The antibiotic minocycline prevents methamphetamine-induced rewarding effects in mice

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 04/2012; 101(2):303-6. DOI: 10.1016/j.pbb.2012.01.005
Source: PubMed


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.

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    • "Mice were anesthetized with sodium pentobarbital prior to the stereotaxic implantation of a probe into the nucleus accumbens (+1.1 mm anteroposterior, +1.0 mm mediolateral from the bregma, and −4.0 mm dorsoventral from the dura), according to the Franklin and Paxinos Atlas [48], as reported previously [49]. Probes were secured onto the skull using stainless-steel screws and dental acrylic. "
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    ABSTRACT: The N-methyl-D-aspartate (NMDA) receptors play a role in behavioral abnormalities observed after administration of the psychostimulant, methamphetamine (METH). Serine racemase (SRR) is an enzyme which synthesizes D-serine, an endogenous co-agonist of NMDA receptors. Using Srr knock-out (KO) mice, we investigated the role of SRR on METH-induced behavioral abnormalities in mice. Evaluations of behavior in acute hyperlocomotion, behavioral sensitization, and conditioned place preference (CPP) were performed. The role of SRR on the release of dopamine (DA) in the nucleus accumbens after administration of METH was examined using in vivo microdialysis technique. Additionally, phosphorylation levels of ERK1/2 proteins in the striatum, frontal cortex and hippocampus were examined using Western blot analysis. Acute hyperlocomotion after a single administration of METH (3 mg/kg) was comparable between wild-type (WT) and Srr-KO mice. However, repeated administration of METH (3 mg/kg/day, once daily for 5 days) resulted in behavioral sensitization in WT, but not Srr-KO mice. Pretreatment with D-serine (900 mg/kg, 30 min prior to each METH treatment) did not affect the development of behavioral sensitization after repeated METH administration. In the CPP paradigm, METH-induced rewarding effects were demonstrable in both WT and Srr-KO mice. In vivo microdialysis study showed that METH (1 mg/kg)-induced DA release in the nucleus accumbens of Srr-KO mice previously treated with METH was significantly lower than that of the WT mice previously treated with METH. Interestingly, a single administration of METH (3 mg/kg) significantly increased the phosphorylation status of ERK1/2 in the striatum of WT, but not Srr-KO mice. These findings suggest first, that SRR plays a role in the development of behavioral sensitization in mice after repeated administration of METH, and second that phosphorylation of ERK1/2 by METH may contribute to the development of this sensitization as seen in WT but not Srr-KO mice.
    PLoS ONE 04/2012; 7(4):e35494. DOI:10.1371/journal.pone.0035494 · 3.23 Impact Factor
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    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2012; 32(33):11187-200. DOI:10.1523/JNEUROSCI.0684-12.2012 · 6.34 Impact Factor
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    ABSTRACT: Minocycline is a second-generation, semi-synthetic tetracycline that has been in use in therapy for over 30 years for its antibiotic properties against both gram-positive and gram-negative bacteria. It displays antibiotic activity due to its ability to bind to the 30S ribosomal subunit of bacteria and thus inhibit protein synthesis. More recently, it has been described to exert a variety of biological actions beyond its antimicrobial activity, including anti-inflammatory and anti-apoptotic activities, inhibition of proteolysis, as well as suppression of angiogenesis and tumor metastasis, which have been confirmed in different experimental models of non-infectious diseases. There are also many studies that have focused on the mechanisms involved in these non-antibiotic properties of minocycline, including anti-oxidant activity, inhibition of several enzyme activities, inhibition of apoptosis and regulation of immune cell activation and proliferation. This review summarizes the current findings in this topic, mainly focusing on the mechanisms underlying the immunomodulatory and anti-inflammatory activities of minocycline.
    Pharmacological Research 10/2012; 67(1). DOI:10.1016/j.phrs.2012.10.006 · 4.41 Impact Factor
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