Glutathione peroxidase‐1 gene rescues cocaine‐induced conditioned place preference in mice by inhibiting σ‐1 receptor expression

: The aim of this study was to investigate whether the glutathione peroxidase-1 gene (GPx-1) affects cocaine-induced conditioned place preference (CPP) using a mouse model. Cocaine-induced CPP was accompanied by an increase in the level of σ-1 receptor in the nucleus accumbens (NAc). This phenomenon was more pronounced in the GPx-1 gene knockout (GPx-1 KO) than in wild type (WT) mice. In contrast, the CPP and expression of σ-1 receptor were much less pronounced in GPx-1-overexpressing transgenic (GPx-1 TG) mice than non-transgenic (non-TG) mice. Treatment of the mice with BD1047, a σ-1 receptor antagonist, significantly attenuated both cocaine-induced CPP and c-Fos-immunoreactivity (c-Fos-IR) in WT and GPx-1 KO mice, although the effects were more evident in the latter group. Despite the protective effects of BD1047 on cocaine-induced CPP and c-Fos in non-TG mice, there were no additional protective effects in cocaine-treated GPx-1 TG mice, indicating that the σ-1 receptor is a critical target for GPx-1-mediated psychoprotective activity. Overall, our results suggest that GPx-1 attenuates cocaine-induced CPP via inhibition of σ-1 receptor expression.