The Local Overexpression Of Thioredoxin-1 Prevents Conditioned Place Preference Induced By Methamphetamine

Drug addiction is a chronic recurrent encephalopathy,mainly accompanied with forced drug use,loss control of drug use,and withdrawal symptoms after withdraw.Addictive drugs initially work through activating reward circuits,and lead to decreased control of drug craving,sensitivity to stress and negative emotions.The dopaminergic system projecting from the ventral tegmental area(VTA)to the nucleus accumbens(NAc)and the prefrontal cortex(PFC)plays an important role in drug addiction.Methamphetamine(METH)is a strong psychostimulant that acts on the central nervous system and results in strongly excitatory,hyperactivity,affective impulse,uncontrol,offensive,aggressive or violent behaviors.The mechanism on METH addiction is complicated and related to neurotransmitters,synaptic plasticity and neural circuits in the ventral tegmental area(VTA),nucleus accumbens(NAc),hippocampus(Hip),striatum and prefrontal cortex(PFC)and other brain regions.The PFC is divided into the anterior cingulate cortex(ACC),lateral orbifrontal cortex,dorsolateral prefrontal cortex(dlPFC),inferior frontal cortex.The rodent PFC is divided into the medial,lateral and ventral,75-80% of the neurons in the PFC are glutamatergic neurons projected to the VTA,NAc and Hip.The mPFC receives excitatory afferents from the thalamus,amygdala,Hip and contralateral mPFC.PFC is associated with higher level of brain function,regulates mental activity,and is thought to have multiple social,emotional,and cognitive functions.PFC is also closely related to the roles of psychotropic drugs.PFC is impaired in addicted individuals,and the neural circuit of mPFC-NAc is associated with reward effects.There are direct projections of PFC to the Hip,which are originated from the AC region of mPFC and terminated in the CA1 and CA3 in the dorsal Hip.The dorsal Hip is associated with formation,expression and extinction of conditioned place preference(CPP).Thioredoxin-1(Trx-1),an important antioxidant protein,is an important regulatory protein that maintains the redox balance.It is ubiquitously existed in prokaryotes and eukaryotes,the molecular weight of 12 KD,has the active site sequence:-Cys-Gly-Pro-Cys-.Trx-1 achieves its redox regulation function through the transformation of disulfide and sulfhydryl groups between two Cys at the active site,and Trx-1 regulates activity of transcription factors,NF-?B,AP-1 and p53.The purpose of this paper is to explore the role and molecular mechanism of overxpression Trx-1 in the mPFC regulating METH addiction.The role and molecular mechanism of Trx-1 regulating METH-induced CPP expression was investigated by constructing overexpression in the mPFC,using transgenic mice and METH-induced CPP model in mice.We detected the effects of Trx-1 on the expression of glutamatergic receptors and LTP/LTD.The main findings of this paper are follows:(1)Overexpression of Trx-1 in the mPFC resists METH-induced CPP formation.Behavioral tests showed that Trx-1 overexpression in the mPFC region significantly inhibited METH-induced CPP expression compared to wild-type mice.Analysis of histological findings showed that Adeno-Associated Viral Vector(AAV)was expressed in the mPFC region,and fiber projection signals were observed in the hippocampal CA3.Western blot analysis showed that METH reduced the expression of Trx-1 in the mPFC and Hip of wild-type mice.Trx-1 overexpression significantly restored METHinduced Trx-1 expression reduction.METH increased the expression of the NMDA receptor 2B subtype(GluN2B)in the mPFC and Hip of wild-type mice.Trx-1 overexpression significantly inhibited METH-induced GluN2 B expression.METH increased the expression of AMPA receptor,GluR1 in the mPFC and Hip of wild-type mice.Trx-1 overexpression increased the METH-induced increase GluR1 expression.(2)Western blot analysis of Trx-1 overexpression transgenic mice model showed that METH induced the expression of GluN2 B in the mPFC and Hip of wild-type mice;Trx-1 overexpression significantly inhibited the increase of GluN2 B expression induced by METH.METH induced the expression of GluR1 in the mPFC and Hip of wild-type mice.Electrophysiological results analysis showed that LTP was enhanced after METH in the hippocampal CA1 in wild-type mice.Trx-1 overexpression inhibited LTP induced by METH in Trx-1 transgenic mice.LTD was enhanced after METH treatment in the hippocampal CA1 in wild-type mice.Trx-1 overexpression enhanced LTD in Trx-1 transgenic mice,however,the LTD was not enhanced further after METH treatment.Conclusion: Overexpression of Trx-1 in mPFC or transgenic mice blocks CPP induced by METH.Trx-1 bocks the METH-CPP through regulating the expressions of GluN2 B and GluR1,altering LTP and LTD.Trx-1 may be a therapeutic target for METH addcition.