Original Article
MK-801 Inhibits Methamphetamine-Induced Conditioned Place Preference and Behavioral Sensitization to Apomorphine in Mice

https://doi.org/10.1016/S0361-9230(97)00093-2Get rights and content

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.

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 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 dopaminergic 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 methamphetamine-induced 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 methamphetamine-induced 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 apomorphine-induced selective dopaminergic activity, climbing behavior, was also measured.

Section snippets

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 ± 2°C).

Drugs

The drugs used were methamphetamine hydrochloride (National Institute of Toxicological Research, Seoul, Korea), MK-801 hydrogen maleate [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo-(a,d)

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) = 4.38, p < 0.05. The group pretreated with MK-801 0.1 mg/kg showed a marked inhibition of methamphetamine-induced 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

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.

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

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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