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

Drug addiction usually refers to the repeated use of some psychoactive drugs, which acts on the brain’s reward system and induces dependence and relapse, it is chronic and recurrent brain disorder. The mechanisms of addiction is complex and not clear.Morphine is a kind of opiate, clinically used to suppress the pain, but long-term use can lead to tolerance and dependence.Dependence can be divided into physical and psychological dependence. Physical dependence is due to adaptive changes of the body to morphine and cause physiological disorders after stopping.Psychological dependence is the the drug craving and compulsive drug-seeking after withdrawal.The addiction-related brain regions of morphine includes the ventral tegmental area of the midbrain (VTA), the nucleus accumbens (NAc), the prefrontal cortex (PFC), the amygdala and hippocampus. VTA and its projected area NAc belong to the mesolimbic dopamine reward system, involved in the pathological process of drug dependence.VTA is the brain area of the dopamine neurons focused on addictive drugs act on VTA and cause elevated level of dopamine (DA).VTA has projection nerve fibers to the NAc, and induces DA level increase in NAc and then acts on DA neurons and induces the changes of downstream molecules.The cAMP response element binding protein (CREB), tyrosine hydroxylase (TH) and cell cycle-dependent protein kinase 5 (CDK5) are associated with the drug produced rewarding effects.The administration of morphine causes the oxidative stress and redox balance disorders. Thioredoxin-1 (Trx-1) is an important antioxidant protein in body. It has the roles in promoting cell proliferation, regulating activity of transcription factor and suppressing apoptosist.However, the role and mechanism of Trx-1 in regulating addiction induced by morphine is unclear.We choose Trx-1 as a target and study the related signaling pathways on morphine addiction.We used nucler 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 morphine-induced conditioned place preference (CPP) and motor ability between control group and downregulation group. Finally,we detected expressions of addcition related proteins, Trx-1, p-CREB, TH, D1 and CDK5 in VTA and NAc by using western blot.Results:This study showed that CPP and motor ability induced by morphine in mice were enhanced in group of downregulation of Trx-1 in VTA. The results of Western blot showed that the expression of Trx-1 was decreased and the expressions of p-CREB, TH, D1 and CDK5 were significantly increasesd in group of downregulation expression of Trx-1 in VTA..Summary:The downregulation of Trx-1 enhances CPP caused by morphine, downregulation of Trx-1 in VTA enhances signaling pathways related to the CPP induced by morphine.Thus,Trx-1 may be a new therapeutic target for morphine addiction.This study prodives a theory reference on furture study of morphine addcition.