors seems to occur in the striatum of primates. For instance, in normal monkeys, the administration of dopamine D 2 receptor agonists (quinpirole) and mixed agonists (apomorphine) induces locomotor hyperactivity and stereotypes whereas the D 1 agonist SKF 38393 causes a dose-related decrease in locomotor activity and also inhibits the motor response induced by quinpirole. In addition, locomotor activity and stereotypes elicited by quinpirole are equally inhibited by selective dopamine D 1(SCH 23390) and D 2 (raclopride) receptor antagonists (L6schmann et al., 1991). This functional interaction also seems to occur in primates with nigrostriatal lesions induced by 1-methyl4-phenyl-l,2,3,6-tetrahydropyridine. Thus, selective d o p a m i n e D 2 receptor agonists ((+)-4-propyl-9-hydroxynaphthoxazine and quinpirole) and mixed agonists (apomorphine and l-dopa) dose dependently re-

verse parkinsonism and also induce hyperactivity (Barone et al., 1987; Nomoto et al. 1985; Close et al., 1991; G6mez-Mancilla et al., 1992; Elliot et al., 1992). By contrast, the dopamine D 1 receptor agonist SKF 38393, like the dopamine D I receptor antagonist SCH 23390, does not improve parkinsonism in marmosets and causes a reduction in the anti-bradykinetic effects of l-dopa and quinpirole (Close et al., 1985; Barone et al., 1987; Nomoto et al., 1988; Elliot et al., 1992). Therefore, it appears that dopamine D 1 receptor stimulation in primates exerts an inhibitory influence on the motor activity and stereotypes produced by dopamine D 2 receptor stimulation. However, it is not clear whether this oppositional D~/D 2 interaction reflects intrinsic properties of the drugs used or whether it can be extended to all dopamine receptor agonists. We now report the motor responses elicited by independent and simultaneous administration of selective dopaminergic drugs, (+)-PHNO (dopamine D 2 receptor agonist) and CY 208-243 (partial dopamine D~ receptor agonist), in 5 parkinsonian monkeys. In addition, the effect of specific D 2 and D~ antagonists (sulpiride and SCH 23390) on the motor responses produced by CY 208-243 and (+)-PHNO (4-propyl-9hydroxynaphtoxazine) respectively, was assessed in order to evaluate the role of endogenous dopamine on the motor responses elicited by selective dopamine agonists.

2. Materials and methods

2.1. General characteristics Five monkeys (Macaca Fascicularis) of either sex weighing 2.1-2.7 kg were used in the present study. The monkeys were housed in cages in an animal room under standard conditions of temperature (21 +_ I°C), relative humidity (55 + 5%), air exchange (16 times/h) and light (8 a.m. to 8 p.m.). They were given fruit and had free access to commercial pellets and water. MPTP (1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine) was dissolved in saline (NaC1 0.9%) and given i.v. (0.5-1 mg/kg), to a cumulative dose of 0.94-5.3 mg/kg, once a week under anaesthesia (Ketamine 10 mg/kg). Injections were repeated until a stable moderate or severe parkinsonism was achieved. No additional MPTP injections were administered throughout the whole experiment. (+)-PHNO (3.3-6.6 /zg/kg per day, i.m.) was administered occasionally within acute phases after MPTP, when severe bradykinesia hindered normal feeding. In two cases (+)-PHNO (0.04-3.3 /zg/day) had to be continued for 7 and 10 days until a partial recovery from the last MPTP injection occurred. These 2 animals were free of any dopaminergic drug for at least 2 weeks before the experiment was started. The

M.R. Luquin et al. / European Journal of Pharmacology253 (1994) 215-224

other 3 monkeys were maintained drug-free for 6-8 weeks before the study was begun. 2.2. Drugs

( + )-4-propyl-9-hydroxynaphthoxazine (( + )-PHNO) (gifted by Merck Sharp and Dhome, Rahway, N J) was given i.m. (0.04-0.3 /zg/kg). CY 208-243 ((-)4,6,6, a7,8,12b-hexahydro-7-methylindolo[4,3a-b]phenanthyxidine) (gifted by Sandoz, Basle, Switzerland) was dissolved in saline (NaC1 0.9%) with an equivalent quantity of tartaric acid and was administered i.m. (0.1-0.8 mg/kg). Sulpiride (Sigma, St Louis, MO) and SCH 23390 (Research Biomedical, Natick, MA) were dissolved in saline (NaCI 0.9%) and injected i.m. (60 and 0.8 mg/kg, respectively). 2.3. Dose-response curves 2.3.1. Independent and simultaneous administration of dopaminergic drugs In every experiment, drugs were administered between 10 and 11 a.m. and the animals remained free of any medication until the next study day. (+)-PHNO was given i.m. at four different doses (0.04, 0.12, 0.2 and 0.3/zg/kg) on consecutive days so that a dose-response curve was obtained for each animal. During the following week, a dose-response curve was made for CY 208-243 by giving 4 consecutive doses on different days (0.1, 0.2, 0.4 and 0.8 mg/kg). For each drug the minimal effective dose was defined as the dose capable of producing a reduction in the disability score of 50% by at least 30 min. The minimal dose for each animal was found by trial and error. The largest dose of either (+)-PHNO and CY 208-243 used in this study elicited marked hyperactivity in all animals, precluding any further increment. These doses (0.3/zg/kg for (+)-PHNO and 0.8 m g / k g for CY 208-243) were therefore considered as the maximal effective doses. In a separate experiment, (+)-PHNO and CY 208243 were administered simultaneously. The minimal effective dose of (+)-PHNO (0.04 /xg/kg)was tested against the whole range of CY 208-243 doses used previously. In addition, the minimal effective dose of CY 208-243 (0.1 m g / k g ) w a s administered simultaneously with each one of the previous doses of (+)PHNO. In both cases, the experiments were undertaken on consecutive days starting with the dose-response curve of ( + )-PHNO + CY 208-243. 2.3.2. Administration of D 1 and D 2 antagonists Both the (+)-PHNO and the CY 208-243 dose-response curves were estimated again in all the animals a few days before these experiments were started and they were repeated subsequently in order to test the

217

effect of dopamine D 1 and D 2 receptor antagonist. Monkeys received sulpiride (60 rag/kg) 2 h before CY 208-243 administration. The dose of sulpiride used was that which is able to abolish the motor improvement induced by the maximal dose of (+)-PHNO (0.3 /zg/kg) in these animals and it was chosen based on previous data from marmosets (Temlett et al., 1988). Experiments were separated by a minimum of 2 days so as to avoid a possible cumulative effect of repeated sulpiride administration. Animals were pretreated with the dopamine D l receptor antagonist SCH 23390 (0.8 mg/kg) 1 h before they were given the corresponding (+)-PHNO dose. In this case, the test was repeated every day. The dose of SCH 23390 was selected in accordance with data from experiments with marmosets (Temlett et al., 1988) and was able to block the motor improvement produced by the maximal dose of CY 208-243 in our macaque monkeys. 2.4. Evaluation

The degree of motor improvement was assessed by a disability score which ranged from 0 (normal) to 25 (maximal disability). This scale independently scores akinesia, tremor, balance, freezing and feeding from 0 (normal) to 3 (extremely severe) and spontaneous activity from 0 (normal) to 5 (absence of spontaneous movements). Evaluations were made by the authors by means of direct and continuous observation every 10 min, until the motor benefit elicited by each drug had disappeared. For both drugs, the lowest disability score recorded ('on' score) was the one considered for statistical analysis. The 'off' score (basal disability score) was defined as the disability score recorded before the administration of any dopaminergic drug. The presence of dyskinesias was assessed every 10 min according to type (chorea, dystonia) and severity (0 = absent, 1 = mild, 2 =moderate and 3 = severe). Since the severity of dyskinesias changed during the observation period, the arithmetic mean value of all scores was used for the final analysis. An index of dyskinesias was calculated and expressed as the ratio between the duration of dyskinesias and motor benefit (min). 2.5. Statistical analysis

The magnitude of the motor improvement and the intensity and index of dyskinesias produced by independent and simultaneous administration of (+)PHNO and CY 208-243 were compared by using a Wilcoxon test for paired samples. The effect of sulpiride and SCH 23390 pretreatment on the motor responses elicited by CY 208-243 and (+)-PHNO, was also compared by using a Wilcoxon test. A Friedman-Anova test was used for comparing the intensity of motor response and the severity and index of dyskinesias

218

M.R. Luquin et al. /European Journal of Pharmacology 253 (1994) 215-224

Table 1 Motor response and dyskinesia induced by (+)-PHNO and CY 208-243 in 5 parkinsonian monkeys A

(+)-PHNO (0.04 txg/kg) Disability score OFF ON

9.2 3.28

Latency ON (min) 4 Duration of the 47.4 response (rain) Intensity of 0.78 dyskinesias Index of dyskinesias 0.46

CY 208-243 (0.1 mg/kg) 13 3.72 5.6 57.8

B

C

(+)-PHNO CY 208-243 (0.12 txg/kg) (0.02 mg/kg)

(+)-PHNO (0.2/xg/kg)

9.6 2.96 2.4 94.6

13.4 3.72

D

10.4 2.68

4.2 88.4

2.4 114.8

CY 208-243 (0.4 mg/kg) 12.8 2.92 4.4 109.6

(+)-PHNO (0.3/xg/kg)

CY 208-243 (0.8 mg/kg)

10.4 3

12.2 2.5

NS NS

1.4 126.8

4.2 131.6

NS NS

1.16

1.28

0.94

1.38

1.04

1.26

1.02

NS

0.28

0.6

0.38

0.62

0.27

0.7

0.4

NS

Mean values of the intensity of the motor response and dyskinesias induced by independent administration of (+)-PHNO and CY 208-243. The motor response induced by the minimal effective dose of each dopamine agonist (A) was compared to that elicited by the corresponding doses of (+)-PHNO and CY 208-243 (B, C and D). No significant differences were found when comparing the motor response and the dyskinesias induced by increasing doses of either dopamine receptor agonist. NS: no significant differences.

induced by the different doses of each drug. Modifications of the duration of the motor responses induced by (+)-PHNO and CY 208243 alone and after the different combinations observed in this study were compared by a paired t-test.

sias were not observed in the other animal throughout the whole experiment.

3.2. Dose-response curves 3.2.1. Independent and simultaneous administration of

dopaminergic drugs Independent administration of ( + ) - P H N O and CY

3. Results

3.1. General findings MPTP administration produced a parkinsonian syndrome in all animals equivalent to stage III-IV of the Hoehn and Yahr rating scale. The total dose required for the development of parkinsonism varied widely (0.94-5.3 rag/kg). Three animals developed mild choreic dyskinesias rapidly after a few doses of (+)-PHNO given within the acute phases following MPTP administration. One animal developed chorea when the first (+)-PHNO dose-response curve was made. Dyskine-

208-243 induced a similar relief of parkinsonism in all the animals in terms of the reduction of the disability score ( P > 0.05). The effect started within 2 - 3 rain and reached the peak effect in 30 min. Over the whole range of doses used, no difference was observed in the magnitude of the motor response (expressed as reduction in the disability score) and the intensity and index of dyskinesias for either of the drugs, but the duration of the motor response increased in a dose-dependent manner (Table 1). No significant differences were found when comparing the intensity of the motor response induced by

Table 2 Motor response induced by (+)-PHNO and (+)-PHNO + 0.1 m g / k g of CY 208-243 in 5 parkinsonian monkeys ( + )-PHNO 0.04/xg/kg Disability score OFF ON Latency ON (rain) Duration of the response (rain) Intensity of dyskinesias Index of dyskinesias

( + )-PHNO + 0.1 mg/kg of CY 208-243 0.12/xg/kg

0.2 txg/kg

0.3 txg/kg

0.04/xg/kg

0.12/xg/kg

0.2 txg/kg

P 0.3 # g / k g

16 1.2

16.6 1.6

15.2 1.4

14.8 1.6

15.8 1.6

15.4 1.2

15 1.2

15 1.4

3.6 74.6

2.8 106.8

3.2 120.2

2.8 137.4

2.6 89.8

2.8 117

2 127.8

2.03

1.6

1.5

1.7

1.5

1.5

1.6

1.8

NS

0.63

0.43

0.41

0.46

0.57

0.48

0.40

0.41

NS

2 140

NS NS NS NS

Mean values of the motor responses induced by the administration of (+)-PHNO and (+)-PHNO + 0.1 mg/kg of CY 208-243 in 5 parkinsonian monkeys. No significant differences with respect to the duration of the motor response and the intensity of the dyskinesias were observed between the motor responses induced by (+)-PHNO and (+)-PHNO + 0.1 m g / k g of CY 208-243.

219

M.R. Luquin et al. / European Journal of Pharmacology 253 (1994) 215-224 Table 3 Motor response induced by simultaneous administration of CY 208-243 and 0 . 0 4 / z / k g of ( + ) - P H N O CY 208-243

CY 208-243 + 0.04/xg/kg of ( + ) - P H N O

0.1 m g / k g

0.2 m g / k g

0.4 m g / k g

0.8 m g / k g

0.1 m g / k g

0.2 m g / k g

0.4 m g / k g

0.8 m g / k g

13 1.4 5 58.2

13.4 1.4 4 92

12.8 1.6 3.8 108.6

12.2 1.4 3.4 133

12.4 1 3 95.2 a

12 1.6 3.6 93.6

12.6 1 3.2 107.8

11 1.2 2.2 125.4

1.4

1.2

1.3

1.2

1.65

1.6

1.4

1.62

NS

0.77

0.7

0.59

0.79

0.83

0.91

0.77

0.82

NS

Disability score OFF ON Latency ON (min) Duration of the reponse (min) Intensity of dyskinesias Index of dyskinesias

a

NS NS NS P < 0.05

Mean values of the motor response and dyskinesias induced by CY 208-243 and the 0 . 0 4 / z g / k g of ( + ) - P H N O + CY 208-243 in 5 parkinsonian monkeys. No significant differences were observed with respect to the duration of the motor response and the intensity of the dyskinesias when both drugs were given simultaneously. Only the duration of the motor response elicited by 0.1 and 0.4 m g / k g of CY 208-243 was increased when co-administered with 0 . 0 4 / z g / k g of (+)-PHNO. NS: no significant differences, a p < 0.05.

( + )-PHNO and CY 208-243. In 4 animals with choreic dyskinesias induced by previous (+)-PHNO treatment, CY 208-243 administration caused similar abnormal movements. No differences in the dyskinetic scores were found as compared to those that appeared after (+)-PHNO administration (Table 1). When the minimal effective dose of CY 208-243 (0.1 m g / k g ) w a s given simultaneously with the 4 (+)PHNO doses, no differences between the dose-response curves for (+)-PHNO alone and (+)-PHNO plus CY 208-243 were obtained. The magnitude and the duration of the motor improvement induced by (+)-PHNO plus CY 208-243 were similar to those observed with (+)-PHNO given alone. The intensity and index of dyskinesias also remained unmodified (Table 2). The dose-response curves obtained by administration of the minimal effective dose of (+)-PHNO plus

the range of 4 CY 208-243 doses used previously did not show any difference when compared with those found with CY 208-243 given alone. The magnitude of the motor response and the dyskinetic scores were also similar for CY 208-243 and (+)-PHNO plus CY 208243 (Table 3). 3.2.2. 01 and D 2 blockade 3.2.2.1. SCH 23390 pretreatment. SCH 23390 administration elicited a significant increase in the basal parkinsonism of all 5 animals in each of the 4 experiments undertaken ( P = 0.02, Table 4) and induced dystonic postures of the neck and lower limbs in 3 animals. In addition, a significant decrease of the duration of the motor response elicited by 0.04, 0.12 and 0.3 tzg/kg of (+)-PHNO doses was observed (P=0.02; P < 0.005 and P = 0.02 respectively; Table 4). The in-

Table 4 Motor response induced by ( + ) - P H N O after pretreatment with SCH 23390 ( + )-PHNO 0.04/~g/kg

( + )-PHNO + SCH 23390 (0.8 mg/kg) 0.12/zg/kg

0.2/zg/kg

0.3 ~ g / k g

0.04 ~ g / k g

0.12/zg/kg

0.2/zg/kg

0.3/zg/kg

19 a 1.8

19.8 a 2

17.8 1.4

17.4 a 1

8.4

2.2 a 117.4 a

Diasbility score OFF ON Latency ON (min) Duration of the response (min) Intensity of dyskinesias Index of dyskinesias

15.8 1

15.4 1.4

14.8 1.2

15.2 0.6

1.6

2.2

2.4

1.6

10.6 a

16.2 a

92.6

122.2

130.4

143.8

68.4 a

82 b

93.2

1.38

1,66

1.54

1.59

1.32

1.6

1.6

1.6

0.74

0.67

0.62

0.58

0.78

0.76

0.75

0.68

Mean values of the intensity of the motor response and dyskinesias induced by 4 different doses of ( + ) - P H N O after pretreatment with SCH 23390 (0.8 m g / k g ) in 5 parkinsonian monkeys. The intensity of basal parkinsonism (OFF score) and the latency to ON increased, while the duration of the motor response decreased. No changes in the intensity of the motor response and dyskinesias were observed, a p = 0.02; b p < 0.005.

M,R, Luquin et al. / European Journal ~f" Pharmacolok, y 253 ( 19941 215-224

22(1

Table 5 Motor response and dyskinesia induced by CY 208-243 after pretreatment with sulpiride CY 208-243

Disability score OFF ON Latency ON (min) Duration of the response (rain) Intensity of dyskinesias Index of dyskinesias

CY 208-243 + supliride (6(1 m g / k g )

0.1 m g / k g

0.2 m g / k g

0.4 m g / k g

0.8 m g / k g

0.1 m g / k g

0.2 m g / k g

0.4 m g / k g

(1.8 m g / k g

13.8 1.2 6.8 50.6

13.8 1.2 2.4 88.4

13.8 1.2 1.2 120.6

13.4 1.6 w 169.6

22.2 ~' 14.4 ,L 3.8 7.6 b

22.2 ~' 7.4 :' 3 37.4 ~

22,2 '~ 4,2 ~l 6,2 ~ 59 b

22.2 ~' 6.6 2 48.2 b

(/.96

1.12

1.2

1.08

0.4

0.94

0.86

1

0.68

0.63

0.5(I

0.57

0.94

0.48

(/.41

0.43

Mean values of the intensity of the motor response and dyskinesias induced by 4 different doses of CY 208-243 in 5 parkinsonian monkeys after pretreatment with sulpiride (60 m g / k g ) . Basal parkinsonism (OFF score) increased significantly following sulpiride administration, while the intensity and duration of the motor response decreased. Dyskinesias remained unmodified after pretreatment with sulpiride. ~ P < 0.05; h P < 0.01.

tensity of the motor response and the severity and index of dyskinesias remained unmodified (P > 0.05, Table 4).

the animals with selective dopamine receptor antagonists but the intensity and duration of dyskinesias remained unmodified.

3.2.2.2. Sulpiride pretreatment. After pretreatment with sulpiride, the basal disability score of parkinsonism significantly increased in all animals (P = 0.04, Table 5). Two animals (CYN-3 and CYN-4) showed dystonic postures affecting the neck and both legs within 1 h after sulpiride administration. The duration of the motor response induced by the minimal effective dose of CY 208-243 (0.1 mg/kg) was less than 30 min in all animals (2 failed completely to improve parkinsonism). The duration of the effect of each of the 3 higher doses of CY 208-243 (0.2, 0.4 and 0.8 mg/kg) after pretreatment with sulpiride was significantly reduced as compared to basal values (P < 0.01, Table 5). The magnitude of each of the responses (reduction in the disability score) induced by the 4 different doses of CY 208-243 was significantly reduced after treatment with sulpiride (P < 0.05, Table 5) but the dyskinetic scores induced by CY 208-243 administration remained unmodified.

4.1. Motor response induced by independent administration of ( + )-PHNO and CY 208-243

4. Discussion

The present findings demonstrate that the dopamine D e receptor agonist (+)-PHNO and the partial dopamine D t receptor agonist CY 208-243 are equally potent in reversing parkinsonism in MPTP-treated monkeys. Both drugs induced a similar reduction of the parkinsonian disability score and dyskinesias. Co-administration of dopamine Dj and D 2 receptor agonists did not modify the dose-response curve and dyskinesias elicited by each drug given alone. However, the magnitude and the duration of the motor response induced by each drug were significantly reduced by pretreating

The dopamine D 2 receptor agonist (+)-PHNO has been widely shown to relieve parkinsonism both in patients and monkeys rendered parkinsonian by MPTP administration (Jenner et al., 1986; G6mez-Mancilla and B6dard, 1992; Luquin et al., 1992; Muenter et al., 1988). Its antiparkinsonian activity seems to be related to selective stimulation of dopamine D 2 receptors as demonstrated by in vitro and in vivo studies (Martin et al., 1984). On the other hand, the motor behaviour elicited by CY 208-243 administration appears to be mediated by dopamine D~ receptor stimulation. Thus, CY 208-243 does not provoke marked behavioural effects in intact rats as do dopamine D e receptor agonists, and only some episodes of sniffing and grooming have been reported (Markstein et al., 1988). In rats with unilateral 6-OHDA-induced lesion of the nigrostriatal pathway, CY 208-243 causes long-lasting contralateral circling behaviour which is almost completely blocked by pretreatment with SCH 23390 and unaffected by sulpiride (Karobath, 1987). In binding studies, CY 208-243 exhibits low affinity for D 2 sites labelled with [3H]spiperol and also interferes with the binding of ligands labelling [3H]naloxone receptors in brain membranes (Foote et al., 1988). All these data are consistent with a predominant D 1 effect of CY 208-243. Earlier studies using the dopamine D~ receptor agonist SKF 38393 in parkinsonian monkeys suggested an inhibitory role of dopamine D~ receptor stimulation on the expression on dopamine-related motor activity. In fact, SKF 38393 administration causes worsening rather

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than improvement of parkinsonian features in MPTP monkeys and inhibition of locomotor activity in normal monkeys (Elliot et al., 1992; Boyce et al., 1990; L6schmann et al., 1992). However, Temmlet et al. (1988) and more recently G6mez-Mancilla et al. (1993) have demonstrated that the partial D 1 agonist CY 208-243 has a potent antiparkinsonian effect in MPTP-treated monkeys which is blocked by SCH 23390 and slightly reduced by the dopamine D 2 receptor antagonist sulpiride. Several authors have also reported similar results in patients with Parkinson's disease (Temlett et al., 1989, Tsui et al., 1989). Our results confirm and extend previous results showing that both D e or D 1 dopamine receptor agonists reverse motor deficits induced by MPTP in primates and demonstrate that dopamine D1 and D 2 receptor stimulation produces a similar pattern of behaviour in parkinsonian monkeys. In fact, we found no significant differences with respect to the intensity of the motor response and dyskinesias elicited by independent administration of ( +)-PHNO and CY 208-243 at any of the doses administered. It should be considered that the motor improvement induced by CY 208243 in our parkinsonian monkeys might have been potentiated by previous exposure to the dopamine D 2 receptor agonist (+)-PHNO (heterologous sensitization) as demonstrated by Morelli and Di Chiara (1987) to occur in rats lesioned unilaterally with 6-OHDA. However, chronic (+)-PHNO administration to MPTP marmosets decreased the density of dopamine O 2 receptors compared to that of controls with no changes in the number of D~-labelled sites (Alexander et al. 1991). In addition, in this study, the anti-bradykinetic activity of CY 208-243 still persisted in spite of the blockade of D 2 dopamine receptors by sulpiride (60 mg/kg) which completely abolished the motor improvement induced by the highest dose of (+)-PHNO. Although CY 208-243 possesses in vitro a weak affinity for Dz-labelled sites, these data strongly indicate that the ability of CY 208-243 to reverse parkinsonism is directly associated to dopamine D 1 receptor stimulation. The contradictory results reported in the literature with respect to the ability of D~ stimulation to reverse parkinsonism could be explained by the use of different dopamine D 1 receptor agonists and distinct models of parkinsonism. In fact, SKF 38393 possesses a low ability to cross the blood-brain barrier and it has also been suggested that it could generate some compounds with potential antidopaminergic activity when it is used at high doses (Andersen and Jansen, 1990; Boyce et al., 1990; Elliot et al., 1992). This fact could partially account for the lack of antiparkinsonian effect of SKF 38393. The present findings are in apparent discrepancy with the current hypothesis concerning the normal

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function of the basal ganglia. In 6-OHDA rats, Gerfen et al. (1990) have demonstrated that dopamine differentially regulates the expression of enkephalin and D 2 receptors, and substance P and D 1 receptors in striatal neurons. Thus, a reduced input to striatal neurons enhanced the expression of enkephalin and D 2 receptors labelling in striatopallidal neurons whilst substance P expression and D 1 receptor labelling were decreased in striatal neurons projecting to entopeduncular nucleus and substantia nigra pars reticulata. In addition, these changes were specifically reversed by the administration of the selective dopamine agonists quinpirole and SKF 38393, respectively. On the other hand, studies employing similar pharmacological treatments and measuring 2-deoxyglucose utilization also indicate that dopamine D~ and D 2 receptor stimulation in the basal ganglia is mediated by different striatal outputs (Trugman and Wooten, 1987; Engber et al., 1990). Hence the indirect striato-globus pallidus lateralis-subthalamic nucleus-globus pallidus medialis pathway would be involved in the expression of motor responses mediated by dopamine D 2 receptor stimulation while the direct striato-globus pallidus medialis pathway would mediate dopamine D~ receptor activity. In fact, Anderson et al. (1992) have recently reported that subthalamic nucleus lesions dramatically reduced the circling behaviour elicited by dopamine D 2 receptor agonists in 6-OHDA rats but did not alter the rotatory response produced by dopamine D 1 receptor agonists. In addition, in MPTP-treated marmosets, Boyce et al. (1990) identified different behavioural patterns depending on selective dopamine D 1 or D z receptor stimulation. These authors found that ldopa-induced dyskinesias were abolished by pretreatment with SCH 23390 with no changes in the motor improvement, indicating that dyskinesias are associated with dopamine D~ receptor stimulation while dopamine D 2 receptor activation is responsible for motor improvement. In this study, we were not able to differentiate between motor improvement and dyskinesias by selective dopamine receptor stimulation. The dopamine D 2 receptor agonist (+)-PHNO relieved parkinsonism and also induced choreic dyskinesias in 4 untreated MPTPmonkeys after very few doses of (+)-PHNO, as did the dopamine D 1 receptor agonist CY 208-243. Moreover, pretreatment with selective dopamine antagonists did not modify the intensity or the type of dyskinesias induced by (+)-PHNO or CY 208-243. The similar antiparkinsonian effect of dopamine D~ and D 2 receptor stimulation can be explained by the fact that both striato-pallidal pathways convey a similar effect upon globus pallidus medialis neurons. Thus, inhibition of globus pallidus medialis activity, which leads to movement facilitation, is the net result of either dopamine D~ receptor stimulation via the direct striato-pallidal circuit or dopamine D 2 receptor stimu-

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lation via the indirect striato-globus pallidus lateralissubthalamic nucleus-globus pallidus medialis pathway. The question is why there should be two segregated circuits to mediate similar motor functions. It may be that D~ and D 2 striatal dopamine receptors mediate different aspects of the motor control, but such discriminative action is not apparent by simple clinical evaluation of the motor improvement observed in parkinsonian monkeys. Finally, it should be taken into account that Surmeier et al. (1993) have demonstrated recently that about 60% of striatal neurons express both dopamine D~ and D 2 receptors which could explain why selective dopamine D~ and D 2 receptor agonists can produce the same pattern of behaviour and also account partially for the existence of a functional interaction between these two subtypes of dopamine receptors. 4.2. Functional interaction o f dopamine D l and D 2 receptors

The existence of a synergistic effect of dopamine D~ and D 2 receptors in the expression of dopamine-mediated behaviour has been extensively demonstrated in both intact rats and unilaterally lesioned rats with 6-OHDA (Waiters et al., 1987; Robertson and Robertson, 1986; Sonsalla et al., 1986). For instance, in rats with unilateral lesion of the nigrostriatal pathway, circling behaviour induced by dopamine D 2 receptor agonists is markedly increased when the drugs are co-administered with non-effective doses of the dopamine D~ agonist SKF 38393. Similar findings have also been reported by Robertson et al. (1992) using bromocriptine and CY 208-243 as dopamine D 2 and D~ receptor agonists. By contrast, most of the studies undertaken in MPTP monkeys suggest opposing rather than synergistic effects between these two subtypes of dopamine receptors. Accordingly, the dopamine D~ receptor agonist SKF 38393, like the dopamine D 1 receptor antagonist SCH 23390, significantly reduced the motor responses induced by LY 171555 or l-dopa indicating an inhibitory effect of dopamine D 1 receptor stimulation on dopamine D e receptor activity (Barone et al., 1987; Nomoto et ai.,1988; Elliot et al., 1992). However, SKF 38393 did not modify the motor benefit induced by i.v. l-dopa in patients with Parkinson's disease (Braun et al., 1986). More recently, G6mez-Mancilla et al. (1993) have reported that simultaneous administration of submaximal doses of bromocriptine and CY 208-243 to 4 MPTP-monkeys, dose dependently potentiated the motor improvement induced by bromocriptine, indicating an additive effect between D~ and D 2 dopamine receptors. Our findings with larger monkeys are not in agreement with earlier reported results. Thus, simulta-

neous administration of ( + ) - P H N O and CY 208-243 did not result in either potentiation or reduction of the intensity and duration of the motor responses induced by each drug given independently. The explanation for these discrepant results is not easy to find. It could be postulated that the doses of each dopamine agonist used in these experiments are large enough to induce the maximal motor improvement and therefore a potentiation of the magnitude of the motor response could not be expected. However, the duration of the motor response, which was the parameter more closely linked to the dose of dopamine agonist administered, did not change even when both dopamine receptor agonists were co-administered. An alternative explanation could be found by the use of different types of dopamine receptor agonists. Thus, it could be postulated that the selective dopamine D~ and D z receptor agonists employed exhibit different affinity for the distinct subtypes of dopamine receptor recently cloned (D 3, D4, D 5) and thereby a positive or a negative interaction might depend on the subtype of dopamine receptor preferentially activated. Further studies with more selective dopamine receptor agonists for the different subtypes of dopamine receptor are required in order to know the real role of dopamine receptors in the control of voluntary movements and their possible functional interaction. Although we found that D I and O 2 striatal receptors were equally and independently involved in the control of motor activity, some form of linkage between D~ and D 2 dopamine receptors was apparent as the magnitude and the duration of the motor response to ( + ) - P H N O and CY 208-243 was reduced by pretreatment with SCH 23390 and sulpiride. This effect cannot be solely attributed to the non-selectivity of these two compounds for D~ and O 2 dopamine receptors since in vitro studies have shown a high affinity of SCH 23390 and sulpiride for D~ and De-labelled sites (Hyttel, 1983; Closse et al., 1984), and both antagonists completely blocked the motor response elicited by the corresponding dopamine receptor agonist. Several biochemical studies performed with parkinsonian monkeys have shown that MPTP administration is followed by a marked reduction ( > 95%) in the striatal dopamine content (Burns et al., 1983; P6rezOtafio et al., 1991). However, SCH 23390 and sulpiride administration significantly increased parkinsonism in all the animals, suggesting that surviving dopaminergic neurons maintain a certain degree of stimulation of striatal neurons sufficient to allow the execution of voluntary movements. Thus, it appears that either dopamine D~ or O 2 receptor stimulation is enough to independently reverse parkinsonism, but this effect is to some extent linked to the stimulation of the other subtype a n d / o r subtypes of dopamine receptor (D1, D2, D3, D 4 or D 5) by endogenous dopamine. It should

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be considered that the effect of dopamine D I and D 2 receptor blockade might not be similar to that produced by endogenous dopamine depletion, since the blockade of dopamine receptors can induce effects totally different from those caused by the lack of stimulation of dopamine receptors. However, we have found a similar modification of the motor responses induced by dopamine agonists after pretreatment with reserpine (Luquin et al., 1991). Therefore, the lack of stimulation of the other subtypes of dopamine receptors by endogenous dopamine could be the main mechanism by which SCH 23390 and sulpiride reduce the magnitude and the duration of the motor response induced by each dopamine receptor agonist. The present results may have some relevance for the pharmacology of Parkinson's disease. First, it has been demonstrated that both D 1 and D 2 dopamine receptor agonists are equally effective in the control of motor deficits induced by MPTP in primates and both induced dyskinesias which did not change after simultaneous administration of dopamine D 1 and D 2 receptor agonists. Therefore, there is no reason for the use of selective (D 1 or D 2) versus mixed dopamine receptor agonists when intending to avoid the development of /-dopa-induced dyskinesias. In addition, our results show that dyskinesias are not abolished by selective blockade of D a and D 2 dopamine receptors. This is contrary to the idea that /-dopa-induced dyskinesias are mediated by activation of D 1 receptors and could be dissociated from the motor improvement. Second, our results confirm some preliminary findings in parkinsonian monkeys and patients indicating a potent antiparkinsonian effect of CY 208-243. Previous negative results with SKF 38393 in parkinsonian monkeys and patients (Nomoto et al, 1988; Braun et al., 1986) were probably due to a relatively poor intracerebral bioavailability of this compound or to the formation of metabolites which could act as dopamine antagonists. Finally, our findings give rise to the possibility of using a neuroleptic drug with selective D e or D 4 antagonistic effect (i.e. sulpiride, clozapine) to treat the psychiatric complications of dopaminergic drugs while still retaining the capacity to improve parkinsonism with a potent D1 agonist. 5. References Alexander, G.M., D.L. Brainard, S.W. Gordon, M, Hichens, J.R.Grothusen and R.J.Shawartzman, 1991, Dopamine receptor changes in untreated and (+)-PHNO-treated MPTP parkinsonian monkeys, Brain Res. 547, 181. Andersen, P.H. and J.A. Jansen, 1990, Dopamine receptor antagonists: selectivity and D-1 receptor efficacy, Eur. J. Pharmacol. 188, 335. Anderson, J.J., T.N. Chase and T.M. Engber, 1992, Differential effect of subthalamic nucleus ablation on D1 and D2 agonist-induced rotation in 6-hydroxydopamine-lesioned rats, Brain Res. 588, 307.

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