Blockade by ginseng total saponin of methamphetamine-induced hyperactivity and conditioned place preference in mice

Gen. Pharmac. Vol. 27, No. 2, pp. 199-204, 1996 Copyright © 1996 Elsevier Science Inc. Printed in the USA.

ISSN 0306-3623/96 $15.00 + .00 0306-3623(95)02023-7 All rights reserved ELSEVIER

Blockade by Ginseng Total Saponin of Methamphetamine-Induced Hyperactivity and Conditioned Place Preference in Mice Hack-Seang Kim, 1, Choon-Gon Jang 1, Woo-Kyu Park, 1 Ki- Wan Oh, 1 Hang-Mook Rheu, 2 Dae-Hyun Cho 2 and Seikwan Oh 3 I DEPARTMENT OF PHARMACOLOGY, COLLEGE OF PHARMACY, CHUNGBUK NATIONAL

UNIVERSITY,CHEONGIO360-763, [TEL: 43 1-61-2813; FAX: 431-68-2732], 2THE INSTITUTE OF NATIONAL SAFETY RESEARCH, SEOUL 122-040, KOREA ANn 3DEPARTMENT OF PHARMACOLOGY AND TOXICOLOGY, UNIVERSITY OF MISSISSIPPIMEDICAL CENTER, JACKSON, M S 39216-4045, U.S.A. ABSTRACT. Ginseng total saponin (GTS) inhibited methamphetamine-induced hyperactivity and conditioned place preference (CPP). Dopamine (DA) receptor supersensitivity was developed in methamphetamine-induced CPP mice and it was inhibited by GTS. GTS also inhibited apomorphine-induced climbing behavior, showing the antidopaminergic activity of GTS. These results suggest that GTS inhibition of the methamphetamine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by methamphetamine. GENPHARMAC27;2:199-204, 1996. KEY WORDS. Hyperactivity, conditioned place preference, dopamine receptor supersensitivity, methamphetamine, panax ginseng. INTRODUCTION Methamphetamine and amphetamine facilitate the release of newly synthesized dopamine (DA) and inhibit the intake of DA, causing hyperactivity (Fischman, 1987; Kuribara and Tadokoro, 1982). The chronic administration of amphetamine derivatives produces longlasting depletion of DA (Ellinwood, 1979) and develops conditioned place preference (CPP) (Duncan et al., 1983; Trazon et al., 1992; Gilbert and Cooper, 1983), as well as behavioral sensitization (Kuribara and Uchihashi, 1994). The CPP paradigm has been used as a model for studying the reinforcing effects of dependence-liable drugs (Van der Kooy, 1987). Many dependence-liable drugs are known to induce CPP, including methamphetamine (Duncan et al., 1983; Trazon et al., 1992), amphetamine (Gilbert and Cooper, 1983), cocaine (Morency and Beninger, 1987; Spyraki et HI., 1982a) and morphine (Blander et al., 1984; Reid et al., 1989). These drugs produce a reinforcing effect as seen through their common property of facilitating dopaminergic transmission, either by stimulating the release of DA or inhibiting DA uptake. Some neuropharmacological investigations have suggested an involvement of the mesolimbic and mesocortical dopaminergic systems as a neuronal mechanism mediating amphetamine-induced hyperactivity (Jackson and Kelly, 1983) and CPP (Carr and White, 1983; 1986). In support of these investigations, DA receptor antagonists such as haloperidol and SCH23390 antagonize the amphetamine-induced hyperactivity (Ujike et al., 1989; Kuribara and Uchihashi, 1994) and CPP (Leone and Dichiara, 1987; Spyraki et al., 1982b). Moreover, 6-OHDA lesions of DA innervation of the nucleus accumbens are shown to decrease amphetamine-induced hyperactivity (Kelly and Iversen, 1976) and CPP (Spyraki et al., 1982b). It has been demonstrated that the behavioral sensitization after repeated administration of a reinforcing drug., such as methamphetamine, can be attributed to the dopaminergic hyperfunction in the central nervous system (Robinson and Becker, 1986). This can be demonstrated *To whom all correspondence should be addressed. Received 7 July 1995.

by the blocking of sensitization by neuroleptics (Beninger and Hahn, 1983). This result shows that the development of DA receptor supersensitivity is a possible mechanism underlying behavioral sensitization induced by psychomotor stimulants. Thus, it is presumed that DA receptor supersensitivity may be one of common mechanisms underlying methamphetamine-induced CPP and behavioral sensitization. Panax ginseng, as a folk medicine, has been used in far eastern countries for thousands of years. Recently, the chemical and pharmacological properties of panax ginseng have been reported by investigators in many countries. Many reports have provided evidence that ginseng has a variety of effects on the activity of the central nervous system, promoting stimulation as well as inhibition of cortical activity (Petkov, 1959). Ginseng saponin exhibits suppression of the condition avoidance response (Nabata et al., 1973), prolongs pentobarbital sleeping time and delays the onset of convulsions in high doses (Oh et al., 1969). Panax ginseng also acts as a modulator of neurotransmission in the brain (Kim et al., 1985; Tsang eta/., 1983). Kim et al. (1995) have demonstrated that GTS inhibits the development of methamphetamine-induced reverse tolerance and DA receptor supersensitivity, thereby suggesting that the inhibitory effect of ginseng saponin on this action may be associated with the interruption of chronic methamphetamine action at the presynaptic terminals. Tokuyama et al. (1992) have demonstrated that ginseng extract inhibits the development of reverse tolerance to the ambulation-accelerating effect of methamphetamine. These studies suggest that the inhibitory effect of ginseng saponin on methamphetamine-induced reverse tolerance is related to recovery from dysfunction in the dopaminergic system. Thus, these results suggest the possibility that GTS inhibits methamphetamine-induced hyperactivity and CPP mediated by the dopaminergic system. It has also been hypothesized that addictive substances, such as methamphetamine, derive their reinforcing quality by stimulating the same neurochemical system that mediates psychomotor activity (Wise and Bozarth, 1987). Because GTS inhibited the locomotor stimulant action of methamphetamine, we hypothesized that GTS might also counteract the reinforcing effect of methamphetamine. For these reasons, the present experiments were undertaken to investi-

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gate the inhibitory effect of GTS on the hyperactivity and CPP induced by methamphetamine. Moreover, to determine the neuropharmacological mechanisms underlying the CPP induced by methamphetamine, DA receptor supersensitivity was examined in CPP mice. In addition, apomorphine-induced climbing behavior was also measured in mice treated with a single dose of GTS to examine the acute effect of GTS on postsynaptic DA receptors. MATERIALS AND METHODS

A n i m a l s a n d drugs ICR male mice weighing 20-26 g in a group of 10-20 were used in all experiments. They were housed 10 mice in an acrylic cage with water and food available ad libimm under an artificial 12 hr light-dark cycle (light at 7:00 a.m.) and constant temperature (22_+2 *C). The drugs used were methamphetamine hydrochloride (National Institute of Safety Research, Korea), apomorphine hydrochloride (Sigma, USA) and GTS [characterized saponin mixture quantitatively containing at least 11 glycosides: Rbl (18.26%), Rb2 (9.07%), Rc (9.65%), Rd (8.24%), Re (9.28%), Rf(3.48%), Rgl (6.42%), Rg2 (3.62%), Rg3 (4.70%), Ro (3.82%), Ra (2.91%) and other minor ginsenosides and components (20.55%), from Panax ginseng, extracted and purified by the method of Namba et al. (1974) and supplied by Korea Ginseng and Tobacco Research Institute]. Except for apomorphine, all drugs were dissolved in physiological saline (0.1 ml/10 g). Apomorphine was dissolved in saline containing 0.1% ascorbic acid, just prior to the experiment.

M e a s u r e m e n t o[ hyperactivity i n d u c e d b y methamphetamine Hyperactivity of mice was measured by a tilting-type ambulometer (AMB-10, O'Hara Co., Ltd., Japan). Each mouse was placed in the activity cage (20 cm in diameter; 18 cm in height) and, after an adaptation period of 10 min, drug administration was carried out. The dosage of methamphetamine used was chosen on the basis of a preliminary experiment. When the combined effect ofmethamphetamine and GTS was investigated at various time intervals, the reliable inhibitory effect of GTS was observed 3 hr prior to the intraperitoneal injection of methamphetamine (data not shown). Therefore, GTS (100 or 200 mg/ kg) was injectedintraperitoneallyin mice 3 hr prior to the administration ofmethamphetamine. Also, the preliminary experiments indicated that the ambulatory activity of methamphetamine 2 mg/kg (i.p.) for 2 hr produced consistent and reliable activity. Therefore, the ambulatory activity was measured for 2 hr after the administration of methamphetamine.

Measurement o[ CPP induced by methamphetamine APPARATUS. The CPP apparatus was made by a modification of the method ofMucha et al. (1982). It consisted of two square-b ase PlexiglasTM compartments (15 x 15 x 15 cm), one with a white and the other with a black box jointed by a gray tunnel (3 x 3 x 7.5 cm) that could be closed by guillotine doors. To provide tactile difference between the floors of the compartments, the white compartment had wire mesh and the black compartment had a metal grid. Removal of the guillotine doors during the pretesting and the final testing phase allowed animals free access to both compartments, and the time spent by mouse in each of the two compartments was recorded for 15 min using photobeam detectors connected via electrical interface to an IBM-compatible PC computer. PROCEDURES. The control mice received an intraperitoneal injection of saline immediately before exposure to the white or black compart-

ment. Methamphetamine (i.p. of base) was given immediately before the mice were placed in the white compartment. To test the effect of GTS (50 and 100 mg/kg, i.p.) alone o r i n combination with methamphetamine, GTS was administered 1 hr prior to the methamphetamine or saline injection, respectively. Phase I (Pretesting phase): on day 1, the mice were preexposed to the test apparatus for 15 min. The guillotine doors were raised and each animal was allowed to move freely between the two compartments. On day 2, the time spent by a mouse in each of the two compartments was recorded for 15 min. Phase II (Conditioning phase): on days 3, 5, 7 and 9, the mice were injected with the drug before being confined in the white compartment, the nonpreferred side, for 60 min. On days 4, 6, 8 and 10, the mice were injected with saline before being confined in the black compartment, the preferred side, for 60 min. Phase III (Testing phase): on day 11, the guillotine doors were raised. The mice were placed in the tunnel of the central part and the time spent by the mice in the two compartments was recorded for 15 min. The scores were calculated from the changes of the testing phase and the pretesting phase in the white compartment.

Measurement o[ postsynaptic D A receptor supersenslt/vlty in CPP mice Additional groups of mice subjected to the same confinement and repeated injection of methamphetamine or GTS were used in this experiment. Development of DA receptor supersensitivity was determined by the enhancement of ambulatory activity caused by a DA agonist, apomorphine, 24 hr after the final CPP confinement. The ambulation-accelerating activity due to apomorphine was measured by the modified Bhargava (1980) method. Mice were first allowed to preambulate for 10 min and were given apomorphine (2 mg/kg, s.c.), a dosage that produced a significant increase in their ambulatory activity. The ambulatory activity induced by apomorphine was measured for 20 min.

Measurement o[ apomorphine.induced climbing behavior In the previous experiment, chronic treatment with GTS inhibited the development of DA receptor supersensitivity induced by methamphetamine. Therefore, the apomorphine-induced climbing behavior in mice treated with a single dose of GTS was determined, to investigate the acute behavioral effects of GTS on the central dopaminergic system. The climbing behavior in mice was measured by a modification of the method of Protais et al. (1976). GTS (50, 100 and 200 mg/kg) was administered intraperitoneally to mice 1 hr prior to the injection of apomorphine. Immediately after a subcutaneous injection of apomorphine (2 mg/kg), the mice were put into cylindrical individual cages (12 cm in diameter; 14 cm in height) with walls of vertical metal bars (2 mm in diameter; 1 cm apart). After a 5-min period of exploratory activity, the climbing behavior was measured by an all-or-none score at 10, 20 and 30 min after the administration of apomorphine, and the 3 scores were averaged. The scores of this behavior were evaluated as follows: four paws on the floor, 0 point; forefeet holding the wall, 1 point; four paws holding the wall, 2 points. STATISTICS. The data were expressed as a mean_+SE. The significance of drug effects was assessed by an analysis of variance (ANOVA). In the case of significant variation, the significance between individual dose conditions and the corresponding control group was analyzed by a Dunnett's test in all experiments, except for the climbing result that used a Mann-Whitney U-test from pharmacologic calculations program (Tallarida and Murrary, 1987).

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methamphetamine.induced hyperactivity There was no significant difference in ambulatory activity between any groups of the mice treated with either saline or GTS alone (Fig. 1). However, the group that was treated with 2 mg/kg ofmethamphetamine showed a marked increase in ambulatory activity, reaching 1671 counts, 1559 counts more than that of the saline control group (P<0.01). Meanwhile, the group pretreated with 200 mg/kg of GTS showed a significant inhibition in ambulatory activity, with 946 counts, 725 counts less than that of the methamphetamine control group (P<0.01).

Inhibitory effect o f G T $ on methamphetamine.induced CPP Groups treated only with GTS 50 mg/kg and 100 mg/kg did not show any CPP compared with that of the saline control group. The group treated with 2 mg/kg of methamphetamine showed a significant effect of CPP with 130 sec, 136 sec more than that of the saline control group (P<0.01). The group pretreated with 100 mg/kg of GTS showed a marked inhibition of 2 mg/kg methamphetamine-induced CPP, with 22 sec, 108 sec less than that of the methamphetamine control group (P<0.05) (Fig. 2).

Inhibitory effect of G T S on the development of D A receptor supersensitivity in methamphetamine.induced CPP mice Ambulatory activity induced by apomorphine was enhanced in mice treated with methamphetamine (2 mg/kg), compared with the ambulatory activity of the saline group. The group treated with methamphetamine showed a significant increase in ambulatory activity induced by apomorphine (2 mg/kg) with 229 counts, 70 counts more than that of the saline control group (P<0.05). The group pretreated with 50 mg/ kg ofGTS, however, did not show any significant inhibition of enhanced ambulatory activity to apomorphine, compared with that of the methamphetamine control group. But, pretreatment with 100 mg/kg of GTS significantly inhibited the enhanced ambulatory activity, with 154 counts, 75 counts less than that of the methamphetamine control

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group (P<0.05) (Fig. 3). These results suggest that DA receptor supersensitivity is developed in methamphetamine-induced CPP mice and that GTS blocks the development of DA receptor supersensitivity in methamphetamine-induced CPP mice.

Inhibitory effect of G T $ on apomorphine.induced climbing behavior Apomorphine 2 mg/kg was used in this experiment because the maximum response was observed with this dose in a preliminary experiment using apomorphine 0.5, 1.0, 2.0 and 4.0 mg/kg (data not shown). Pretreatments with GTS 100 and 200 mg/kg significantly inhibited apomorphine-induced climbing behavior, with scores of I. 14 and 0.95, 0.78 and 0.97 scores less than that of apomorphine control group, respectively, (P<0.05 and P<0.02) (Fig. 4). These results indicate that single-dose administration of GTS inhibits apomorphine-induced climbing behavior, showing the antidopaminergic activity of GTS at the postsynaptic DA receptor. DISCUSSION In this study, a single treatment with GTS inhibited the hyperactivity induced by methamphetamine in mice. There are reports that GTS is able to modulate the dopaminergic system. Kim et al. (1985) have shown that DA content is increased in mouse brain by ginseng saponin treatment. Tsang et al. (1983) have demonstrated that ginseng saponin inhibits the uptake of DA into the rat brain synaptosomes. These results suggest that GTS may modulate dopaminergic hyperactivity induced by methamphetamine at the presynaptic DA receptor. Because the action of methamphetamine on the DA receptor is indirect (Moore et al., 1977) and this indirect action results in the activation ofpostsynaptic DA receptor, it causes hyperactivity. Generally, it has been postulated that the drugs that reduce the availability of catecholamines in the presynaptic neuron or that block the action of the catecholamines on the postsynaptic receptor attenuate the behavioral effects, such as hyperactivity and reinforcing effects, of stimulants in the monkey and rat (Wilson and Schuster, 1972; Pickens et al., 1968). Accordingly, it is hypothesized that GTS inhibition of

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FIGURE 2. Inhibitory effect of GTS on methamphetamineinduced CPP. GTS (50 or 100 mglkg, i.p.) was administered 1 hr prior to the injection of methamphetamine (2 mg/kg) or saline (i.p.) in the conditioning phase, the mice were injected with saline or methamphetamine just before being confined in the black or white compartment for 60 rain every day during 8 days. The scores were calculated from the changes of the testing phase (15 rain) and the pretesting phase (15 rain) in the white compartment. **P<0.0 I, compared with that of the saline group; ~P<0.05, compared with that of the methamphetamine group. Abbreviations: SAL, saline; G, GTS; MAP, methamphetamine.

FIGURE 3. Inhibitory effect of GTS on the development of DA receptor supersensitivity in methamphetamine.induced CPP mice. T h e development of DA receptor supersensitivity was determined by the enhancement of ambulatory activity to apomorphine 24 hr after the final CPP confinement. Mice were injected with apomorphine 2 mg/kg (s.c.) and first allowed to preambulate for 10 rain and then tested for 20 rain. */><0.05, compared with that of the saline group; raP<0.05, compared with that of the methamphetamine group. Abbreviations: SAL, saline; G, GTS; MAP, methamphetamine.

methamphetamine-induced hyperactivity may be closely related to the inhibition of methamphetamine-induced dopaminergic activation at both the presynaptic and postsynaptic DA receptors via direct and indirect effects. In this experiment, repeated treatment with methamphetamine produced CPP. This result is consistent with results reported from other studies (Gilbert and Cooper, 1983; Trazon et al., 1992). Many investigations have implicated the dopaminergic system in the reinforcing effect produced by administration of methamphetamine (Carr and White, 1983; 1986). Therefore, the reinforcing effects ofmethamphetamine are due to the enhanced mesolimbic DA release resulting in an activation of the mesolimbic DA pathway (Wise and Rompre, 1989; Koob and Bloom, 1988). The initial support for DA involvement is increased by the finding that DA receptor antagonists attenuate the reinforcing effects of amphetamine (Leone and Dichiara, 1987; Hiroi and White, 1989). The injection of DA receptor antagonists into the nucleus accumbens blocks the amphetamine-induced CPP (Aulisi and Hoebd, 1983). The present study showed that the development of CPP induced by methamphetamine was also inhibited by GTS. So, it is tempting to speculate that the inhibitory effect of GTS on this action may be associated with the interruption of chronic methamphetamine-induced dopaminergic activation at the reinforcing dopaminergic system in the nucleus accumbens. In connection with this result, there are reports that GTS or ginseng extracts inhibit the development of reverse tolerance to the locomotor accelerating effect of methamphetamine (Kim e t al., 1995; Tokuyama et al., 1992).

The postsynaptic DA receptor supersensitivity to apomorphine was developed in methamphetamine-induced CPP mice. It has been demonstrated that DA receptor sensitivity is increased in the postsynaptic sites following the chronic administration of methamphetamine (Klawans and Margolin, 1975). Repeated treatment with GTS inhibited the development of postsynaptic DA receptor supersensitivity to apomorphine in methamphetamine-induced CPP mice. In association with this result, GTS inhibits development of the postsynaptic DA receptor supersensitivity to apomorphine in reverse tolerant mice treated with methamphetamine (Kim et al., 1995). In addition, it has been reported that ginseng extract lowers adenylate cyclase activity in high doses (Petkov, 1978) and that ginsenoside Rb2, one of the active components of GTS, inhibits adenylate cyclase activity (Park et al., 1984). These results suggest that GTS may modulate directly the development of postsynaptic DA receptor supersensitivity. Also, in this experiment, GTS showed an antidopaminergic property at the postsynaptic DA receptor by inhibiting apomorphine-induced climbing behavior. This result suggests that GTS can also directly modulate methamphetamineinduced dopaminergic activation at the postsynaptic DA receptor. Thus, it is presumed that the development of methamphetamineinduced CPP may be associated with the development of postsynaptic DA receptor supersensitivity in mice. Accordingly, with all of the results taken together, it is presumed that GTS inhibition of methamphetamine-induced hyperactivity, CPP and DA receptor supersensitivity may be closely related to inhibition ofmethamphetamine-induced dopaminergic activation at both the presynaptic and postsynaptic DA recep-

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peritoneal injection of GTS prior to and during the methamphetamine treatment in mice inhibited methamphetamine-induced hyperactivity and CPP. Postsynaptic dopamine (DA) receptor supersensitivity was shown in methamphetamine-induced CPP mice by measurement of enhanced ambulatory activity caused by the DA agonist, apomorphine (2 mg/kg, s.c.). GTS inhibited postsynaptic DA receptor supersensitivity in methamphetamine-induced CPP mice. A single dose of GTS also inhibited apomorphine-induced climbing behavior, showing the antidopaminergic activity of GTS at the postsynaptic DA receptor. These results suggest that the development of methamphetamineinduced CPP may be associated with enhanced DA receptor sensitivity, and that GTS inhibition of methamphetamine-induced hyperactivity and CPP may be closely related to the inhibition of dopaminergic activation induced by methamphetamine.

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This study was supported by a grant (1995-1996) from the Research Center [or New Drug Development, College of Pharmacy, Se0ul National University, Republic of

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FIGURE 4. Inhibitory effect o f GTS o n apomorphine-induced climbing behavior. GTS (50, 100 and 200 mg/kg, i.p.) was administered to mice 1 hr prior to the injection of apomorphine (s.c.). Immediately after the injection of apomorphine, the mice were put into cylindrical individual cages. After a 5-min period of exploratory activity, climbing behavior was measured by all-or-none scores at 10, 20 and 30 m i n after the administration of apomor. phine, and the three scores were averaged. ***P<0.002, compared with that of the saline group; #P<0.05; HP<0.02, compared with that o f the apomorphine group. Abbreviations: SAL, saline; G, GTS.

tors via direct and indirect effects, because the action of methamphetamine on the DA receptor is indirect (Moore et al., 1977). Then, this indirect action results in the activation of the postsynaptic DA receptor, and the sensitivity of postsynaptic DA receptor is increased following chronic administration of methamphetamine (Klawans and Margolin, 1975). In conclusion, the administration of GTS prior to and during treatment with methamphetamine inhibited, not only methamphetamineinduced hyperactivity and CPP in mice, but also development of postsynaptic DA receptor supersensitivity. These results suggest that development of methamphetamine-induced CPP may be associated with enhanced DA receptor sensitivity, and that GTS inhibition of methamphetamine-induced hyperactivity and CPP may be closely related to the inhibition ofdopaminergic activation produced by methamphetamine. From these results, we can presume that GTS may be useful for prevention and therapy of these adverse actions of methamphetamine. SUMMARY Intraperitoneal injection of methamphetamine (2 mg/kg) in mice produced hyperactivity and conditioned place preference (CPP). The hyperactivity induced by methamphetamine was determined by measuring the ambulatory activity using a tilting-type ambulometer. The development of CPP was shown by the increased time spent by the mice in response to methamphetamine, and the inhibition of CPP by the decreased time spent by the mice in the white compartment. The intra-

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