The Role And Molecular Mechanism Of Thioredoxin-1 Resisting Conditioned Place Preference Induced By Methamphetamine

Drug addiction is a chronic, relapsing encephalopathy. It is characterized by compulsive drug use and seeking, and loss of ability of controlling behaviour. Since the 21 century, amphetamine type stinylants(ATS) has become the most widely used, and the most serious drug. Methamphetamine (METH) is typical representative. METH is a pure white crystal, commonly known as "ice". It induces the effects fast and sustains long term, long-term use can lead to abnormal neuronal compensatory adaptation, tolerance, dependence, sensitization and relapse. However, the mechanism of addiction by METH is not fully clear.Methamphetamine is a kind of central nervous system stimulant, it can directly effect the central nervous system, use for a long time leads to mental dependence. Mesolimbic dopamine system (MOLDS) is considered as the areas of reward effects of addictive drugs, mainly included the midbrain Ventral Tegmental Area (VTA), and its projection Areas, the nucleus accumbens (NAc), and prefrontal cortex (PFC), it is the most important neural circuits of and compulsive using drug and relapse. Thus, the VTA-NAc-PFC is common pathways of drug abuse. The neuronal cell bodies in MLDS are mainly concentrated in the VTA which is the area of dopamine neurons. The addiction drugs target VTA and induce the releases dopamine (DA). In addition to the nerve endings, cell bodies and dendrites also release DA. DA levels of NAc also play an important role and regulate the near receptors. METH induces the adaptive changes of structures and functions of neurons by regulating D1 receptor mediated pathways of adenylate cyclase (AC), downstream Cyclic Adenosine monophosphat (cAMP) and D2 mediated pathways of phosphatidyl inositol 3 kinase (PI3K), Akt/Glycogen synthase kinase-3p (GSK-3(3). In addcition to cAMP response element binding protein (CREB), ΔFosB and Cyclin-depdent kinase 5 (Cdk5) are involved in reward effects of abuse drugs.Methamphetamine addiction disorders can also lead to oxidative stress and dysfunction of yredox state. Thioredoxin-1 (Trx-1) is an important antioxidant protein in organisms, widely existed in prokaryotes and eukaryotes, its molecular weight is about 12KDa. Besides the antioxidant role it has a variety of biological functions:cell proliferation, regulation of gene transcription and inhibition of apoptosis. Trx-1 and thioredoxin-1 reductase (Trx-1 R), nicotinamide adenine dinucleotide phosphate (NADPH) together constitute the thioredoxin-1 system in vivo and maintain redox balance.Our previous study found that Trx-1 inducer pretreatment resisted the addcition by METH. To further study the role of Trx-1 in METH addiction, we cpmpared the difference of CPP between wild type mice and Trx-1 oversxpression transgenic mice by using conditioned place preference(CPP) model and detected the expressions of Trx-1, CREB, ΔFosB and CDK5 which are related to addiction in VTA, NAc, PFC and Hippocampus (HP).Results:This paper demonstrated that the Trx-1 overexpression resisted the CPP and alleviate CPP and motion enhancement in mice induced by METH. From the molecular levels, Trx-1 overexpression restored Trx-1 expressions in VTA and NAc and significantly suppressed the increases of p-CREB, AFosB and CDK5.Conclusion:Trx-1 played a role in resisting CPP induced by METH. The further study on relationship between METH and Trx-1, may provide a new theoretical basis for treatment of METH addiction.