Gen. Pharmac. Vol. 22, No. 6, pp. 1027--1031, 1991

0306-3623/91 $3.00 + 0.00 Pergamon Press plc

Printed in Great Britain

DIFFERENTIAL EFFECTS OF DOPAMINE AGONISTS ON LOCOMOTION IN INTACT AND RESERPINE-TREATED MICE M. R. ZARRINDASTand A. ELIASSI Department of Pharmacology, Medical Faculty, University of Tehran, Tehran, Iran (Received 11 February 1991) Abstract--1. Apomorphine and bromocriptine induced a dose-dependent locomotion in mice. The responses of both drugs were decreased by SCH 23390 or sulpiride pretreatment. 2. Locomotor activity induced by apomorphine was increased and that of bromocriptine was decreased by reserpine. 3. SKF 38393 or quinpirole also induced locomotion. The response of SKF 38393 was decreased by reserpine. 4. Combination of SKF 38393 with bromocriptine induced a significant locomotor activity different from that of SKF 38393 or bromocriptine in reserpinized animals. 5. Combination of quinpirole with brnmocriptine even decreased the response of bromocriptine in intact animals. 6. In conclusion, bromocriptine needs intact dopaminergic neurons and activation of D-1 receptor for expression of locomotion. High doses of quinpirnle may induce locomotor activity possibly through D-I/D-2 receptor activation and quinpirole may potentiate the effect of bromocriptine on autoreceptor for inducing sedation.

INTRODUCTION

Dopamine, neurotransmitter of the central nervous system, is considered to be involved in both behaviour and movement. This transmitter exerts its effects via at least two different populations of dopamine receptor sites termed D-1 and D-2 (Garau et al., 1978; Kebabian and CaMe, 1979; Stool and Kebabian, 1984, Onali et al., 1985; Weiss et al., 1985). Both D-1 and D-2 receptors are present in the substantia nigra (Boyson et al., 1986), striatum (Creese et al., 1977) and nucleus accumbens (White and Wang, 1986). Biochemically, the activation of D-1 dopamine receptors leads to increase in the cAMP production, whereas the stimulation of D-2 dopamine receptor inhibits or does not influence adenylate cyclase activity of cAMP production (Stoof and Kebabian, 1981, 1984; Onali et al., 1984). Recently D-3 receptor sites also have been identified. The novel receptors do not affect on adenylate cyclase and is not influenced by GTP (Sokoloff et al., 1990; Snyder, 1990). Some behavioural studies indicate that combination D-1 with D-2 agonists show at least additive effects for locomotor behaviour in reserpine (Jackson and Hashizume, 1986) and nonreserpine-treated mice (Barone et al., 1986). The D-1 receptor had been reported to have no role in motor activity (Seeman, 1980; Creese et al., 1983) or no role at all (Laduron, 1983). There are also suggestion that D-2 mechanism modulate the expression of locomotion initiated by D-1 stimulation (Molloy and Waddington, 1985). Although, there are suggestion that D-1 and D-2 systems influence each others but there is some evidence that D-1 and D-2 systems are also in some way separate and distinct (Joyce, 1983; Robertson

and Robertson, 1986; Zarrindast and Poursoltan, 1989). The present study was undertaken to further evaluate the actions of D-1 and D-2 dopamine agonists on locomotion in non- and reserpine-treated mice. METHODS

Male albino mice weighing between 20-25 g were used in our experiments. Each animal was used once only. In all cases the mice were housed 10 per cage in an animal room lightened 12 hr per day and kept at 20 + 2°C. The animals had free access to food and water. Locomotor activity measurement Locomotion was measured with an activity meter, Animex, Type S(LKB Earrad). Each animal was placed in a plastic cage for 15rain to acclimatize the environment. Immediately after drug injection, the animals were returned to the cage for test trials lasting between 45-60 min. Drugs The drugs used were: apomorphine hydrochloride (MacFarlan Smith Ltd, England), bromocriptine (Sandoz, Switzerland), SCH 23390 [R-(+ )-8-chloro-2,3, 4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepine-7-ol maleate; Schering, Italy], ( - )sulpiride (Delgrange, France), SKF 38393 (l-pbenyi-7,8-dihydroxy-2,3,4,5-tetrahydro-lH3-benzazepine hydroclfloride; R.B. Inc. Wayland, U.S.A.), quinpirole hydrochloride (Eli Lilly, U.S.A.), reserpine (Sigma, England), DL-u-methyl-p-tyrosine methylester (AMPT, Sigma, England). The drugs were dissolved in distilled water, except for bromocriptine which was dissolved in water using crystalline tartaric acid and a few drops of alcohol. Sulpiride and reserpine were dissolved in a drop of acetic acid and then diluted with distilled water.

1027

M. R. ZARRINDASTand A. ELIASSI

1028

7o0

36o0

I

lOOO

5o0 v

4o0

200 f

°

I00 _1

600-

o

I

I

0

I

15

)

30 45 Time(mini Fig. 1. Time-course effects of apomorphine induced locomotor activity in mice. Each point represents the mean + SEM of locomotion of at least 7 mice after subcutaneous (s.c.) injection of saline 1 ml (V) or apomorphine (11) 0.125, (A) 0.25 and (O) 0.5 mg kg-L Re.suits are shown for total 15 rain locomotor activity counts 15, 30 and 45 min after apomorphine injection.

Statistical analysis Analysis of variance (ANOVA) followed by Student's t-test were used to evaluate significance of the results obtained. RESULTS

Locomotor activity induced by apomorphine Figure 1 illustrates the locomotion induced by subcutaneous (s.c.) injection of different doses of apomorphine (0.125-0.5mg k g - ' ) . The m a x i m u m effect was obtained with 0.5 mg k g - ' . The response lasted 45 min after drug administration.

Effects of dopamine receptor antagonists on apomorphine-induced locomotion As shown in Fig. 2, the S C H 23390 D - l antagonist (0.05 mg k g - t, s.c., 30 min) or sulpiride D-2 antagon-

O

"~

o

I

0.125

I 0.25

I 0.5

Apomorphine (rng kg-1 ) Fig. 3. Effect of reserpine pretreatment on locomotion induced by apomorphine in mice. Animals were pretreated either with saline (O, I0 ml kg-', i.p.) or reserpine( 1 , 5 mg kg-', i.p.) 18 hr before apomorphine injection. Locomotor activity was recorded during the 45 min after apomorphine (0.125-0.5 mg kg-', s.c.) administration. Each point is the mean+SEM of locomotion of at least 7 animals. *P < 0.01 different from control saline-treated animals. ist (25 mg k g - ' , s.c., 90 min) pretreatment reduced the locomotor activity induced by different doses of apomorphine (0.125-0.5mg kg -l, s.c.). Intraperitoneal (i.p.) administration of reserpine (5 mg k g - ' ) 18 hr prior to apomorphine increased response of lower doses of apomorphine significantly (Fig. 3). SCH 23390 (0.05 mg kg -], s.c., 30 min) or sulpiride (25 mg k g - l, s.c., 90 min) pretreatment decreased the

1200

•~ 1000

A C

~

ao0

600

tD

O

2OO E

200

8

O ._1

eee

I

I

J

0.1~'5

0.:~5

0.5

Apomorphine (rng kg-~ )

Fig. 2. Effects of sulpiride or SCH 23390 on locomotion induced by different doses of apomorphine in mice. Animals were pretreated either with saline (O, 10mi kg-', s.c.) 30min, SCH 23390 ([], 0.05mg kg-', s.c.) 30min or sulpiride (©, 25 mg kg- ', s.c.) 90 min before different doses of apomorphine (0.12-0.5mg kg-', s.c.) injection. Locomotor activity was recorded during the 45 rain after apomorphine administration. Each point is the mean :f:SEM of locomotion/45 rain (n = 7). *P < 0.05, **P < 0.02, ***P < 0.01 different from apomorphine controls groups.

0

I

I

011~5

O.~5

I 0"5

A pomorphine(rng kffll Fig. 4. Effect of sulpiride or SCH 23390 on locomotion induced in reserpine-treated mice. All the animals were pretreated with reserpine (5mg kg-', i.p.) 18hr before apomorphine injection. Animals were treated with different doses of apomorphine (0.125--0.5 mg kg-l, s.c.) alone (11) or with SCH 23390 (I-q, 0.05 mg kg-', s.c.) 30 min and sulpiride (O, 25 mg kg- ', s.c.) 90 min before apomorphine administration. Locomotor activity was recorded during 45 rain after drug injection. Each point is mean + SEM of at least 7 animals. *P