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MK-801 Inhibits Methamphetamine-Induced Conditioned Place Preference and Behavioral Sensitization to Apomorphine in Mice
Brain Research Bulletin, Vol. 44, No. 3, pp. 221–227, 1997 Copyright © 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0361-9230/97 $17.00 1 .00
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MK-801 Inhibits Methamphetamine-Induced Conditioned Place Preference and Behavioral Sensitization to Apomorphine in Mice HACK-SEANG KIM*1 AND CHOON-GON JANG† *Department of Pharmacology, College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea, and †Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216-4045, USA [Received 18 September 1996; Revised 10 March 1997; Accepted 14 March 1997] ABSTRACT: Intraperitoneal administration of MK-801 (0.1 mg/ kg), an N-methyl-D-aspartate (NMDA) receptor antagonist, before and during methamphetamine treatment inhibited methamphetamine-induced conditioned place preference (CPP) in mice. Behavioral sensitization to a dopamine (DA) receptor agonist apomorphine that developed in methamphetamine-induced CPP mice was also inhibited by MK-801. Furthermore, MK-801 inhibited apomorphine-induced postsynaptic dopaminergic action, cage-climbing behavior. Therefore, the present studies suggest that methamphetamine-induced behaviors, such as CPP and behavioral sensitization, may be closely related to the dopaminergic activation mediated via the NMDA receptor. The behavioral sensitization to apomorphine may be a possible underlying mechanism of methamphetamine-induced CPP, because behavioral sensitization developed in methamphetamine-induced CPP mice, as well as apomorphine-induced climbing behavior in mice, were inhibited by MK-801. © 1997 Elsevier Science Inc.
reinforcement [6,7]. In support of these investigations, DA receptor antagonists such as haloperidol and SCH23390 antagonize amphetamine-induced CPP [36,48]. A 6-OHDA lesion of DA innervation of the nucleus accumbens appeared to decrease the amphetamine-induced CPP [48]. Therefore, it is likely that the dopaminergic system may be more closely related in mediating the rewarding effect of methamphetamine. It has been also reported, however, that the blockade of DA transmission inhibited aversive stimuli as well as the motivational properties of rewarding [1]. Recently, it has been reported that repeated treatment with a noncompetitive NMDA receptor antagonist, MK-801, inhibited the development of reverse tolerance to the ambulation accelerating effects of amphetamine and cocaine, suggesting the modulation of the dopaminergic system by MK-801 [21]. Moreover, 6,7-dinitroquinoxaline-2,3-dione (DNQX), a nonspecific glutamate receptor antagonist, also inhibits the acquisition of CPP produced by amphetamine [35]. It has been demonstrated that striatal dopaminergic nerve terminals possess the NMDA receptor [30], and that these presynaptic receptors are involved in a facilitative control of DA release [9], suggesting that the regulation of the central DA release may be mediated via the NMDA receptor. In addition, an intranucleus accumbens microinjection of an NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (AP-5), reduced the locomotor activation induced by both cocaine (IP) acting as a presynaptic uptake blocker and DA injected directly into the nucleus accumbens acting as a postsynaptic DA agonist [42]. Similar results of other noncompetitive NMDA receptor antagonists such as ketamine [33] and dextromethorphan [3] have also been reported. Meanwhile, previous work in our laboratory has shown that MK-801 inhibited the developments of cocaine-induced dopaminergic behaviors such as reverse tolerance to ambulatory activity and CPP in mice [26]. In addition, apomorphine-induced striatal dopaminergic action, climbing behavior, was inhibited by the noncompetitive NMDA receptor antagonists such as MK-801, ketamine, dextrorphan and dextromethorphan in mice [27]. These studies suggest not only the possibility that glutamatergic neurotransmission may modulate DA function, both at the pre- and postsynaptic levels [41], but also that the dopam-
KEY WORDS: Methamphetamine, MK-801, N-Methyl-D-aspartate Receptor, Dopamine, Conditioned place preference, Sensitization, Climbing behavior.
INTRODUCTION Psychomotor stimulants such as amphetamine, methamphetamine, or cocaine are known to induce conditioned place preference (CPP) [15,18,49]. These drugs produce the rewarding effect, as seen through their common property of facilitating dopaminergic transmission either by stimulating the release of dopamine (DA) or inhibiting DA uptake. Methamphetamine and amphetamine facilitate the release of newly synthesized DA and inhibit the uptake of DA [17,32]. Chronic administration of amphetamine derivatives produces long lasting depletion of DA [15] and develops reinforcement as well as behavioral sensitization. Although CPP can be induced by treatment regimens that induce sensitization to other behaviors, it can also occur in the absence of this phenomenon. Some neuropharmacological investigations have suggested an involvement of the mesolimbic and mesocortical dopaminergic systems as a neuronal mechanism mediating amphetamine-induced 1
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inergic system activated by the glutamatergic system is involved in producing the rewarding effects of methamphetamine [35]. It has been demonstrated that the behavioral sensitization after repeated administration of psychomotor stimulants such as methamphetamine can be attributed to the dopaminergic hyperfunction in the central nervous system [44]. It has been also reported that the mice sensitized to methamphetamine or cocaine show an enhanced response to apomorphine, a direct DA receptor agonist [24,25], indicating the development of behavioral sensitization between methamphetamine and dopaminergic systems. These results suggest that behavioral sensitization of DA receptor may be a possible underlying mechanism mediating methamphetamineinduced CPP or reverse tolerance to ambulatory activity. However, it is unclear whether this behavioral sensitization is due to an increase in the sensitivity of the postsynaptic DA neuron or to an increase in the amount of neurotransmitter released by presynaptic DA neuron. There is evidence that the underlying mechanisms of locomotor stimulation and rewarding effect are the same, and a common denominator underlying the addictive qualities of a variety of substance is their ability to cause psychomotor activation [51]. Therefore, it is likely that methamphetamine-induced CPP, as well as ambulation-accelerating activity and reverse tolerance to ambulatory activity, may be inhibited by NMDA receptor antagonist MK-801. However, little is known about the involvement of NMDA receptor in CPP induced by methamphetamine, especially with regard to the behavioral interaction of DA-NMDA systems at the postsynaptic DA receptors. Thus, to assess whether methamphetamine-induced CPP are produced by dopaminergic activation mediated via the NMDA receptor, it is necessary to investigate that an NMDA receptor antagonist, MK-801, will commonly inhibit methamphetamine-induced CPP and behavioral sensitization to apomorphine developed in CPP mice. The present studies, therefore, were designed to investigate the inhibitory effect of MK-801 on methamphetamine-induced CPP. In addition, the degree of the development of behavioral sensitization to apomorphine was also examined in methamphetamineinduced CPP mice to determine the involvement of the NMDA receptor in the dopaminergic modulation. Furthermore, to investigate the direct effect of the NMDA receptor in the postsynaptic dopaminergic functions, the effect of MK-801 on apomorphineinduced selective dopaminergic activity, climbing behavior, was also measured. MATERIALS AND METHODS Animals ICR male mice (Samyuk Laboratory Animal Inc., Osan, Korea) weighing 20 –26 g in a group of 10 –15, were used in all experiments. They were housed 10 mice in a cage with water and food available ad lib under an artificial 12-h light/dark cycle (light at 0700 h) and constant temperature (22 6 2°C). Drugs The drugs used were methamphetamine hydrochloride (National Institute of Toxicological Research, Seoul, Korea), MK-801 hydrogen maleate [(1)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d) cyclo-hepten-5,10-imine, Research Biochemicals Inc., Natick, MA], apomorphine hydrochloride (Sigma Chemical Co., St. Louis, MO) and haloperidol Injection (Whan-In Pharm. Co., Seoul, Korea). Except for apomorphine, all drugs were dissolved in physiological saline. Apomorphine was dissolved in saline containing 0.1% ascorbic acid, just before the experiment.
Measurement of CPP Induced by Methamphetamine Apparatus. The CPP apparatus and procedure used were the same as described in our previous report [23] and others [18,45]. The CPP apparatus was made by a modification of the apparatus used by Mucha et al. [38]. It consisted of two square-base Plexiglas compartment (15 3 15 3 15 cm), one with a white and the other with a black box jointed by a small gray tunnel (3 3 3 3 7.5 cm) that could be closed by guillotine doors. To provide tactile difference between the two compartments, the white compartment had a wire-mesh floor, and the black compartment had a metal-grid floor. Removal of the guillotine doors during the pretesting and the final testing phase allowed animals free access to all two compartments, and the time (seconds) spent by a mouse in each of the two compartments was recorded for 15 min using photobeam detectors connected via electrical interface to an IBM-compatible PC. All conditioning and test sessions were conducted under ambient light (20 –30 Lux). Procedures. 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 baseline preference was determined for nonpreferred side vs. preferred side for 15 min. All animals initially preferred the black compartment. Thus, to establish conditioning, we paired drug (methamphetamine) with the initially nonpreferred white compartment. Phase II (Conditioning phase): on days 3, 5, 7, and 9, the mice were pretreated with MK-801; 30 min later, they received saline or methamphetamine (2 mg/kg) and were immediately confined to the white compartment, the non-preferred side, for 60 min. On days 4, 6, 8, and 10, the mice were injected only with saline before being confined in the black compartment, the preferred side, for 60 min. Phase III (Testing phase): on day 11, neither saline nor a drug was administered to mice. As in the pretesting phase, the guillotine doors were raised, and the drug-free mice were placed in the tunnel of the central part, and the time (seconds) spent by the mice in the two compartments was recorded for 15 min. The scores were expressed as the difference in the time spent by the mice between the testing phase and the pretesting phase in the drug-paired (nonpreferred) compartment [18,23,45]. In our preliminary experiment, methamphetamine (1, 2, and 4 mg/kg) showed 48 s, 197 s, and 122 s of preference scores in the nonpreferred (drug-paired) side, respectively. The higher dose of methamphetamine 4 mg/kg is less effective in producing CPP than that of lower dose, 2 mg/kg. In addition, it seems that this higher dose of methamphetamine 4 mg/kg produces some problems of drug effect on sensory and motor processes such as excessive locomotion and stereotypy, that might interfere with the measurement of CPP. Therefore, methamphetamine 2 mg/kg (IP) was used in this experiment because the maximum response was observed in this dose. Meanwhile, we also obtained from the preliminary studies that the higher doses of MK-801 (above 0.3 mg/kg) alone produce the place preference effect and a dose-dependent increase in locomotion in mice. In addition, it has been reported that MK-801 elicits CPP in rats [34]. Therefore, lower doses of MK801 (0.05 and 0.1 mg/kg), which did not by themselves produce either any CPP or any influence on the locomotor activity, were selected and administered 30 min before the every injection of methamphetamine in this experiment. Measurement of Behavioral Sensitization to Apomorphine in Methamphetamine-Induced CPP Mice Behavioral sensitization to apomorphine was investigated by measuring the enhanced ambulatory activity induced by apomor-
MK-801 INHIBITS METHAMPHETAMINE CPP
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phine. Additional groups of mice that had received the same conditioning regimen as well as repeated administration of methamphetamine as in the CPP experiment were used to determine the inhibitory effect of MK-801 on the development of behavioral sensitization to apomorphine, a DA receptor agonist. To determine the development of behavioral sensitization in methamphetamineinduced CPP mice, methamphetamine (2 mg/kg, IP) was administered once every other day for 8 days (four times) according to the paradigm of the CPP test, and on day 9, 24 h after the final injection of methamphetamine, the behavioral sensitization was evidenced by an increased ambulatory activity induced by apomorphine 2 mg/kg (SC). The apparatus and procedure used were the same as described in our previous report [23] and others [4]. The ambulatory activity induced by apomorphine was measured by a tilting type ambulometer (AMB-10, O’Hara Co., Ltd., Tokyo, Japan). The mice were first allowed to preambulate for 10 min in the activity cages (20 cm in diameter and 18 cm in height) followed by a 20-min test period immediately after the injection of apomorphine 2 mg/kg (SC), a dose that produce a significant increase in ambulatory activity. MK-801 (0.05 and 0.1 mg/kg) was administered 30 min before each injection of methamphetamine. The inhibitory effect of MK-801 on the development of methamphetamine-induced behavioral sensitization to apomorphine was evidenced by a lesser ambulatory activity to apomorphine. Measurement of Apomorphine-Induced Climbing Behavior The climbing behavior in mice was measured using the threepoint rating scale of Protais et al. [40]. The apparatus and procedure used were the same as described in our previous report [23] and others [40]. Immediately after a subcutaneous injection of apomorphine (2 mg/kg), the mice were put into cylindrical individual cages (12 cm in diameter and 14 cm in height) with the floor and wall consisting of vertical metal bars (2 mm in diameter and 1 cm apart). After a 5-min period of exploratory activity, climbing behavior was measured by all or none score at 10, 20, and 30 min after the administration of apomorphine, and the three scores were averaged. The scores of this behavior were evaluated as follows: four paws on the floor (0 point), fore feet holding the wall (1 point), and four paws holding the wall (2 points). MK-801 (0.05, 0.1 and 0.2 mg/kg) was administered intraperitoneally to mice 30 min before the injection of apomorphine. In addition, to compare the effect of MK-801 with that of a selective DA receptor antagonist, the effect of haloperidol (0.1 mg/kg) on the apomorphineinduced climbing behaviors was also investigated. Statistics The data were expressed as means 6 SEM. The statistical significance of drug effects were first analyzed by 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 both tests of CPP and behavioral sensitization. Apomorphine-induced climbing behavior was analyzed by one-tailed Mann–Whitney U-test, because nonparametric statistics are needed with all or none or rating scale scores. RESULTS Inhibitory Effect of MK-801 on Methamphetamine-Induced CPP The group treated only with MK-801 0.1 mg/kg did not show any CPP compared with that of the saline control group (Fig. 1). However, MK-801 administered 30 min before the methamphetamine injection decreased the methamphetamine-induced CPP, F(2, 33) 5 4.38, p , 0.05. The group pretreated with MK-801 0.1 mg/kg showed a marked inhibition of methamphetamine-induced
FIG. 1. Inhibitory effect of MK-801 on methamphetamine-induced CPP. In the conditioning phase, mice were injected with methamphetamine once every other day for 8 days according to the CPP test paradigm. MK-801 (MK, 0.05 or 0.1 mg/kg, IP) was administered 30 min before the injection of methamphetamine (MAP, 2 mg/kg). The scores were expressed as the differences in time (s) spent by the mice between the testing phase and the pretesting phase in the drug-paired compartment. Each value is the mean 6 SEM of at least 12 mice. ** p , 0.01, compared with that of the saline (SAL) group. # p , 0.05, compared with that of the methamphetamine group.
CPP, showing 112 s, which was 47% less than that of the methamphetamine control group (p , 0.05, Dunnett’s test). However, MK-801 0.05 mg/kg did not show any significant inhibition of methamphetamine-induced CPP, compared with that of the methamphetamine control group. Inhibitory Effect of MK-801 on the Behavioral Sensitization to Apomorphine in Methamphetamine-Induced CPP Mice Ambulatory activity induced by apomorphine was enhanced in mice treated chronically with methamphetamine according to the paradigm of CPP experiment. The group treated with methamphetamine showed a significant increase in ambulatory activity to apomorphine 2 mg/kg, showing 291 counts, 70% more than the 171 counts of the saline control group (p , 0.01, Dunnett’s test) (Fig. 2). The group treated chronically with only MK-801 (0.1 mg/kg) did not show any increase of ambulatory activity to apomorphine, compared with that of the saline control group. These results suggest that the chronic administration of MK-801 does not in itself produce any influence on the behavioral sensitization to apomorphine in this experiment. However, MK-801 administered 30 min before the methamphetamine injection reduced the ambulatory activity to apomorphine, F(2, 33) 5 5.85, p , 0.01. The group pretreated with MK-801 0.1 mg/kg showed a significant inhibition of ambulatory activity to apomorphine, showing 198 counts, 32% less than that of the methamphetamine control group (p , 0.01, Dunnett’s test). These results suggested that behavioral sensitization to apomorphine was developed in methamphetamine-
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FIG. 2. Inhibitory effect of MK-801 on the behavioral sensitization to apomorphine in methamphetamine-induced CPP mice. Additional groups of the mice that received the same chronic methamphetamine as in CPP test were used, to investigate the effect of MK-801 on the development of behavioral sensitization to apomorphine in methamphetamine-induced CPP mice. The degree of development of methamphetamine-induced behavioral sensitization was evidenced by measuring the ambulatory activity to apomorphine (2 mg/kg, SC), 24 h after the final injection of methamphetamine. Each value is the mean 6 SEM of at least 12 mice. ** p , 0.01, compared with that of the saline group. ## p , 0.01, compared with that of the methamphetamine group.
induced CPP mice, and this development of behavioral sensitization was inhibited by MK-801. Inhibitory Effect of MK-801 on Apomorphine-Induced Climbing Behavior In our previous study, 2 mg/kg of apomorphine (SC) appeared to be a submaximal dose for inducing climbing behavior in mice [27]. Therefore, 2 mg/kg of apomorphine was used in this experiment. MK-801 (0.05, 0.1 and 0.2 mg/kg) alone did not produce either climbing behavior or ataxia in this experiment, when compared to the saline control group (data not shown). However, pretreatment with MK-801 (0.05, 0.1 and 0.2 mg/kg) inhibited apomorphine-induced climbing behavior by about 36% (1.13 points, p , 0.01), 53% (0.83 points, p , 0.001), and 67% (0.59 points, p , 0.001), respectively, compared with the apomorphine control group (1.77 points) (Fig. 3). Meanwhile, the selective DA receptor antagonist haloperidol (0.1 mg/kg) also showed significant inhibition of climbing behavior, showing 0.48 scores, 73% less than the apomorphine control group (p , 0.001). DISCUSSION In this study, repeated treatment with MK-801 inhibited methamphetamine-induced CPP and behavioral sensitization to apomorphine that developed in methamphetamine-induced CPP mice.
FIG. 3. Inhibitory effect of MK-801 on apomorphine-induced climbing behavior. MK-801 (0.05, 0.1 and 0.2 mg/kg, IP) or haloperidol (HAL, 0.1 mg/kg, IP) was administered to mice 30 min before the injection of apomorphine (APO, 2 mg/kg, SC). 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 score at 10, 20, and 30 min after the administration of apomorphine, and the three scores were averaged. Each value is the mean 6 SEM of at least 10 mice. *** p , 0.001, compared with that of the saline group; ## p , 0.01, ### p , 0.001, compared with that of the apomorphine group.
Many investigations have implicated the dopaminergic system in the reinforcing effects produced by the administration of methamphetamine. The initial support for an involvement of DA in the rewarding effects was provided by the finding that DA receptor antagonists attenuate the rewarding effects of amphetamine or cocaine [16,36,48]. The injection of DA receptor antagonists into the nucleus accumbens also blocked amphetamine-induced CPP [2]. In addition, there is evidence that the rewarding properties of both the psychomotor stimulants and the opioids involve central DA-containing neuronal systems [29,52]. Therefore, the present results suggest that methamphetamine-induced dopaminergic action, CPP, may be produced via the activation of NMDA receptor directly or indirectly acting both at the pre- and postsynaptic DA receptors, because the action of methamphetamine on the DA receptor is indirect [37] and DA receptor sensitivity is increased in the postsynaptic sites after the repeated administration of methamphetamine [28]. Meanwhile, in consistent with the present results, the competitive NMDA receptor antagonist AP-5 abolished the conditioned reinforcement of amphetamine [5]. In addition, MK-801 inhibited the CPP and reverse tolerance to ambulatory activity induced by amphetamine or cocaine [21,26]. In contrast to these studies, however, there were reports that MK-801 by itself produces a significant place preference in rats [34] and fails to block amphetamine-induced CPP in rats [20]. In considering the controversial reports on amphetamine/MK-801 interaction, it is likely that the possible reasons for discrepancy in the behavioral interactions between amphetamine-like psychomotor stimulants and MK-801
MK-801 INHIBITS METHAMPHETAMINE CPP were their different experimental conditions and methods: different models of CPP apparatus; discrepant conditioning trials or duration; different drug dosages and administration routes; as well as different species as subjects (mice vs. rats). It has been demonstrated that a-amino-3-hydroxyl-5-methyl-4isoxazole propionic acid (AMPA)/kainate receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DNQX, inhibited the rewarding effects of amphetamine [5,35]. These results suggested that rewarding effect of amphetamine might be produced not only via the activation of NMDA receptors but also non-NMDA receptors. Therefore, the involvement of non-NMDA receptor systems in mediating the rewarding effects of amphetamine cannot be ruled out. The mechanism underlying the development of CPP following repeated administration of psychomotor stimulants remains unknown. The postsynaptic DA receptor supersensitivity is developed after repeated administrations of psychomotor stimulants; thus, it becomes a mechanism of reverse tolerance (sensitization) and rewarding of those drugs [19,39]. At present, there seems to be no simple neurochemical explanation for the sensitization of the central dopaminergic system. However, if an increase in DA receptor number or sensitivity is responsible for enhanced responsiveness of the DA system to psychomotor stimulants following sensitization, one might expect sensitized animals to exhibit either hyperactivity to the ambulatory effects of directly acting DA agonists or changes in DA receptor binding. MK-801 prevents the imipramine-induced DA receptor supersensitivity to quinpirole, a DA receptor agonist [12]. Thus, MK-801 may prevent the development of behavioral sensitization by interfering with the stimulant effect of imipramine on DA neurons or on the mechanism of signal transduction at the D1 DA receptor [12,46]. In our previous study, MK-801 also commonly inhibited the cocaine-induced CPP, reverse tolerance to ambulatory activity, and behavioral sensitization to apomorphine, which developed in CPP or reverse-tolerant mice [26], suggesting that behavioral sensitization of postsynaptic DA receptor may be an underlying common mechanism that mediates cocaine-induced dopaminergic behaviors. In support of these findings, there were reports that MK-801 interferes with the development of sensitization to amphetamine or apomorphine and prevents the development of opioid tolerance and dependence [14,50,53], suggesting that NMDA receptors may play crucial roles in the development of drug-induced changes in sensitivity to neurotransmitters. Thus, the present results suggest that MK-801 may block methamphetamine-induced CPP by inhibiting the development of behavioral sensitization via the suppression of the NMDA receptor acting at the postsynaptic DA receptor. In the present study, a single administration of MK-801 showed antidopaminergic action by inhibiting apomorphineinduced climbing behavior. The climbing behavior induced by apomorphine in mice reveals the stimulation of postsynaptic DA receptors [11,40], because the peculiar behavior appears to be elicited by a stimulation of DA receptors in the striatum [40]. This result of the MK-801-apomorphine interaction study suggests that postsynaptic dopaminergic effects of apomorphine may be modulated directly by NMDA receptors interacting with DA receptors. In addition, our previous studies demonstrated that apomorphine-induced climbing behavior was also inhibited both by low doses of three different noncompetitive NMDA receptor antagonists, ketamine, dextrorphan, and dextromethorphan [27], and competitive NMDA antagonists such as AP-5 and D-CPP [R(2)3-(2-carboxypiperazin-4-yl)-propyl-1-phophonic acid] (data not shown). It has been demonstrated that both dopaminergic and
225 corticostriatal terminals make contact with the dendrites of the striatal output cells, and hypothesized that this arrangement forms the basis of dopaminergic modulation of incoming cortical signals and subsequent influence of outgoing signals [47]. Therefore, it is suggested that blockade of NMDA receptors attenuates apomorphine-induced activation of the output pathway and thereby lowers the general level of DA-induced activation at the postsynaptic DA receptor [22]. Thus, it is likely that the blockade of NMDA receptors results in the inhibition of apomorphine-induced climbing behavior. In contrast with the present results, however, it has been demonstrated that MK-801 produces a dose-dependent increase in locomotion in mice [10] and increase the ambulatory activity of cocaine [31], indicating that MK-801 possesses agonistic action on central dopaminergic systems through an acceleration of the dopaminergic transmission [13,31]. However, MK-801 also caused marked ambulatory stimulation in monoamine-depleted mice and pretreatment by haloperidol, a selective DA receptor antagonist, did not antagonize the MK-801–induced stimulation of ambulation [8,43], suggesting that the ambulation-accelerating effect of MK801 may be DA independent. Therefore, interpretations of MK801–induced increases in locomotor activity and behavioral interactions between MK-801 and other drugs still remain controversial because experimental conditions and methods used are a little bit different from each other, in addition to the untoward side effect of MK-801. Nevertheless, this results with apomorphine provides further evidence for the specificity of the methamphetamine– MK-801 interaction, indicating that the striatal dopaminergic response to apomorphine may be modulated acutely via the NMDA receptor. In conclusion, methamphetamine-induced CPP and behavioral sensitization to apomorphine in methamphetamine-induced CPP mice were commonly inhibited by MK-801. In addition, apomorphine-induced postsynaptic dopaminergic action, climbing behavior, was also attenuated by MK-801. These results suggest that dopaminergic behaviors of methamphetamine may be mediated partially via the activation of the NMDA receptor directly or indirectly acting both at the pre- and postsynaptic DA receptors, and the development of behavioral sensitization may be closely related to the dopaminergic activation modulated by NMDA receptors, because MK-801 inhibited both the methamphetamineinduced dopaminergic behaviors tested and apomorphine-induced climbing behavior in mice. ACKNOWLEDGEMENTS
This study was supported by a grant (1996 –1997) from the Research Center for New Drug Development, College of Pharmacy, Seoul National University, Republic of Korea.
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KIM AND JANG 26. Kim, H. S.; Park, W. K.; Jang, C. G.; Oh, S. K. Inhibition by MK-801 of cocaine-induced sensitization, conditioned place preference and dopamine receptor supersensitivity in mice. Brain Res. Bull. 40:201– 207; 1996. 27. Kim, H. S.; Rhee, G. S.; Jung, J. Y.; Lee, J. H.; Jang, C. G.; Park, W. K. Inhibition by noncompetitive NMDA receptor antagonists of apomorphine-induced climbing behavior in mice. Life Sci. 58:1397– 1402; 1996. 28. Klawans, H. L.; Margolin, O. J. Amphetamine-induced dopaminergic hypersensitivity in guinea pigs. Arch. Gen. Psychiatry 32:725–732; 1975. 29. Koob, G. F.; Bloom, F. E. Cellular and molecular mechanisms of drug dependence. Science 242:715–723; 1988. 30. Krebs, M. O.; Desce, J. M.; Kemel, M. L.; Gauchy, C.; Godeheu, G.; Cheramy, A.; Glowinski, J. Glutamatergic control of dopamine release in the rat striatum: Evidence for presynaptic N-methyl-D-aspartate receptors on dopaminergic nerve terminals. J. Neurochem. 56:81– 85; 1991. 31. Kuribara, H.; Asami, T.; Ida, I.; Tadokoro, S. Characteristics of the ambulation-increasing effects of the noncompetitive NMDA antagonist MK-801 in mice: Assessment by the coadministration with central-acting drugs. Jpn. J. Pharmacol. 58:11–18; 1992. 32. Kuribara, H.; Tadokoro, S. Circadian variation in methamphetamineand apomorphine-induced increase in ambulatory activity in mice. Pharmacol. Biochem. Behav. 17:1251–1256; 1982. 33. Lannes, B.; Micheletti, G.; Warter, J. M.; Kempf, E.; Scala, G. D. Behavioral, pharmacological and biochemical effects of acute and chronic administration of ketamine in the rat. Neurosci. Lett. 128:177– 181; 1991. 34. Layer, R. T.; Kaddis, F. G.; Wallace, L. J. The NMDA receptor antagonist MK-801 elicits conditioned place preference in rats. Pharmacol. Biochem. Behav. 44:245–273; 1993. 35. Layer, R. T.; Uretski, N. J.; Wallace, L. J. Effects of the AMPA/ kainate receptor antagonist DNQX in the nucleus accumbens on drug-induced conditioned place preference. Brain Res. 617:267– 273; 1993. 36. Leone, P.; Dichiara, G. Blockade of D-1 receptors by SCH 23390 antagonizes morphine- and amphetamine-induced place preference conditioning. Eur. J. Pharmacol. 135:251–254; 1987. 37. Moore, K. E.; Chiuch, C. C.; Zelole, G. Release of neurotransmitters from the brain in vivo by amphetamine, methylphenidate and cocaine. In: Ellinwood, E. H., Jr; Kilbey, M. M., eds. Advances in behavioral biology, vol. 21. New York: Plenum Press; 1977:143– 160. 38. Mucha, R. F.; Van der Kooy, D.; O’Shaughnessy, M.; Bucenieks, P. Drug reinforcement studied by the use of place conditioning in rat. Brain Res. 243:91–105; 1982. 39. Nestler, E. J. Molecular mechanisms of drug addiction. J. Neurosci. 12:2439 –2450; 1992. 40. Protais, P.; Costentin, J.; Schwartz, J. C. Climbing behavior induced by apomorphine in mice: A simple test for the study of dopamine receptors in striatum. Psychopharmacology (Berlin) 50: 1– 6; 1976. 41. Pulvirenti, L.; Swerdlow, N. R.; Koob, G. F. Microinjection of a glutamate antagonist into the nucleus accumbens reduces psychostimulant locomotion in rats. Neurosci. Lett. 103:213–218; 1989. 42. Pulvirenti, L.; Swerdlow, N. R.; Koob, G. F. Nucleus accumbens NMDA antagonist decreases locomotor activity produced by cocaine, heroin, or accumbens dopamine, but not caffeine. Pharmacol. Biochem. Behav. 40:841– 845; 1991. 43. Raffa, R. B.; Ortegon, M. E.; Robisch, D. M.; Martin, G. E. In vivo demonstration of enhancement of MK801 by L-glutamate. Life Sci. 44:1593–1599; 1989. 44. Robinson, T.; Becker, J. Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis. Brain Res. Rev. 11:157–198; 1986. 45. Sala, M.; Braida, D.; Calcaterra, P.; Leone, M. P.; Gori, E. Dosedependent conditioned place preference produced by etonitazene and morphine. Eur. J. Pharmacol. 217:37– 41; 1992. 46. Serra, G.; Collu, M.; D’Aquila, P. S.; DeMontis, M. G.; Gessa, G. L.
MK-801 INHIBITS METHAMPHETAMINE CPP Possible role of dopamine D1 receptor in the behavioral supersensitivity to dopamine agonist induced by chronic treatment with antidepressants. Brain Res. 527:234 –243; 1990. 47. Smith, A. D.; Bolam, J. P. The neural network of the basal ganglia as revealed by the study of synaptic connections of identified neurons. Trends Neurosci. 13:259 –265; 1990. 48. Spyraki, C.; Fibiger, H. C.; Phillips, A. G. Dopaminergic substrates of amphetamine-induced place preference conditioning. Brain Res. 253: 185–193; 1982. 49. Trazon, D. B.; Suzuki, T.; Misawa, M.; Watanabe, S. Methylxanthines (caffeine and theophylline) blocked methamphetamine-induced condi-
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PII S0361-9230(97)00093-2
MK-801 Inhibits Methamphetamine-Induced Conditioned Place Preference and Behavioral Sensitization to Apomorphine in Mice HACK-SEANG KIM*1 AND CHOON-GON JANG† *Department of Pharmacology, College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea, and †Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216-4045, USA [Received 18 September 1996; Revised 10 March 1997; Accepted 14 March 1997] ABSTRACT: Intraperitoneal administration of MK-801 (0.1 mg/ kg), an N-methyl-D-aspartate (NMDA) receptor antagonist, before and during methamphetamine treatment inhibited methamphetamine-induced conditioned place preference (CPP) in mice. Behavioral sensitization to a dopamine (DA) receptor agonist apomorphine that developed in methamphetamine-induced CPP mice was also inhibited by MK-801. Furthermore, MK-801 inhibited apomorphine-induced postsynaptic dopaminergic action, cage-climbing behavior. Therefore, the present studies suggest that methamphetamine-induced behaviors, such as CPP and behavioral sensitization, may be closely related to the dopaminergic activation mediated via the NMDA receptor. The behavioral sensitization to apomorphine may be a possible underlying mechanism of methamphetamine-induced CPP, because behavioral sensitization developed in methamphetamine-induced CPP mice, as well as apomorphine-induced climbing behavior in mice, were inhibited by MK-801. © 1997 Elsevier Science Inc.
reinforcement [6,7]. In support of these investigations, DA receptor antagonists such as haloperidol and SCH23390 antagonize amphetamine-induced CPP [36,48]. A 6-OHDA lesion of DA innervation of the nucleus accumbens appeared to decrease the amphetamine-induced CPP [48]. Therefore, it is likely that the dopaminergic system may be more closely related in mediating the rewarding effect of methamphetamine. It has been also reported, however, that the blockade of DA transmission inhibited aversive stimuli as well as the motivational properties of rewarding [1]. Recently, it has been reported that repeated treatment with a noncompetitive NMDA receptor antagonist, MK-801, inhibited the development of reverse tolerance to the ambulation accelerating effects of amphetamine and cocaine, suggesting the modulation of the dopaminergic system by MK-801 [21]. Moreover, 6,7-dinitroquinoxaline-2,3-dione (DNQX), a nonspecific glutamate receptor antagonist, also inhibits the acquisition of CPP produced by amphetamine [35]. It has been demonstrated that striatal dopaminergic nerve terminals possess the NMDA receptor [30], and that these presynaptic receptors are involved in a facilitative control of DA release [9], suggesting that the regulation of the central DA release may be mediated via the NMDA receptor. In addition, an intranucleus accumbens microinjection of an NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (AP-5), reduced the locomotor activation induced by both cocaine (IP) acting as a presynaptic uptake blocker and DA injected directly into the nucleus accumbens acting as a postsynaptic DA agonist [42]. Similar results of other noncompetitive NMDA receptor antagonists such as ketamine [33] and dextromethorphan [3] have also been reported. Meanwhile, previous work in our laboratory has shown that MK-801 inhibited the developments of cocaine-induced dopaminergic behaviors such as reverse tolerance to ambulatory activity and CPP in mice [26]. In addition, apomorphine-induced striatal dopaminergic action, climbing behavior, was inhibited by the noncompetitive NMDA receptor antagonists such as MK-801, ketamine, dextrorphan and dextromethorphan in mice [27]. These studies suggest not only the possibility that glutamatergic neurotransmission may modulate DA function, both at the pre- and postsynaptic levels [41], but also that the dopam-
KEY WORDS: Methamphetamine, MK-801, N-Methyl-D-aspartate Receptor, Dopamine, Conditioned place preference, Sensitization, Climbing behavior.
INTRODUCTION Psychomotor stimulants such as amphetamine, methamphetamine, or cocaine are known to induce conditioned place preference (CPP) [15,18,49]. These drugs produce the rewarding effect, as seen through their common property of facilitating dopaminergic transmission either by stimulating the release of dopamine (DA) or inhibiting DA uptake. Methamphetamine and amphetamine facilitate the release of newly synthesized DA and inhibit the uptake of DA [17,32]. Chronic administration of amphetamine derivatives produces long lasting depletion of DA [15] and develops reinforcement as well as behavioral sensitization. Although CPP can be induced by treatment regimens that induce sensitization to other behaviors, it can also occur in the absence of this phenomenon. Some neuropharmacological investigations have suggested an involvement of the mesolimbic and mesocortical dopaminergic systems as a neuronal mechanism mediating amphetamine-induced 1
To whom requests for reprints should be addressed.
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inergic system activated by the glutamatergic system is involved in producing the rewarding effects of methamphetamine [35]. It has been demonstrated that the behavioral sensitization after repeated administration of psychomotor stimulants such as methamphetamine can be attributed to the dopaminergic hyperfunction in the central nervous system [44]. It has been also reported that the mice sensitized to methamphetamine or cocaine show an enhanced response to apomorphine, a direct DA receptor agonist [24,25], indicating the development of behavioral sensitization between methamphetamine and dopaminergic systems. These results suggest that behavioral sensitization of DA receptor may be a possible underlying mechanism mediating methamphetamineinduced CPP or reverse tolerance to ambulatory activity. However, it is unclear whether this behavioral sensitization is due to an increase in the sensitivity of the postsynaptic DA neuron or to an increase in the amount of neurotransmitter released by presynaptic DA neuron. There is evidence that the underlying mechanisms of locomotor stimulation and rewarding effect are the same, and a common denominator underlying the addictive qualities of a variety of substance is their ability to cause psychomotor activation [51]. Therefore, it is likely that methamphetamine-induced CPP, as well as ambulation-accelerating activity and reverse tolerance to ambulatory activity, may be inhibited by NMDA receptor antagonist MK-801. However, little is known about the involvement of NMDA receptor in CPP induced by methamphetamine, especially with regard to the behavioral interaction of DA-NMDA systems at the postsynaptic DA receptors. Thus, to assess whether methamphetamine-induced CPP are produced by dopaminergic activation mediated via the NMDA receptor, it is necessary to investigate that an NMDA receptor antagonist, MK-801, will commonly inhibit methamphetamine-induced CPP and behavioral sensitization to apomorphine developed in CPP mice. The present studies, therefore, were designed to investigate the inhibitory effect of MK-801 on methamphetamine-induced CPP. In addition, the degree of the development of behavioral sensitization to apomorphine was also examined in methamphetamineinduced CPP mice to determine the involvement of the NMDA receptor in the dopaminergic modulation. Furthermore, to investigate the direct effect of the NMDA receptor in the postsynaptic dopaminergic functions, the effect of MK-801 on apomorphineinduced selective dopaminergic activity, climbing behavior, was also measured. MATERIALS AND METHODS Animals ICR male mice (Samyuk Laboratory Animal Inc., Osan, Korea) weighing 20 –26 g in a group of 10 –15, were used in all experiments. They were housed 10 mice in a cage with water and food available ad lib under an artificial 12-h light/dark cycle (light at 0700 h) and constant temperature (22 6 2°C). Drugs The drugs used were methamphetamine hydrochloride (National Institute of Toxicological Research, Seoul, Korea), MK-801 hydrogen maleate [(1)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d) cyclo-hepten-5,10-imine, Research Biochemicals Inc., Natick, MA], apomorphine hydrochloride (Sigma Chemical Co., St. Louis, MO) and haloperidol Injection (Whan-In Pharm. Co., Seoul, Korea). Except for apomorphine, all drugs were dissolved in physiological saline. Apomorphine was dissolved in saline containing 0.1% ascorbic acid, just before the experiment.
Measurement of CPP Induced by Methamphetamine Apparatus. The CPP apparatus and procedure used were the same as described in our previous report [23] and others [18,45]. The CPP apparatus was made by a modification of the apparatus used by Mucha et al. [38]. It consisted of two square-base Plexiglas compartment (15 3 15 3 15 cm), one with a white and the other with a black box jointed by a small gray tunnel (3 3 3 3 7.5 cm) that could be closed by guillotine doors. To provide tactile difference between the two compartments, the white compartment had a wire-mesh floor, and the black compartment had a metal-grid floor. Removal of the guillotine doors during the pretesting and the final testing phase allowed animals free access to all two compartments, and the time (seconds) spent by a mouse in each of the two compartments was recorded for 15 min using photobeam detectors connected via electrical interface to an IBM-compatible PC. All conditioning and test sessions were conducted under ambient light (20 –30 Lux). Procedures. 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 baseline preference was determined for nonpreferred side vs. preferred side for 15 min. All animals initially preferred the black compartment. Thus, to establish conditioning, we paired drug (methamphetamine) with the initially nonpreferred white compartment. Phase II (Conditioning phase): on days 3, 5, 7, and 9, the mice were pretreated with MK-801; 30 min later, they received saline or methamphetamine (2 mg/kg) and were immediately confined to the white compartment, the non-preferred side, for 60 min. On days 4, 6, 8, and 10, the mice were injected only with saline before being confined in the black compartment, the preferred side, for 60 min. Phase III (Testing phase): on day 11, neither saline nor a drug was administered to mice. As in the pretesting phase, the guillotine doors were raised, and the drug-free mice were placed in the tunnel of the central part, and the time (seconds) spent by the mice in the two compartments was recorded for 15 min. The scores were expressed as the difference in the time spent by the mice between the testing phase and the pretesting phase in the drug-paired (nonpreferred) compartment [18,23,45]. In our preliminary experiment, methamphetamine (1, 2, and 4 mg/kg) showed 48 s, 197 s, and 122 s of preference scores in the nonpreferred (drug-paired) side, respectively. The higher dose of methamphetamine 4 mg/kg is less effective in producing CPP than that of lower dose, 2 mg/kg. In addition, it seems that this higher dose of methamphetamine 4 mg/kg produces some problems of drug effect on sensory and motor processes such as excessive locomotion and stereotypy, that might interfere with the measurement of CPP. Therefore, methamphetamine 2 mg/kg (IP) was used in this experiment because the maximum response was observed in this dose. Meanwhile, we also obtained from the preliminary studies that the higher doses of MK-801 (above 0.3 mg/kg) alone produce the place preference effect and a dose-dependent increase in locomotion in mice. In addition, it has been reported that MK-801 elicits CPP in rats [34]. Therefore, lower doses of MK801 (0.05 and 0.1 mg/kg), which did not by themselves produce either any CPP or any influence on the locomotor activity, were selected and administered 30 min before the every injection of methamphetamine in this experiment. Measurement of Behavioral Sensitization to Apomorphine in Methamphetamine-Induced CPP Mice Behavioral sensitization to apomorphine was investigated by measuring the enhanced ambulatory activity induced by apomor-
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phine. Additional groups of mice that had received the same conditioning regimen as well as repeated administration of methamphetamine as in the CPP experiment were used to determine the inhibitory effect of MK-801 on the development of behavioral sensitization to apomorphine, a DA receptor agonist. To determine the development of behavioral sensitization in methamphetamineinduced CPP mice, methamphetamine (2 mg/kg, IP) was administered once every other day for 8 days (four times) according to the paradigm of the CPP test, and on day 9, 24 h after the final injection of methamphetamine, the behavioral sensitization was evidenced by an increased ambulatory activity induced by apomorphine 2 mg/kg (SC). The apparatus and procedure used were the same as described in our previous report [23] and others [4]. The ambulatory activity induced by apomorphine was measured by a tilting type ambulometer (AMB-10, O’Hara Co., Ltd., Tokyo, Japan). The mice were first allowed to preambulate for 10 min in the activity cages (20 cm in diameter and 18 cm in height) followed by a 20-min test period immediately after the injection of apomorphine 2 mg/kg (SC), a dose that produce a significant increase in ambulatory activity. MK-801 (0.05 and 0.1 mg/kg) was administered 30 min before each injection of methamphetamine. The inhibitory effect of MK-801 on the development of methamphetamine-induced behavioral sensitization to apomorphine was evidenced by a lesser ambulatory activity to apomorphine. Measurement of Apomorphine-Induced Climbing Behavior The climbing behavior in mice was measured using the threepoint rating scale of Protais et al. [40]. The apparatus and procedure used were the same as described in our previous report [23] and others [40]. Immediately after a subcutaneous injection of apomorphine (2 mg/kg), the mice were put into cylindrical individual cages (12 cm in diameter and 14 cm in height) with the floor and wall consisting of vertical metal bars (2 mm in diameter and 1 cm apart). After a 5-min period of exploratory activity, climbing behavior was measured by all or none score at 10, 20, and 30 min after the administration of apomorphine, and the three scores were averaged. The scores of this behavior were evaluated as follows: four paws on the floor (0 point), fore feet holding the wall (1 point), and four paws holding the wall (2 points). MK-801 (0.05, 0.1 and 0.2 mg/kg) was administered intraperitoneally to mice 30 min before the injection of apomorphine. In addition, to compare the effect of MK-801 with that of a selective DA receptor antagonist, the effect of haloperidol (0.1 mg/kg) on the apomorphineinduced climbing behaviors was also investigated. Statistics The data were expressed as means 6 SEM. The statistical significance of drug effects were first analyzed by 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 both tests of CPP and behavioral sensitization. Apomorphine-induced climbing behavior was analyzed by one-tailed Mann–Whitney U-test, because nonparametric statistics are needed with all or none or rating scale scores. RESULTS Inhibitory Effect of MK-801 on Methamphetamine-Induced CPP The group treated only with MK-801 0.1 mg/kg did not show any CPP compared with that of the saline control group (Fig. 1). However, MK-801 administered 30 min before the methamphetamine injection decreased the methamphetamine-induced CPP, F(2, 33) 5 4.38, p , 0.05. The group pretreated with MK-801 0.1 mg/kg showed a marked inhibition of methamphetamine-induced
FIG. 1. Inhibitory effect of MK-801 on methamphetamine-induced CPP. In the conditioning phase, mice were injected with methamphetamine once every other day for 8 days according to the CPP test paradigm. MK-801 (MK, 0.05 or 0.1 mg/kg, IP) was administered 30 min before the injection of methamphetamine (MAP, 2 mg/kg). The scores were expressed as the differences in time (s) spent by the mice between the testing phase and the pretesting phase in the drug-paired compartment. Each value is the mean 6 SEM of at least 12 mice. ** p , 0.01, compared with that of the saline (SAL) group. # p , 0.05, compared with that of the methamphetamine group.
CPP, showing 112 s, which was 47% less than that of the methamphetamine control group (p , 0.05, Dunnett’s test). However, MK-801 0.05 mg/kg did not show any significant inhibition of methamphetamine-induced CPP, compared with that of the methamphetamine control group. Inhibitory Effect of MK-801 on the Behavioral Sensitization to Apomorphine in Methamphetamine-Induced CPP Mice Ambulatory activity induced by apomorphine was enhanced in mice treated chronically with methamphetamine according to the paradigm of CPP experiment. The group treated with methamphetamine showed a significant increase in ambulatory activity to apomorphine 2 mg/kg, showing 291 counts, 70% more than the 171 counts of the saline control group (p , 0.01, Dunnett’s test) (Fig. 2). The group treated chronically with only MK-801 (0.1 mg/kg) did not show any increase of ambulatory activity to apomorphine, compared with that of the saline control group. These results suggest that the chronic administration of MK-801 does not in itself produce any influence on the behavioral sensitization to apomorphine in this experiment. However, MK-801 administered 30 min before the methamphetamine injection reduced the ambulatory activity to apomorphine, F(2, 33) 5 5.85, p , 0.01. The group pretreated with MK-801 0.1 mg/kg showed a significant inhibition of ambulatory activity to apomorphine, showing 198 counts, 32% less than that of the methamphetamine control group (p , 0.01, Dunnett’s test). These results suggested that behavioral sensitization to apomorphine was developed in methamphetamine-
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FIG. 2. Inhibitory effect of MK-801 on the behavioral sensitization to apomorphine in methamphetamine-induced CPP mice. Additional groups of the mice that received the same chronic methamphetamine as in CPP test were used, to investigate the effect of MK-801 on the development of behavioral sensitization to apomorphine in methamphetamine-induced CPP mice. The degree of development of methamphetamine-induced behavioral sensitization was evidenced by measuring the ambulatory activity to apomorphine (2 mg/kg, SC), 24 h after the final injection of methamphetamine. Each value is the mean 6 SEM of at least 12 mice. ** p , 0.01, compared with that of the saline group. ## p , 0.01, compared with that of the methamphetamine group.
induced CPP mice, and this development of behavioral sensitization was inhibited by MK-801. Inhibitory Effect of MK-801 on Apomorphine-Induced Climbing Behavior In our previous study, 2 mg/kg of apomorphine (SC) appeared to be a submaximal dose for inducing climbing behavior in mice [27]. Therefore, 2 mg/kg of apomorphine was used in this experiment. MK-801 (0.05, 0.1 and 0.2 mg/kg) alone did not produce either climbing behavior or ataxia in this experiment, when compared to the saline control group (data not shown). However, pretreatment with MK-801 (0.05, 0.1 and 0.2 mg/kg) inhibited apomorphine-induced climbing behavior by about 36% (1.13 points, p , 0.01), 53% (0.83 points, p , 0.001), and 67% (0.59 points, p , 0.001), respectively, compared with the apomorphine control group (1.77 points) (Fig. 3). Meanwhile, the selective DA receptor antagonist haloperidol (0.1 mg/kg) also showed significant inhibition of climbing behavior, showing 0.48 scores, 73% less than the apomorphine control group (p , 0.001). DISCUSSION In this study, repeated treatment with MK-801 inhibited methamphetamine-induced CPP and behavioral sensitization to apomorphine that developed in methamphetamine-induced CPP mice.
FIG. 3. Inhibitory effect of MK-801 on apomorphine-induced climbing behavior. MK-801 (0.05, 0.1 and 0.2 mg/kg, IP) or haloperidol (HAL, 0.1 mg/kg, IP) was administered to mice 30 min before the injection of apomorphine (APO, 2 mg/kg, SC). 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 score at 10, 20, and 30 min after the administration of apomorphine, and the three scores were averaged. Each value is the mean 6 SEM of at least 10 mice. *** p , 0.001, compared with that of the saline group; ## p , 0.01, ### p , 0.001, compared with that of the apomorphine group.
Many investigations have implicated the dopaminergic system in the reinforcing effects produced by the administration of methamphetamine. The initial support for an involvement of DA in the rewarding effects was provided by the finding that DA receptor antagonists attenuate the rewarding effects of amphetamine or cocaine [16,36,48]. The injection of DA receptor antagonists into the nucleus accumbens also blocked amphetamine-induced CPP [2]. In addition, there is evidence that the rewarding properties of both the psychomotor stimulants and the opioids involve central DA-containing neuronal systems [29,52]. Therefore, the present results suggest that methamphetamine-induced dopaminergic action, CPP, may be produced via the activation of NMDA receptor directly or indirectly acting both at the pre- and postsynaptic DA receptors, because the action of methamphetamine on the DA receptor is indirect [37] and DA receptor sensitivity is increased in the postsynaptic sites after the repeated administration of methamphetamine [28]. Meanwhile, in consistent with the present results, the competitive NMDA receptor antagonist AP-5 abolished the conditioned reinforcement of amphetamine [5]. In addition, MK-801 inhibited the CPP and reverse tolerance to ambulatory activity induced by amphetamine or cocaine [21,26]. In contrast to these studies, however, there were reports that MK-801 by itself produces a significant place preference in rats [34] and fails to block amphetamine-induced CPP in rats [20]. In considering the controversial reports on amphetamine/MK-801 interaction, it is likely that the possible reasons for discrepancy in the behavioral interactions between amphetamine-like psychomotor stimulants and MK-801
MK-801 INHIBITS METHAMPHETAMINE CPP were their different experimental conditions and methods: different models of CPP apparatus; discrepant conditioning trials or duration; different drug dosages and administration routes; as well as different species as subjects (mice vs. rats). It has been demonstrated that a-amino-3-hydroxyl-5-methyl-4isoxazole propionic acid (AMPA)/kainate receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DNQX, inhibited the rewarding effects of amphetamine [5,35]. These results suggested that rewarding effect of amphetamine might be produced not only via the activation of NMDA receptors but also non-NMDA receptors. Therefore, the involvement of non-NMDA receptor systems in mediating the rewarding effects of amphetamine cannot be ruled out. The mechanism underlying the development of CPP following repeated administration of psychomotor stimulants remains unknown. The postsynaptic DA receptor supersensitivity is developed after repeated administrations of psychomotor stimulants; thus, it becomes a mechanism of reverse tolerance (sensitization) and rewarding of those drugs [19,39]. At present, there seems to be no simple neurochemical explanation for the sensitization of the central dopaminergic system. However, if an increase in DA receptor number or sensitivity is responsible for enhanced responsiveness of the DA system to psychomotor stimulants following sensitization, one might expect sensitized animals to exhibit either hyperactivity to the ambulatory effects of directly acting DA agonists or changes in DA receptor binding. MK-801 prevents the imipramine-induced DA receptor supersensitivity to quinpirole, a DA receptor agonist [12]. Thus, MK-801 may prevent the development of behavioral sensitization by interfering with the stimulant effect of imipramine on DA neurons or on the mechanism of signal transduction at the D1 DA receptor [12,46]. In our previous study, MK-801 also commonly inhibited the cocaine-induced CPP, reverse tolerance to ambulatory activity, and behavioral sensitization to apomorphine, which developed in CPP or reverse-tolerant mice [26], suggesting that behavioral sensitization of postsynaptic DA receptor may be an underlying common mechanism that mediates cocaine-induced dopaminergic behaviors. In support of these findings, there were reports that MK-801 interferes with the development of sensitization to amphetamine or apomorphine and prevents the development of opioid tolerance and dependence [14,50,53], suggesting that NMDA receptors may play crucial roles in the development of drug-induced changes in sensitivity to neurotransmitters. Thus, the present results suggest that MK-801 may block methamphetamine-induced CPP by inhibiting the development of behavioral sensitization via the suppression of the NMDA receptor acting at the postsynaptic DA receptor. In the present study, a single administration of MK-801 showed antidopaminergic action by inhibiting apomorphineinduced climbing behavior. The climbing behavior induced by apomorphine in mice reveals the stimulation of postsynaptic DA receptors [11,40], because the peculiar behavior appears to be elicited by a stimulation of DA receptors in the striatum [40]. This result of the MK-801-apomorphine interaction study suggests that postsynaptic dopaminergic effects of apomorphine may be modulated directly by NMDA receptors interacting with DA receptors. In addition, our previous studies demonstrated that apomorphine-induced climbing behavior was also inhibited both by low doses of three different noncompetitive NMDA receptor antagonists, ketamine, dextrorphan, and dextromethorphan [27], and competitive NMDA antagonists such as AP-5 and D-CPP [R(2)3-(2-carboxypiperazin-4-yl)-propyl-1-phophonic acid] (data not shown). It has been demonstrated that both dopaminergic and
225 corticostriatal terminals make contact with the dendrites of the striatal output cells, and hypothesized that this arrangement forms the basis of dopaminergic modulation of incoming cortical signals and subsequent influence of outgoing signals [47]. Therefore, it is suggested that blockade of NMDA receptors attenuates apomorphine-induced activation of the output pathway and thereby lowers the general level of DA-induced activation at the postsynaptic DA receptor [22]. Thus, it is likely that the blockade of NMDA receptors results in the inhibition of apomorphine-induced climbing behavior. In contrast with the present results, however, it has been demonstrated that MK-801 produces a dose-dependent increase in locomotion in mice [10] and increase the ambulatory activity of cocaine [31], indicating that MK-801 possesses agonistic action on central dopaminergic systems through an acceleration of the dopaminergic transmission [13,31]. However, MK-801 also caused marked ambulatory stimulation in monoamine-depleted mice and pretreatment by haloperidol, a selective DA receptor antagonist, did not antagonize the MK-801–induced stimulation of ambulation [8,43], suggesting that the ambulation-accelerating effect of MK801 may be DA independent. Therefore, interpretations of MK801–induced increases in locomotor activity and behavioral interactions between MK-801 and other drugs still remain controversial because experimental conditions and methods used are a little bit different from each other, in addition to the untoward side effect of MK-801. Nevertheless, this results with apomorphine provides further evidence for the specificity of the methamphetamine– MK-801 interaction, indicating that the striatal dopaminergic response to apomorphine may be modulated acutely via the NMDA receptor. In conclusion, methamphetamine-induced CPP and behavioral sensitization to apomorphine in methamphetamine-induced CPP mice were commonly inhibited by MK-801. In addition, apomorphine-induced postsynaptic dopaminergic action, climbing behavior, was also attenuated by MK-801. These results suggest that dopaminergic behaviors of methamphetamine may be mediated partially via the activation of the NMDA receptor directly or indirectly acting both at the pre- and postsynaptic DA receptors, and the development of behavioral sensitization may be closely related to the dopaminergic activation modulated by NMDA receptors, because MK-801 inhibited both the methamphetamineinduced dopaminergic behaviors tested and apomorphine-induced climbing behavior in mice. ACKNOWLEDGEMENTS
This study was supported by a grant (1996 –1997) from the Research Center for New Drug Development, College of Pharmacy, Seoul National University, Republic of Korea.
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