The Study On Interaction Of Trx-1 And TRPC1 Regulated By Methamphetamine

Methamphetamine is commonly known as“ice”due to its appearance of pure white crystal.It is one of kind central nervous system amphetamine type stimulants.Since it costs low,acts fast,lasts long time,the rate of its abuse is gradually increased every year.The long term abuse will result in compulsive drug seeking.Its mechanisms are not unclear,may be related with genetics,environment,and oxidative stress.Because the molecular structure of METH is similar with dopamine,METH binds to dopamine transporter(DAT)and induces release of DA,then stimulates dopamine neurons,produces the exciting and happy feeling.The long time use of METH results in addiction.The ventral tegmental area(VTA),the projection area of the nucleus accumbens(NAc)and prefrontal cortex(PFC)are regarded as mesolimbic dopamine system which is involved in addcition.There are many molecules involved in METH addiction,such as cAMP response element binding protein(CREB),△FosB,Cyclin-depdent kinase 5(Cdk5).Transient receptor potential cation channel 1(TRPC1)is a non selective cation channel located on the cell membrane,regulates Ca2+ flow into the endoplasmic reticulum.The activity of TRPC1 is related with reactive oxygen species(ROS).Thioredoxin-1(Trx-1)is widely distributed in prokaryotic and eukaryotic organisms,has various roles,such as antioxidant activity,promoting cell proliferation,regulating gene transcription and anti-apoptosis.Trx-1,Trx-1 reductase and nicotinamide adenine dinuclcotidc phosphate(NADPH)forms the system of Trx-1.It plays the roles in protecting neurons,enhancing the activity of TRPC1 and regulating the TRP channel.So far,the role of TRPC1 in regulating METH addiction and relationship between the Trx-1 and TRPC1 after METH treatment have not been reported.In this study,we explored the mechanism of TRPC 1 regulating conditioned place preference(CPP)induced by METH and relationship between the Trx-1 and TRPC1 after METH treatment by using CPP model and nucler injection technique.The main results of this study are:expression of Trx-1 was increased after METH treatment in PC 12 cells,but was decreased in mice.We constructed mice of downregulation of TRPC1 in VTA through injection of TRPC1 specific interference RNA in bilateral VTA in mice,and compared METH-induced CPP difference between control group and downregulation group.CPP induced by METH in mice was not enhanced in group of downregulation of TRPC1 in VTA when compared with control group,which may be related with the ceiling effect.The change in NAc is same as in VTA.Trx-1 was decreased by METH,the expressions of DIR,CREB,AFosB and CDK5 were significantly induced by METH,which were further increased in group of downregulation expression of TRPC1 in VTA.The expression of TRPC1 was decreased after siRNA Trx-1 transfection,the expression of Trx-1 was decreased after siRNA TRPC1 transfection,which means that there is interaction between Trx-1 and TRPC1.Summary:The expressions of Trx-1 and TRPC1 were decreased after METH-CPP.The downregulation of TRPC1 in VTA does not enhance METH-CPP(ceiling effect)but the expressions of molecules related addcition were increased further.There is interaction between Trx-1 and TRPC1.Thus,TRPC1 may be a new therapeutic target for METH addiction treatment.