Study On Thioredoxin-1 Resisting Methamphetamine-induced Relapse

Methamphetamine (METH) is a pure white crystal, commonly known as "ice". It induces the effects fast and sustains long term, leads to abnormal neuronal compensatory adaptation, tolerance, dependence, sensitization and relapse. METH relapse is a serious social and health problem in the world. At present, there are no effective treatments on METH relapse. METH induces the rewarding effects and psychostimulating effects by activating the mesolimbic dopamine system(MLDS), which mainly includes the midbrain ventral tegmental area (VTA), and its projecting areas, the nucleus accumbens (NAc), and prefrontal cortex (PFC), in which METH causes a massive dopamine release in the projection areas in the brain. METH increases DA release, DA is metabolized by MAO to produce dihydroxy-phenyl aceticacid (DOPAC) and hydrogen peroxide, leading to oxidative stress. It has been reported that cAMP response element binding protein (CREB), △FosB and Cyclin-depdent kinase 5 (Cdk5) are involved in abuse induced by METH.Thioredoxin-1 (Trx-1) is an important antioxidant protein having a conserved active site sequence:-Cys-Gly-Pro-Cys-, its molecular weight is about 12KDa. Besides the antioxidant role it has a variety of biological functions:such as promoting cell proliferation, regulating activity of transcription factor and inhibiting apoptosis. Trx-1 and thioredoxin reductase (TrxR), nicotinamide adenine dinucleotide phosphate (NADPH) together constitute the thioredoxin-1 system. Accumulating studies have shown that Trx-1 plays a cytoprotective role in resisting stressful perturbations. However, the biological function of Trx-1 in resisting abuse induced by METH has not been reported. We therefore investigated the role of Trx-1 in resisting METH-induced relapse via regulating MLDS.Conditioned place preference (CPP) is a commonly used animal model to assess the rewarding properties of drugs or reward related memory. The CPP reinstatement test measures the ability of drug-related stimuli to trigger affective craving and relapse.We established the mice model of METH relapse, we proved that it was successful through CPP and reinstatement induecd by METH, our result showed that reinstatement and behavioral sensitization in mice were suppressed by Trx-1 overexpression. We detected the expressions of relatived proteins in the regions of VTA, NAc, and PFC, and found that increased expressions of Trx-1, AFosB, Cdk5, D1 dopamine receptor (D1R), D2 dopamine receptor (D2R), tyrosine hydroxylase (TH) and MAO induced by METH were inhibited, decreased dopamine transporter (DAT) expression was restored by Trx-1 overexpression. These results suggest that Trx-1 suppresses the METH induced relapse by regulating DA pathway in the MLDS, VTA-NAc-PFC circuit, and then adjusting the expressions of △FosB and Cdk5.In summary, the present study provided the first evidence that Trx-1 may be useful for the treatment of METH relapse since Trx-1 overexpression inhibited METH-induced relapse behavior and the relatived proteins expressions in the midbrain dopamine system. This study provides a new target and theoretical basis for the treatment of drug abuse and relapse.