Elsevier

Brain Research

Volume 1301, 16 November 2009, Pages 189-196
Brain Research

Research Report
Mithramycin protects against dopaminergic neurotoxicity in the mouse brain after administration of methamphetamine

https://doi.org/10.1016/j.brainres.2009.09.010Get rights and content

Abstract

The present study was undertaken to examine the effects of mithramycin, an inhibitor of transcription factor Specificity protein (Sp)-1, on the behavioral changes and dopaminergic neurotoxicity in the mouse striatum after administration of methamphetamine (METH). Pretreatment with mithramycin (75, 150 or 300Ā Ī¼g/kg) did not alter acute hyperlocomotion in mice after a single administration of METH (3Ā mg/kg). However, the development of behavioral sensitization in mice after repeated administration of METH (3Ā mg/kg/day, once daily for 5Ā days) was significantly blocked by pretreatment with mithramycin (300Ā Ī¼g/kg). Furthermore, pretreatment with mithramycin (300Ā Ī¼g/kg) significantly attenuated the hyperthermia in mice after repeated administration of METH (3Ā mg/kgĀ Ć—Ā 3, 3-h intervals). Moreover, the combination of pretreatment and subsequent administration of mithramycin (75, 150 or 300Ā Ī¼g/kg) significantly attenuated the reductions of dopamine (DA), its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and DA transporter (DAT) in the striatum after repeated administration of METH (3Ā mg/kgĀ Ć—Ā 3, 3-h intervals), and these attenuations were dose dependent. These findings suggest that mithramycin attenuates the development of behavioral sensitization and dopaminergic neurotoxicity in mice after repeated administration of METH. Therefore, mithramycin could have potential for the treatment of METH abusers, particularly since this drug has been approved by the Food and Drug Administration in the United States. In the future, however, another Sp1 inhibitors with fewer side effects might be more appropriate.

Introduction

Abuse of methamphetamine (METH) is an extremely serious and growing worldwide problem. METH is a powerfully addictive stimulant associated with serious health conditions, including memory loss, aggression, psychotic symptoms and behavior and potential heart and brain damage (Ujike and Sato, 2004, Hashimoto, 2007). Repeated administration of METH induces dopaminergic neurotoxicity in rodents and nonhuman primates by producing long-term depletion of dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and of the density of DA transporter (DAT) binding in the striatum (Davidson et al., 2001, Cadet et al., 2003, Zhang et al., 2006, Hashimoto et al., 2004, Hashimoto et al., 2007). In addition, the levels of DA and the density of the DAT have been shown to be reduced in the postmortem striatum of chronic METH users (Wilson et al., 1996). Brain imaging studies using positron emission tomography (PET) have demonstrated that the density of the DAT in the caudate/putamen and nucleus accumbens of METH users was significantly lower than that of normal controls (Sekine et al., 2001, Volkow et al., 2001). Thus, although METH-induced neurotoxicity in the dopaminergic terminals is well documented, the precise mechanism of METH-induced neurotoxicity remains unknown (Cadet et al., 2003, Hashimoto, 2007).

Mithramycin is an aureolic acid polyketide antibiotic traditionally used to treat hypercalcemia/hypercalciuria and certain forms of cancers (Jones et al., 1995). Mithramycin binds to Gā€“C-rich DNA sequences to inhibit the binding of transcription factor Specificity protein (Sp1) (Ray et al., 1989), which is known to affect neuronal survival/death pathways (Jones et al., 1995, Chatterjee et al., 2001, Ferrante et al., 2004, Lee et al., 2006, Citron et al., 2008). In addition, mithramycin may also indirectly regulate gene transcription by altering histone methylation (Ferrante et al., 2004), which is involved in the pathology of neuropsychiatric diseases (Jiang et al., 2008, Akbarian and Huang, 2009). In a mouse (R6/2) model of Huntington's disease, treatment with mithramycin prolonged survival and prevented the increase in histone H3 methylation observed in these mice, suggesting that the enhanced survival and neuroprotection might be attributable to alleviation of the repressed expression of genes vital to neuronal function and survival (Ferrante et al., 2004). Taken together, these findings suggest that mithramycin is likely to have neuroprotective effects in animal models of neurodegenerative diseases.

It is therefore of interest to study whether mithramycin can attenuate behavioral and pathological changes after administration of METH. The present study was undertaken to examine the effects of mithramycin on the behavioral changes and dopaminergic neurotoxicity in mice after administration of METH.

Section snippets

Effects of mithramycin on hyperlocomotion and development of behavioral sensitization after administration of METH

A single administration of METH (3Ā mg/kg, s.c.) markedly increased locomotion in mice. Pretreatment with mithramycin (75, 150 or 300Ā Ī¼g/kg, i.p.) did not alter hyperlocomotion in mice after a single administration of METH (3Ā mg/kg, s.c.; Fig. 1). In addition, mithramycin (300Ā Ī¼g/kg, i.p.) alone did not alter locomotion in the normal mice (Fig. 1).

Repeated administration of METH (3Ā mg/kg, once daily for five consecutive days) significantly increased METH (1Ā mg/kg)-induced hyperlocomotion in mice

Discussion

The major findings of present study are as follows: First, we found that mithramycin could ameliorate the development of behavioral sensitization after repeated METH administration, whereas this drug did not attenuate acute hyperlocomotion in mice after a single administration of METH. Therefore, it is possible that treatment with mithramycin may prevent METH-induced psychosis in abstinent METH users who relapse. Second, we found that pretreatment and subsequent administration of mithramycin

Animals

Male Balb/c AnNCrICrIj mice (8Ā weeks old, 24ā€“30Ā g body weight at the beginning of the experiment; Charles River Japan Inc., Tokyo, Japan) were housed under a 12-h light/12-h dark cycle (lights on from 0700 to 1900Ā h) at room temperature (22Ā Ā±Ā 2Ā Ā°C; humidity, 55Ā Ā±Ā 5%) with free access to food and water. In this study, Balb/c mice were used since this strain has been shown to be sensitive to METH-induced dopaminergic neurotoxicity (Kita et al., 1998, Koike et al., 2005, Zhang et al., 2006). All

Acknowledgments

This study was in part supported by grants from the Ministry of Health, Labor and Welfare, Japan (KH and MI). The authors would like to thank Dr. R. Miyatake for his suggestion on the experiments.

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