MK-801, a non-competitive antagonist of NMDA receptor, prevents methamphetamine-induced decrease of striatal dopamine uptake sites in the rat striatum

Neuroscience Letters, 136{1992) 39 42 ~ 1992 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940/92/$ 05.00

39

NSL 08399

MK-801, a non-competitive antagonist of NMDA receptor, prevents methamphetamine-induced decrease of striatal dopamine uptake sites in the rat striatum Akira M u r a k i , Tsukasa K o y a m a , M a k o t o N a k a y a m a , Tetsuro O h m o r i and Itaru Yamashita DtT~artment ol Psychialry and Neurology, HokkaMo University, School of Medicine, Sapporo (Japan) (Received 29 July 1991: Revised version received 22 November 1991: Accepted 22 November 1991)

Key words. Methamphetamine: MK-801; Dizocilpine maleatc: Excitatory amino acid, NMDA receptor: Dopamine; Dopamine uptake site We investigated the effects of MK-801, a non-competitive antagonist of NMDA receptor, on methamphetamine-mduced decrease in dopamine (DA) uptake sites in the rat striatum. Repeated administrations o1"an escalating dose of methamphetamine (2.5, 5, 7.5. 10 mg/kg s.c. ×2, every other day for a week) produced decreased DA uptake sites assayed by binding with pH]GBR 12935 in the striatum. Co-administration of MK-801 and methamphetaminc significantly prevented the methamphetamine-induced decrease in striatal [~H]GBR 12935 binding. Administration of MK-801 alone did not affect [~H]GBR 12935 binding. These results suggest that some neurochemical effects of methalnphetamine may bc mediated via mechanism involving excitatory amino acids.

It is widely recognized that a schizophrenia-like psychosis occurs following a long-term use of methamphetamine. People who abuse methamphetamine or amphetamine frequently develop a drug-induced paranoid psychotic condition characterized by hallucinations, and delusions of reference and persecution [1,4]. Moreover, in animals, the repeated administration of methamphetamine or amphetamine has been reported to produce an enhanced responsiveness or 'reverse tolerance' to the locomotorstimulant and stereotypy-producing agents [17]. The mechanism of these effects is considered to involve dopaminergic functions. Our colleagues have recently reported that a repeated administration of an escalating dose of methamphetamine produces the decrease of dopamine (DA) uptake sites in the rat striatum [14]. They suggested that the changes of the presynaptic regulation of dopaminergic neural transmission including DA uptake may closely relate to the development of methamphetamine psychosis. Recently, a potential role for excitatory amino acids in methamphetamine-induced neurochemical changes has been suggested. This is based on the ability of MK-801, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, to attenuate the methamphetamineCorre,vmndence." A. Muraki, Department of Psychiatry and Neurology, Hokkaido University, School of Medicine, North 15, West 7, Sapporo 060, Japan.

induced decrease in the activity of striatal tyrosine hydroxylase [19] and hippocampal tryptophan hydroxylase [9]. These effects are in agreement with the known neuroprotective effect of MK-801 in the other types of neuronal injury such as experimental hypoxia-ischemia [13, 18], hypoglycemia [22] and sustained seizures [2, 3, 12] in animal models. This study was conducted to determine whether NMDA antagonists might also provide some protective effects against methamphetamine-induced decrease of DA uptake sites in the rat striatum. Male Wistar-King rats, weighing 200 250 g, were housed 2 per cage in a temperature-controlled room (22°C) with a 12-h light-dark cycle, and access to food and water ad libitum. The rats received methamphetamine or the vehicle according to the repeated escalating dose schedule shown in Table I. The M K-801-treated animals received a 1.0 mg/kg dose, i.p., 30 min prior to the injection of methamphetamine or the vehicle. The animals were killed by decapitation 7 days after the last treatment, and the striatum was immediately removed on a cold plate; all the tissues were stored at -80°C until assayed. [3H]GBR 12935 binding was performed by the method described by Janowsky et al. [8] with minor modifications. Striata were homogenized in 10 volumes of icecold sucrose (0.32 M) using a Potter homogenizer and centrifuged at 1,000 x g for 10 rain. The supernatant was centrifuged at 23,000 x g for 20 rain and the resultant

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Fig. 1. Effects of co-administration of methamphetanfine and MK-801 on the B.... values of [~H]GBR 12935 binding m the rat slriatum. The results are shown by the means t S.E.M.: n:8. * P < 0.01 as compared lo lhe other group';

pellet was resuspended in 200 volmnes of 50 mM TrisHC1 buffer (pH 7.7) containing 120 mM NaC1. Following incubation for 45 rain at 2 5 ° C , bound [3H]GBR 12935 was separated from free compound by vacuum filtration through glass fiber filter (Whatman GF/B) followed by washing with a 10 ml of the incubation buffer. The radioactivity trapped on the filter was counted using liquid scintillation spectrometry. The specific binding was defined as the difference in total binding in tile presence and absence of 5 ~M mazindol. The dissociation constants (Ku) and maximum receptor density (B .... ) values were calculated by Scatchard analysis of the data from saturation experiments. Results are expressed as mean + S.E,M. Statistical analysis of the data was performed using an one-way analysis of w~riance followed by Tukey's test. Table II and Fig. I show the effect of MK-801 on the methamphetamine-induced decrease of [~H]GBR 12935 binding in the striatum. Treatment with methamphefamine decreased B ...... to 75% of control. Co-administration with MK-801 significantly prevented the methamphetamine-induced decrease of [3H]GBR 12935 binding. Administration of MK-801 alone did not affect striatal [3H]GBR 12935 binding. There was no difference in the K,~ between groups. Almost all chronic methamphetamine abusers build up to its high doses gradually as they develop tolerance to the autonomic effects of methamphetamine, lchikawa [7] designed a regimen of the repeated administration of an escalating dose of methamphetamine, which was the same as used in this study, to mimic, to some extent, the

pattern of drug abuse seen in methamphetamine addicts. This treatment regimen produces a progressive and enduring enhancement (sensitization) in the motor stimulant effects of methamphetamine and in methamphetamine-stimulated striatat DA release in vivo [7]. Our group has reported that this treatment regimen also produces a decrease of [3H]GBR 12935 binding sites in the rat striatum [t4]. [3H]GBR 12935 is a highly selective radioligand of the presynaptic DA transport complex in the rat brain [8]. The multiple high doses of methamphetamine cause damages of nigrostriatal dopaminergic neurons as evidenced by marked decrements in the striatal content of DA and its metabolites, the number of DA uptake sites [20], and the activity of tyrosine hydroxylase [6], as well as histochemical indications of nerve terminal degeneration within the striatum [16]. However, we have demonstrated that administration of an escalating dose of methamphetamine dose not decrease content of DA and its metabolites (unpublished observation). It is unlikely that methamphetamine-induced decrease in DA uptake sites is due simply to neuronal death. Thus, the neurochemical changes induced by multiple high doses and escalating dose may not be directly comparable. Recently, a potential role for excitatory amino acids in

TABLE I1 EFFECTS OF C O - A D M I N I S T R A T I O N OE METHAMPHE"FAMINE A N D MK-801 ON THE [3H]GBR 12935 B I N D I N G IN THE RAT STRIATUM The results are shown by the means _+ S.E.M.; n=8. Treatment group

Saline-Saline Saline--MAP MK-801 Saline MK-801 MAP

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(riM)

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1.78 _+ 0.13 1.88 ± 0.12 1.93 _+ 0.12 1.96_+0.13

323.0 _+ 5.2 242.6 ± 18.2" 331.8 :!. 7.3 332.7±9.5

*P < 0.01 as compared to the other groups.

41

methamphetamine-induced neurochemical changes has been suggested. Sonsalla et al. [19] reported that the striatal-DA depleting effects of methamphetamine are inhibited by systemically administered non-competitive N M D A receptor antagonists. They suggested that N M D A receptor activation and perhaps alterations in excitatory amino acid transmission play an important role in the toxic mechanism of action of methamphetamine. Furthermore, it is reported that 'reverse tolerance" or behavioral sensitization produced by repeated administration of amphetamine is blocked by co-administration of MK-801 [10]. MK-801 pretreatment in the mice could block the development of sensitization to the locomotive effect of cocaine and amphetamine. These data suggest that the glutamate system also participates in the mechanism of'reverse tolerance' to dopaminergic effects of cocaine and amphetamine. This study indicates that MK-801, a non-competitive antagonist of N M D A receptor, prevents the methamphetamine-induced decrease in striatal DA uptake sites. It is not known whether this effect of MK-801 is due to direct or indirect actions on dopaminergic neurons. One of the major pathways innervating the neostriatum is the corticostriatal glutamatergic pathway [5]. It has been attempted to speculate that excess activity in these corticostriatal neurons occurs alter methamphetamine treatment and that it is this activity which ultimately plays an importanl role in the decrease of striatal DA uptake sites, which is prevented by MK-801. In support of this hypothesis, our group t\mnd that N M D A stimulated the release of endogenous DA from striatal slices and MK-801 showed a dose dependent inhibition of DA release [151. Moreover, systemic administration of M K801 was reported to attenuate the striatal DA overflow induced by methamphetamme in vivo [21]. Dopaminergic terminals in the striatum may contain N M D A receptors which play a significant role in modulation of striatal DA overflow. Oxidized products of excessively released DA may cause the decrease in striatal DA uptake sites. On the olher hand, the ability of DA to inhibit glutamate uptake [11] may provide a mechanism whereby the methamphetarnine-induced release of DA can raise extracellular levels of ghttamate and thus produce pharmacological effects sensitive to antagonism by MK-801. In conclusion, it was shown that MK-801 prevents the methamphetamine-induced decrease of striatal DA uptake sites, indicating that excitatory amino acids may be involved in this drug-induced change. The interrelationship between the DA and glutamate system in mediating this response remains to be clarified. This research was supported by a Grant-in-Aid l\~r

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