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Methamphetamine (METH) is a highly addictive drug of abuse which induces behavioral sensitization and rewarding effects. Thioredoxin-1 (Trx-1) is a redox protein and plays roles in regulating activity of transcription factor, such as cAMP responsive element-binding protein (CREB), AP-1, p53, is emerging as an important modulator of neuronal function. It has been reported that Trx-1 is involved in morphine dependence. In this study, we examined the rewarding effect after METH administration by conditioned place preference (CPP) of mice, and detected the levels of dopamine and the activity of cAMP responsive element-binding protein (CREB), the expressions of ΔFosB and cyclin-dependent kinase 5 (CDK5) in the ventral tegmental area (VTA) and nucleus accumbens (NAc) in mice. Our results showed that the expression of METH-CPP was occluded in Trx-1 overexpression transgenic (TG) mice. The increase of dopamine level induced by METH was not further higher in Trx-1 TG mice. METH decreased the expression of Trx-1 which was restored in TG mice. The activity of CREB and the expressions of ΔFosB and CDK5 were increased by METH in wile-type mice, which were not further increased in TG mice. These results suggest that overexpression of Trx-1 may occlude the CPP induced by METH through regulating the activity of CREB and the expression of ΔFosB.