The Downregulation Of Thioredoxin-1 In Nucleus Accumbens Delays The Extinction Of Conditioned Place Preference Induced By Morphine

Morphine is one kind of opioid drug,its chronic use causes dependence and addiction.Morphine addiction has become one of the public health problems in world.Ventral tegmental area(VTA),nucleus accumbens(NAc),prefrontal cortex(PFC),hippocampus(HiP)are known as important components of the central nervous system(CNS)involved in drug abuse.The dopamine system is involved in rewarding effects.The NAc receives the dopamine neuron projects form VTA and glutamatergic inputs from prefrontal cortex and hippocampus,and is involved in relapse.Hippocampus plays an important role in reward and circumvent cues associated memory.The morphine stopped after addiction results in withdrawal and rewarding effects extinction.The extinction is believed to result in formation of a new memory rather than simple forgetting or erasure of original learning.The glutamate-dependent synaptic plasticity within the NAc is involved in rewarding effects extinction.Thioredoxin-1(Trx-1)is a redox protein,and plays a role in regulation of cellular redox homeostasis.It is also pivotal for neuroprotection and inhibiting apoptosis.Morphine induces expression of Trx-1,however,whether Trx-1 is involved in regulating the extinction of conditioned place preference(CPP)induced by addictive drugs has not been reported.The aim of the present study is to investigate whether Trx-1 modulates the extinction of conditioned place preference induced by morphine through regulating glutamatergic signaling pathway.The CPP and nuclei injection technique are used,after the CPP is induced by morphine and Trx-1 specific interference RNA is injected in bilateral nucleus accumbens in mice,mice of the downregulation of Trx-1 in the NAc are constructed and difference of morphine-induced CPP among control group,negative control group and downregulation group are compared.Our findings showed that Trx-1 downregulation in the NAc delayed morphine-CPP extinction.We detected the expressions of related proteins in the regions of NAc,VTA and HiP.We found that morphine induced the increase of a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors(AMPAR),which was inhibited by the downregulation of Trx-1.Morphine induced expressions of 2B subtype of N-methyl-d-aspartate(NMDA)receptor(NR2B),postsynaptic density-95(PSD95,phosphorylated calcium/calmodulin-dependent protein kinase Ⅱ(p-CaMKII),phosphorylated extracellular signal-regulated protein kinase(p-ERK1)and phosphorylated cAMP response element binding protein(p-CREB),which were enhanced further by downregulation of Trx-1.In summary,the present study showed that the morphine-CPP extinction was involved in glutamatergic system.The downregulation of Trx-1 in the NAc delays morphine-CPP extinction through regulating glutamatergic system.This study provides a new idea and target for the treatment of morphine withdrawl.