The Synaptic Plasticity Mechanism On Thioredoxin-1 Overexpression In The MPFC Inhibiting Methamphetamine Induced Conditioned Place Preference

Drug abuse is a class of chronic and recurrent brain disorders.The abused substances use will induce rewarding effects,adaption,withdrawl symptom and relapse.Methamphetamine(METH)is a psychostimulant and its longterm use will result in addcition.The mechanism of METH addcition is very complicated.METH will induce the large release of dopamine,glutamate,norepinephrine,and serotonin and these neurotransmitters in turn activate various brain areas such as the prefrontal cortex(PFC),ventral tegmental area(VTA),hippocampus(Hip)and nucleus accumbens(NAc).The rodent PFC is divided into the medial prefrontal cortex(mPFC),lateral prefrontal cortex,and ventral prefrontal cortex,in which the mPFC is implicated in higher brain functions such as cognition,learning,and working memory.METH also induces synaptic plasticity,long-term potentiation(LTP)and long-term depression(LTD).The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR),N-methyl-D-aspartate receptor subunit 2B(GluN2B),postsynaptic density 95(PSD95)and neurogranin(Ng)are involved in LTP and LTD.The epigenetics plays the important role in METH addiction.Thioredoxin-1(Trx-1)is an important protein regulating redox with activity site:Cys Gly Pro Cys-).Trx-1 molecule weight is 12KD and is increased under stresses in organism and cell.Trx-1 plays roles in anti-oxidative stress,anti-inflammation,regulating the activity of transcriptional factors and protecting nerves.Trx-1 overexpression resists the rewarding effects induced by morphine and METH.Cnditioned place preference(CPP)is widely used to study the rewarding effects induced by drug abuse and reinstatement of CPP after withdrawl.In this paper,Trx-1 overexpression in the mPFC was constructed by injecting AAV2/9TRXN into the mPFC of mice,and METH-CPP training and measured rewarding effects induced by METH,detected electrophysiologically LTP and LTD and the expressions of protein related to synapses.The findings of this paper are as follows:1.Trx-1 overexpression in the mPFC inhibited METH induced CPP formation.Trx-1 overexpression in the mPFC did not cause a difference in motor viability,and METHCPP training did not cause a difference in motor viability between mice with Trx-1 overexpression in the mPFC and control mice.METH significantly induced CPP formation in the control but not in the Trx-1 overexpression group in the mPFC.The above results showed that Trx-1 overexpression in the mPFC inhibited METH induced CPP formation,but did not cause changes in the locomotor viability of mic.2.Trx-1 overexpression in the mPFC regulates METH induced changes in synaptic plasticity.Control and mPFC Trx-1-overexpression mice were subjected to Hip slice electrophysiological testing after METH-CPP.The analysis of the data from the electrophysiological experiments revealed that METH significantly potentiated LTP in the Hip and LTD,whereas Trx-1 overexpression in the mPFC significantly suppressed LTP induced by METH and enhanced LTD.3.Trx-1 overexpression in the mPFC modulates METH induced alterations in the levels of proteins related to synaptic plasticityWestern blotting showed that METH significantly decreased Trx-1 expression,histone deacetylase 5(HDAC5),phosphorylated eukaryotic translation initiation factor 2 alpha(p-eIF2a)in the mPFC and Hip,whereas Trx-1 overexpression in the mPFC significantly reversed these expressions.METH significantly increased expressions of AMPAR,GluN2B,PSD-95 and Ng both in the mPFC and Hip,whereas Trx-1 overexpression in the mPFC significantly inhibited these expressions.In addiction,Trx-1 overexpression in the mPFC increased the expressions of Trx-1、HDAC5、p-eIF2α、GluN2B、PSD-95 and Ng,but decreased the expression of AMPAR.In conclusion,Trx-1 overexpression in the mPFC inhibited METH-CPP.Trx-1 overexpression in the mPFC regulated LTP and LTD in the Hip induced by METH.The decreased expressions of HDAC5 and p-eIF2α as well as the increased expressions of APMAR,GluN2B,PSD-95and Ng were reversed by Trx-1 overexpression in the mPFC.Thus,Trx-1 overexpression in the mPFC inhibited the rewarding effects induced by METH.