European Journal of Pharmacology, 213 (1992) 243-249

243

© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00

EJP 52355

Effects of dopamine receptor agonists on passive avoidance learning in mice: interaction of dopamine D 1 and D 2 receptors Kenji I c h i h a r a a, T o s h i t a k a N a b e s h i m a a,b a n d T s u t o m u K a m e y a m a a a Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468, Japan and o Department of Hospital Pharmacy, Nagoya University School of Medicine, Nagoya 466, Japan Received 27 June 1991, revised MS received 23 October 1991, accepted 24 December 1991

The present study examined the effects of dopamine D 1 and D 2 receptor agonists on the acquisition stage of passive avoidance learning and on locomotor activity in mice. The D 2 agonist, RU 24213 (1-10 mg/kg s.c.), and the non-selective agonist, apomorphine (0.3-3 mg/kg s.c.), but not the D l agonist, SKF 38393 (1-10 mg/kg s.c.), impaired learning and activated locomotion. RU 24213 (1 mg/kg s.c.) was more effective in impairing learning than in activating locomotion. The concurrent administration of SKF 38393 (10 mg/kg i.p.) and RU 24213 (1 and 3 mg/kg s.c.) produced a synergistic effect in both behavioral situations. The D 1 antagonist, SCH 23390 (0.025 mg/kg i.p.), slightly inhibited the effects of apomorphine and of the combination of SKF 38393 and RU 24213 on learning but not on locomotion. The D 2 antagonist, (-)-sulpiride (40 mg/kg i.p.), completely blocked these effects in both situations. These results suggest that dopamine receptor agonists impair passive avoidance learning through the D2 receptor, and that D1 and D 2 receptors act synergistically in this impairment, as they do in their effects on locomotion. The involvement of D 1 and D 2 receptors is qualitatively similar in each of these behaviors, although some small differences may exist. Dopamine D 1 receptors; Dopamine D 2 receptors; Passive avoidance learning; (Mouse)

I. Introduction

If memory is defined as the retention of information, this information must first be acquired. However, the acquisition of information may be affected by the arousal level of an animal. Activation of dopamine receptors has been reported to disrupt selective attention in animals (Cheal, 1980, 1983; Sara, 1985). In this way, the acquisition of memory for novel stimuli could be attenuated, which would lead to the impairment of learning. For instance, when dopamine and apomorphine are administered before training, they impair passive avoidance learning in various animals (Bracs et al., 1984; Fernandez-Tom et al., 1979; Ichihara et al., 1988b) and apomorphine impairs latent learning in a maze task in mice (Ahlenius et al., 1977). Dopamine receptors in the brain have been divided into two subtypes, D 1 and D 2 (Kebabian and Calne, 1979). Recent, extensive studies on the contribution of D~ receptors to the mediation of dopamine-induced

behavioral responses and physiological phenomena (Arnt et al., 1987; Barone et al., 1986; Carlson et al., 1987; Molloy et al., 1986; Sonsalla et al., 1988; Walters et al., 1987) have suggested that there is a functional interaction between O 1 and D2 receptors. The interactions of dopamine D t and D 2 systems with acetylcholine mechanisms have been proposed to be important in cognitive learning tasks (Levin, 1988; McGurk et al., 1989). The purpose of the present study, for which we used a passive avoidance task, was to investigate which dopamine receptor subtype, D 1 or D2, is closely associated with a deficiency in memory acquisition. In addition, the functional interaction of these receptor subtypes in learning deficits was compared to that found in locomotor responses.

2. Materials and methods 2.1. Animals

Correspondence to: T. Nabeshima, Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468, Japan. Tel. 81.52.832 1781, fax 81.52.834 8780.

Male ddY mice (Nihon SLC, Japan) weighing 28-32 g were used. The animals were housed under standard conditions (23 _+ 1°C; 50 + 5% humidity; 8 a.m./8 p.m.

244 light/dark cycle) with free access to water and food. Following adaptation to laboratory conditions for at least 3 days, the mice were used for the experiments.

2.2. Drugs

alone, and of the combination of SKF 38393 and RU 24213 was studied, in the last part of this experiment SCH 23390 and ( - ) - s u l p i r i d e were administered i.p. 30 and 60 min, respectively, before treatment with apomorphine, RU 24213 alone, and RU 24213 in combination with SKF 38393.

The following drugs were used as selective dopamine receptor agonists and antagonists: SKF 38393 (Smith Kline and French Laboratories, U.S.A.), a D 1 agonist (Setler et al., 1978); SCH 23390 maleate (ScheringPlough, U.S.A.), a D1 antagonist (Iorio et al., 1983); RU 24213 (Roussel-UCLAF, France), a D 2 agonist (Euvrard et al., 1979); ( - ) - s u l p i r i d e (Fujisawa Pharmaceutical Co., Japan), a D 2 antagonist (Stoof and Kebabian, 1984), and apomorphine hydrochloride (Sigma Chemical Co., U.S.A.), a mixed D 1 / D 2 agonist (Seeman, 1980). SKF 38393, RU 24213 and apomorphine were dissolved in 0.9% saline. ( - ) - S u l p i r i d e was initially dissolved in a minimum volume of 0.1 N HC1 solution and was then diluted with distilled water; its pH was adjusted to about 4 with N a H C O 3. SCH 23390 was dissolved in distilled water. Each drug was injected i.p. or s.c. in a volume of 10 ml/kg.

A rectangular Plexiglas box (20 x 30 x 13 cm high) was used as the test apparatus. The floor of the box was divided into six identical squares for measuring ambulation of the mice. The animals were placed individually into the test box immediately after administration of dopamine receptor agonists or vehicle. Ambulation was measured 20 min later by counting the number of times the animals crossed from one floor square to another in 5 min. In order to compare the effects of D 1 and D 2 receptor antagonists on the learning deficit and hyperlocomotion induced by dopamine receptor agonists, the conditions drug treatment and the intervals between drug administration and behavioral observations were kept identical.

2.3. Passive avoidance studies

2.5. Statistical analysis

The step-down type of one-trial passive avoidance task was used because training for this task can be carried out despite the behavioral changes that may occur following the administration of apomorphine (Ichihara et al., 1988b). The test apparatus was constructed as described previously (Kameyama et al., 1986). Briefly, it consisted of a rectangular Plexiglas box (30 x 30 x 40 cm high) with a steel rod grid floor and a wooden platform (4 x 4 X 4 cm high) located in the center of this grid floor. For training, each mouse was placed gently on the wooden platform. When the mouse stepped down from the platform and placed all its paws on the grid floor, electrical shocks (1 Hz, 0.5 s, 60 V DC) were delivered over a period of 15 s. The animals received electrical shocks in the range of 0.24-0.6 mA. A retention test was carried out 24 h after training without drug administration. For this retention test, each mouse was again placed on the platform and the step-down latency was measured with a stopwatch to obtain a value for learning. An upper cut-off time of 300 s was set. In the first part of the experiment, SKF 38393, RU 24213 and apomorphine were administered s.c. 30, 20 and 20 min, respectively, before training started. In the second phase, in order to study the synergistic effect of D 1 and D 2 receptor agonists, the mice were given i.p. SKF 38393 10 min before treatment with R U 24213. The training trial was.do~le 20 min after treatment with RU 24213. The ability of D~ and O 2 receptor antagonists to block the effects of apomorphine, of RU 24213

The results of the passive avoidance task were expressed in terms of medians and interquartile ranges (Q1-Q3), since an upper cut-off time was set. The results for locomotor activity were expressed as means + S.E. Statistical comparisons were made with the Kruskal-Wallis test, a non-parametric analysis of variance (ANOVA), followed by a Tukey- or Dunn-type non-parametric test. A P value less than 0.05 was accepted as statistically significant for all evaluations.

2. 4. Locomotor activity in mice

3. Results

3.1. Effects of SKF 38393, RU 24213, and apomorphine on passive avoidance learning Table 1 shows the effects of the selective D~ agonist, SKF 38393, the selective D 2 agonist, RU 24213, and the mixed D J D 2 agonist, apomorphine, on step-down latency in the passive avoidance task. None of the dopamine agonists changed the step-down latency in training. However, in the retention test, RU 24213 significantly shortened step-down latency at doses of 1, 3 and 10 mg/kg; the ceiling effect being achieved with 3 mg/kg. Apomorphine also significantly reduced step-down latency at doses of 0.3, 0.5, 1, and 3 mg/kg. The maximum effect was observed at a dose of 1 mg/kg. In contrast, no significant change was observed in mice treated with SKF 38393 (1-10 mg/kg). H = 0.487, P > 0.05 (ANOVA). The effects of combinations

245 TABLE 1 Effects of SKF 38393, RU 24213 and apomorphine on step-down latency in passive avoidance learning in mice. SKF 38393, RU 24213 and apomorphine were administered (s.c.) 30, 20 and 20 min, respectively, before training started. Treatment

Dose (mg/kg)

N

Latency (s) to step-down Median (Q1-Q3) Training

Vehicle SKF 38393

Vehicle RU 24213

Vehicle Apomorphine

Retention test

1 3 10

20 20 20 20

7.0 (5-9) 7.0 (4-8) 9.5 (5-11) 7.0 (5-8)

185.5 (103-300) 188.5(133-300) 177.5(106-242) 196.5 (79-300)

0.3 1 3 10

20 20 20 20 20

7.5 (4-9) 7.0 (5-8) 8.0 (6-9) 9.0(7-11) 10.5(6-13)

264.0(133-300) 246.0(147-300) 111.0 (27-154) a 50.5 (31-93) b 83.0 (40-153) a

0.3 0.5 1 3

18 20 22 20 20

8.0 (5-11) 8.0 (5-10) 8.5 (6-12) 9.0(6-11) 11.5(7-13)

190.5(136-300) 85.5 (53-188) a 58.5 (32-95) b 24.5 (18-33) h 36.5 (20-52) b

a p < 0.05, b p < 0.01 compared to the corresponding vehicle (Tukeyor Dunn-type test).

of R U 24213 (1 m g / k g ) a n d S K F 38393 (1 a n d 3 m g / k g ) p r o d u c e d synergistic effects.

3.2. Effects of selective D r and D 2 antagonists on the impairment of passive avoidance learning induced by D r and D e agonists W e e x a m i n e d the effects of the D~ antagonist, S C H 23390, a n d the D2 antagonist, ( - ) - s u l p i r i d e , o n the i m p a i r m e n t of passive avoidance l e a r n i n g i n d u c e d by R U 24213, a p o m o r p h i n e alone, a n d R U 24213 in comb i n a t i o n with S K F 38393 (figs. 1, 2 a n d 3). Figure 1 shows the a n t a g o n i s t i c effects of S C H 23390 (fig. 1A) a n d ( - ) - s u l p i r i d e (fig. 1B) on the r e d u c t i o n in s t e p - d o w n latency i n d u c e d by R U 24213. SCH 23390 (0.025 a n d 0.05 m g / k g ) failed to block the effect of R U 24213 (3 m g / k g ) . Since S C H 23390 a l o n e significantly r e d u c e d step-down latency at a dose of 0.05 m g / k g , a dose of 0.025 m g / k g was used in the s u b s e q u e n t experiments. In contrast to S C H 23390. ( - ) - s u l p i r i d e (40 m g / k g ) c o m p l e t e l y blocked the effect of R U 24213 (3 m g / k g ) . F i g u r e 2 shows the a n t a g o n i s t i c effects of S C H 23390

3OO

of D] a n d D 2 r e c e p t o r agonists o n passive avoidance l e a r n i n g are shown in table 2. T h e c o m b i n a t i o n of S K F 38393 (10 m g / k g ) with R U 24213 (1 a n d 3 m g / k g ) p o t e n t i a t e d the s h o r t e n i n g effect of R U 24213 o n s t e p - d o w n latency. N e i t h e r the c o m b i n a t i o n of R U 24213 (0.3 m g / k g ) a n d S K F 38393 (10 m g / k g ) n o r that

A

b

7] O-

TABLE 2

SCH

Effects of RU 24213 in combination with SKF 38393 on step-down latency in passive avoidance learning in mice. SKF 38393 and RU 24213 were administered 30 and 20 min, respectively, before training started.

(23) m

23390

I~J 2 4 2 1 3

300 -

--

(20) 0.025 --

(20) 0.05 --

RU 24213 (mg/kg)

N

Latency (s) to step-down Median (Q1-Q3) Training

Retention test

Vehicle 10 Vehicle Vehicle Vehicle 10 10 10

Vehicle Vehicle 0.3 1 3 0.3 1 3

20 20 20 20 20 20 20 20

9.0 (7-10) 8.0 (4-9) 8.5 (5-10) 7.0 (5-9) 9.0 (6-11) 8.0 (4-9) 11.0 (7-13) 12.5 (6-14)

197.0(128-300) 187.5 (128-300) 179.0 (97-243) 94.0 (58-149) a 72.0 (34-156) a 186.5 (72-241) 39.5 (30-64) b,c 32.5 (11-77) b.c

Vehicle Vehicle 1 3 10

Vehicle 1 1 1 1

20 20 20 20 20

7.0 (4-9) 7.0 (4-8) 10.0 (6-12) 8.5 (5-11) 8.5 (6--10)

230.0(132-300) 92.5 (52-132) a 105.5 (43-126) b 75.0 (35-120) b 35.5 (22--58)b,c

a p < 0.05, b p < 0.01 compared to the corresponding vehicle alone, and ¢ P < 0.05 compared to the corresponding dose of RU 24213 alone (Tukey-type test).

~

(23)

(23)

(23)

--

0.025

0.05

(mg/kg }

3

3

3

(mg/kg)

B

¢4

SKF 38393 (mg/kg)

b

C

20C -

~ 10G

(20)

(20)

(- }oSUlp|rlde

--

(20)

40

--

RU ;)4213

__

--

3

(20) 40

3

(mg/kg) {mg/kg)

Fig. 1. Effects of SCH 23390 (A) and (-)-sulpiride (B) on reduction in step-down latency induced by RU 24213 in a retention test of passive avoidance learning in mice. SCH 23390 and (-)-sulpiride were administered (i.p.) 30 and 60 min, respectively, before the administration of RU 24213. RU 24213 was administered (s.c.) 20 min before training started. Each value represents the median (horizontal bar) and the interquartile range (column) for the number of animals shown in parentheses. Dotted lines show the median for training, a p < 0.05, b p < 0.01 compared to vehicle, and ¢ P < 0.01 compared to RU 24213 (Tukey- or Dunn-type test).

246 (fig. 2A) and (-)-sulpiride (fig. 2B) on the reduction in step-down latency i n d u c e d by a p o m o r p h i n e (0.5 m g / k g ) . S C H 23390 (0.025 m g / k g ) partially, but not significantly, blocked the effect of a p o m o r p h i n e , while ( - )-sulpiride (40 m g / k g ) blocked it almost completely. Figure 3 shows the antagonistic effects of S C H 23390 (fig. 3A) and (-)-sulpiride (fig. 3B) on the reduction in step-down latency induced by R U 24213 in combination with SKF 38393. T h e coadministration of SKF 38393 (10 m g / k g ) with R U 24213 (1 m g / k g ) p r o d u c e d a synergistic effect. This effect was partially, but not significantly, inhibited by S C H 23390 (0.025 m g / k g ) , whereas (-)-sulpiride (40 m g / k g ) blocked it almost completely.

A

l°°V 0,-

-

Effects of dopamine receptor agonists on passive avoidance learning in mice: interaction of dopamine D1 and D2 receptors.

The present study examined the effects of dopamine D1 and D2 receptor agonists on the acquisition stage of passive avoidance learning and on locomotor...
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