The antibiotic minocycline prevents methamphetamine-induced rewarding effects in mice.
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.
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ABSTRACT: Several lines of evidence suggest that the brain-derived neurotrophic factor (BDNF) - tropomyosin-related kinase B (TrkB) signaling pathway plays a role in behavioral abnormalities observed after administration of psychostimulants, such as methamphetamine (METH). This study was undertaken to examine whether the potent TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) could improve prepulse inhibition (PPI) deficits in mice seen after a single dose of METH. Treatment with 7,8-DHF (3.0, 10 or 30mg/kg) improved PPI deficits in mice associated with exposure to METH (3.0mg/kg), in a dose dependent manner. Furthermore, co-administration of ANA-12 (0.5mg/kg), a TrkB antagonist, significantly blocked the effects of 7,8-DHF (30mg/kg) on METH-induced PPI deficits. In contrast, administration of 5,7-dihydroxyflavone (5,7-DHF: 30mg/kg), an inactive TrkB ligand, did not affect METH-induced PPI deficits in mice. An in vivo microdialysis study in conscious mice showed that 7,8-DHF (30mg/kg) significantly attenuated increased dopamine release in the striatum, after METH administration (3mg/kg). This study suggests that 7,8-DHF can improve PPI deficits in these mice, through the inhibition of METH-induced dopamine release. Therefore, it is likely that TrkB agonists, such as 7,8-DHF, may constitute a novel class of therapeutic drugs for neuropsychiatric diseases such as METH-use disorder and schizophrenia.Pharmacology Biochemistry and Behavior 04/2013; · 2.61 Impact Factor
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ABSTRACT: Neuroinflammation induced by activated microglia and astrocytes can be elicited by drugs of abuse. Methamphetamine administration activates glial cells and increases proinflammatory cytokine production, and there is recent evidence of a linkage between glial cell activation and drug abuse-related behavior. We have previously reported that ibudilast (AV411; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine), which inhibits phosphodiesterase (PDE) and pro-inflammatory activity, blocks reinstatement of methamphetamine-maintained responding in rats, and that ibudilast and AV1013, an amino analog of ibudilast, which has similar glial-attenuating properties but limited PDE activity, attenuate methamphetamine-induced locomotor activity and sensitization in mice. The present study's objective was to determine whether co-administered ibudilast, AV1013, or minocycline, which is a tetracycline derivative that also suppresses methamphetamine-induced glial activation, would attenuate active methamphetamine i.v. self-administration in Long-Evans hooded rats. Rats were initially trained to press a lever for 0.1mg/kg/inf methamphetamine according to a FR1 schedule during 2-h daily sessions. Once stable responding was obtained, twice daily ibudilast (1, 7.5, 10mg/kg), AV1013 (1, 10, 30mg/kg), or once daily minocycline (10, 30, 60mg/kg), or their corresponding vehicles, were given i.p. for three consecutive days during methamphetamine (0.001, 0.03, 0.1mg/kg/inf) self-administration. Ibudilast, AV1013, and minocycline all significantly (p<0.05) reduced responding maintained by 0.03mg/kg/inf methamphetamine that had maintained the highest level of infusions under vehicle conditions. These results suggest that targeting glial cells may provide a novel approach to pharmacotherapy for treating methamphetamine abuse.European journal of pharmacology 01/2013; · 2.59 Impact Factor
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ABSTRACT: Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4(-/-) mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.Journal of Neuroscience 08/2012; 32(33):11187-200. · 6.91 Impact Factor