The Downregulation Of Thioredoxin-1 In Ventral Tegmental Area Of The Midbrain Enhances Conditioned Place Preference Induced By Methamphetamine

Drug addiction usually refers to the repeated use of some psychoactive drugs,it is a chronic,relapsing encephalopathy.Long term use of these drugs can lead to compulsive drug seeking,out of control of craving for drugs,relapse and so on,however,the mechanisms of addiction are complex and unclear.Methamphetamine(METH)is a new drug of amphetamine type stimulants(ATS),commonly known as "ice",pure METH is white crystal.It sustains long term and induces effects rapidly.In recent years,METH becomes the second most widely abused drug after cannabis,its long-term use can produce drug dependency and neurotoxicity,lead to physical diseases and mental disorders.Methamphetamine is recognized as a central nervous system stimulant,and targets the mesolimbic dopamine system produced reward effect(MLDS),which includes the ventral tegmental area of the midbrain(VTA),the nucleus accumbens(NAc),the prefrontal cortex(PFC)and other brain regions.Therefore.VTA-NAc-PFC may be neural circuits for the reward effects caused by addiction drugs.The dopamine(DA)neuron activity in VTA in the midbrain,NAc and other forebrain regions is closely related with action of addictive drugs.The addictive drugs cause elevated level of DA in VTA.NAc as the projection area of VTA.DA level is also increased.The increase of level induces the changes of DA receptors and the downstream molecules.The cAMP response element binding protein(CREB),AFosB and cell cycle-dependent protein kinase 5(CDK5)are associated with the rewarding effects produced by drugs.Trx-1 is a ubiquitous protein in virtually all cell tissue types,and is evolutionarily conserved from prokaryotes to mammals.The Trx-1 system consists of Trx1,Trx-1 reductase(TrxR).and an electron donor,Nicotinamide adenine dinucleotide phosphate(NADPH).Trx-1 has a variety of biological functions:regulating gene transcription,promoting cell growth,regulating embryo growth,development and survival.Moreover.Trx-1 also has the important roles in nerve system.Methamphetamine addiction disorders can also lead to oxidative stress and dysfunction of redox state.Trx-1 is an important antioxidant protein in vivo,which can regulate the redox balance and plays a role in resisting oxidative stress induced by METH.The research shows that overexpression of Trx-1 suppressing inflammation induced by methamphetamine in spleen by increasing anti-inflammatory cytokine and decreasing proinflammatory cytokines.In addition,the siRNA targeted to Trx-1 reduced the level of phosphorylated CREB by METH.The results obtained in these study showed that Trx-1 might play a role in the actions of METH.Our previous study demonstrated that the Trx-1 overexpression alleviated addcition.and resisted the conditioned place preference(CPP)induced by METH.To further study the mechanism of Trx-1 in special areas after METH treatment,we used CPP model and nuclei injection technique,and injected Trx-1-specific interference RNA in bilateral VTA in mice,constructed mice of the downregulation of Trx-1 in VTA and compared METH-induced CPP difference between control group/negative control group and downregulation group.Finally,we detected expressions of addiction related molecules.Trx-1,D1 dopamine receptor(D1R),CREB,△FosB and CDK5 in VTA and NAc by using western blot.Results:Our results showed that CPP induced by METH in mice were enhanced in group of downregulation of Trx-1 in VTA when compared with control group.The change in NAc is same as in VTA.The expression of Trx-1 was decreased by METH.The expressions of D1R,CREB,△FosB and CDK5 were significantly induced by METH,which were further increased in group of downregulation expression of Trx-1 in VTA.Summary:The downregulation of Trx-1 in VTA enhances CPP related pathways and CPP caused by METH.Thus,Trx-1 may a new therapeutic target for METH addiction.This study provides a theory reference on future study on mechanism of METH addiction.