The antibiotic minocycline prevents methamphetamine-induced rewarding effects in mice

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Abstract

Repeated use of methamphetamine (METH) causes dependence in humans, and to date, there are no effective medication treatments for METH addiction. We previously reported that the antibiotic minocycline attenuated behavioral abnormalities (hyperactivity and behavioral sensitization) and dopaminergic neurotoxicity in mice and monkeys, after the administration of METH. In this study, we examined the effect of minocycline on METH-induced rewarding effects in mice using the conditioned place preference (CPP) paradigm. Minocycline (40 mg/kg, IP) significantly attenuated METH (1.0 mg/kg, SC)-induced place preference in mice. In vivo microdialysis experiments using free-moving mice, showed that minocycline (40 mg/kg, IP) significantly attenuated the increased extracellular dopamine (DA) levels within the nucleus accumbens, typically seen after the administration of METH (1.0 mg/kg, SC). These findings suggest that minocycline may block METH-induced rewarding effects by down regulating extracellular DA levels in the nucleus accumbens of mice. This would make minocycline a potential therapeutic drug for the treatment of METH induced disorders.

Highlights

► Methamphetamine (METH) induced rewarding effects in rodents and humans. ► Minocycline blocked METH-induced rewarding effects in mice. ► Minocycline blocked METH-induced release of dopamine in nucleus accumbens. ► Minocycline may be a potential therapeutic drug for METH dependence.

Introduction

Abuse of methamphetamine (METH) is a worldwide, public health problem (Hashimoto, 2007, Gonzales et al., 2010, Karila et al., 2010, Chen et al., 2010). The abuse of METH has significant psychiatric and medical consequences, including psychosis, dependence, overdose, and death. However, there are currently no pharmacological treatments for METH-induced symptoms (Hashimoto, 2007, Sofuoglu and Sewell, 2009, Gonzales et al., 2010, Karila et al., 2010, Sofluoglu, 2010, Chen et al., 2010).

Minocycline is a second-generation tetracycline that readily crosses the blood–brain barrier, and has powerful anti-inflammatory and neuroprotective properties (Domercq and Matute, 2004, Hashimoto, 2007, Chen et al., 2010). Previously, we reported that minocycline attenuated hyperlocomotion and the development of behavioral sensitization in mice, after the administration of METH (Zhang et al., 2006a). Furthermore, the reduction of dopamine (DA) and DA transporter (DAT) in the striatum of mouse and monkey brains associated with repeated METH administration, was significantly attenuated by subsequent treatment with minocycline (Zhang et al., 2006a, Hashimoto et al., 2007). Moreover, minocycline ameliorated 3,4-methylenedixoymethamphetamine (MDMA)-induced neurotoxicity of serotonergic neurons within mouse brains (Zhang et al., 2006b). It has also been reported that minocycline alleviated symptoms (e.g., hyperlocomotion, prepulse inhibition deficits, cognitive deficits) in mouse and rat models of schizophrenia, after the administration of N-methyl-d-aspartate (NMDA) receptor antagonists, such as, phencyclidine (PCP) and dizocilpine (Fujita et al., 2008, Zhang et al., 2007, Levkovitz et al., 2007). These findings suggest that minocycline may represent a promising therapeutic drug, for the treatment of long-term symptoms associated with METH abuse (Hashimoto, 2007, Hashimoto, 2008a, Chen et al., 2010).

In this study, we examined the effect of minocycline on METH-induced rewarding effects in mice, using the conditioned place preference (CPP) paradigm. We also examined the effects of minocycline on METH induced increases of extracellular levels of DA in the nucleus accumbens, since DA levels in this brain region play an important role in METH-induced rewarding effects (Ikemoto, 2007).

Section snippets

Animals

C57BL/6 mice (6 weeks old) weighing 25–30 g were purchased from SLC Japan (Hamamatsu, Shizuoka, Japan). The mice were housed in clear polycarbonate cages (22.5 × 33.8 × 14.0 cm) in groups of 5 or 6 per cage, under a controlled 12/12-h light–dark cycle (lights on from 7:00 AM to 7:00 PM), at a room temperature of 23 ± 1 °C and humidity of 55 ± 5%. The mice were given free access to water and food pellets. The experimental procedure was approved by the Animal Care and Use Committee of Chiba University.

Conditioned place preference (CPP)

The

Effects of minocycline on METH-induced rewarding effects in mice

We investigated the effects of minocycline on the rewarding effects of METH, using the CPP paradigm, which measures the rewarding properties of abused drugs. One-way ANOVA revealed significant differences among the four groups (df = 3.87, F = 5.402, p = 0.002)(Fig. 2). Post hoc analysis showed that METH (1.0 mg/kg, SC) significantly increased CPP scores in mice, compared with the vehicle-treated group. When mice were treated with minocycline (40 mg/kg, IP) 30 min before receiving METH (1.0 mg/kg, SC),

Discussion

In this study, we found that minocycline attenuated both METH-induced rewarding effects and the marked increases of extracellular DA in the nucleus accumbens, induced by METH administration. It is well known that increased DA signaling in the nucleus accumbens after METH exposure plays an important role in the development of METH-induced rewarding effects (Ikemoto, 2007, Lüscher and Malenka, 2011). Therefore, it is likely, that by inhibiting the increases in extracellular DA within the nucleus

Conclusion

This study suggests that minocycline can block METH-induced rewarding effects in mice. Therefore, minocycline would appear to be a potential therapeutic drug for METH use disorder, although further studies of minocycline in patients with METH use disorder will be necessary

Acknowledgments

The authors thank Dr. M. Funada (National Center of Neurology and Psychiatry, Tokyo, Japan) and Dr. Y. Takamatsu (Tokyo Institute of Psychiatry, Tokyo, Japan) for their invaluable advice on the CPP paradigm. This study is supported partly by a grant for Intramural Research Grant (19-2) for Neurological and Psychiatric Disorders of NCNP, Japan (to K.H.) and a grant from Japan China Medical Association (to K.H.). The authors have no financial interests or conflicts of interest to declare.

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      In mice, the concomitant administration of METH (1.0 mg/kg, subcutaneous (s.c.) and minocycline (40 mg/kg, i.p.) during the conditioning phase in a CPP protocol tempered their preference for the METH-paired compartment. Notably, minocycline mitigated the increase in extracellular DA levels in the NAc that were induced by a single dose of METH (1.0 mg/kg, s.c.) [11]. Cocaine.

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