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: Glia (including astrocytes, microglia, and oligodendrocytes), which constitute the majority of cells in the brain, have many of the same receptors as neurons, secrete neurotransmitters and neurotrophic and neuroinflammatory factors, control clearance of neurotransmitters from synaptic clefts, and are intimately involved in synaptic plasticity. Despite their prevalence and spectrum of functions, appreciation of their potential general importance has been elusive since their identification in the mid-1800s, and only relatively recently have they been gaining their due respect. This development of appreciation has been nurtured by the growing awareness that drugs of abuse, including the psychostimulants, affect glial activity, and glial activity, in turn, has been found to modulate the effects of the psychostimulants. This developing awareness has begun to illuminate novel pharmacotherapeutic targets for treating psychostimulant abuse, for which targeting more conventional neuronal targets has not yet resulted in a single, approved medication. In this chapter, we discuss the molecular pharmacology, physiology, and functional relationships that the glia have especially in the light in which they present themselves as targets for pharmacotherapeutics intended to treat psychostimulant abuse disorders. We then review a cross section of preclinical studies that have manipulated glial processes whose behavioral effects have been supportive of considering the glia as drug targets for psychostimulant-abuse medications. We then close with comments regarding the current clinical evaluation of relevant compounds for treating psychostimulant abuse, as well as the likelihood of future prospects.Advances in pharmacology (San Diego, Calif.) 01/2014; 69:1-69.
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ABSTRACT: Methamphetamine (METH) is a major criminal justice and public health problem. Repeated use of METH causes dependence in humans and there are currently no particular pharmacological treatments for METH addiction. Glial cell activation is linked with METH abuse and METH administration causes activation of these cells in many areas of the brain. Many studies have demonstrated that glia cell modulators can modulate drug abuse effects. In this study, we examined the effect of the putative microglial inhibitor, minocycline on maintenance and prime-induced reinstatement of METH seeking behavior using the conditioned place preference (CPP) paradigm. CPP induced with METH (1mg/kg, i.p. for 3days) lasted for 11days after cessation of METH treatment and priming dose of METH (0.5mg/kg, i.p.) reinstated the extinguished METH-induced CPP. Daily treatment of minocycline (40mg/kg, i.p.) followed by establishment of CPP blocked the maintenance of METH-induced CPP and also could attenuate priming-induced reinstatement. Furthermore, daily bilateral intra-accumbal injection of minocycline (10 and 20μg/0.5μl saline), during extinction period blocked the maintenance of METH CPP but just the highest dose of that could attenuate priming-induced reinstatement. We showed that minocycline administration during extinction period could facilitate extinction and maybe abolish the ability of drug-related cues evoke reinstatement, suggesting that minocycline might be considered as a promising therapeutic agent in preventing relapse in METH dependent individuals.Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2014; · 3.55 Impact Factor
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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