We demonstrated that the gene of glutathione peroxidase-1 (GPx-1), a major antioxidant enzyme, is a potential protectant against the neurotoxicity and conditioned place preference induced by cocaine. Because the sigma (σ)-1 receptor is implicated in cocaine-induced drug dependence, we investigated whether the GPx-1 gene modulates the σ-1 receptor in the behavioral sensitization induced by cocaine. Cocaine-induced behavioral sensitization was more pronounced in GPx-1 knockout (KO) than wild-type (WT) mice and was less pronounced in GPx-1 overexpressing transgenic (GPx-1 TG) than non-TG mice. Cocaine treatment significantly enhanced the oxidative burden and reduced the GSH levels in the striatum of WT, GPx-1 KO, and non-TG mice but not in that of GPx-1 TG mice. In addition, cocaine significantly increased the nuclear translocation, its DNA binding activity of nuclear factor erythroid-2-related factor 2 (Nrf2) as well as the mRNA expression of γ-glutamylcysteine (GCL). The genetic depletion of GPx-1 inhibited the Nrf2-related glutathione system, whereas the genetic overexpression of GPx-1 activated this system against behavioral sensitization. BD1047, a σ-1 receptor antagonist, and U0126, an ERK inhibitor significantly induced the Nrf2-related antioxidant potential against behavioral sensitization. Unlike BD1047, U0126 did not affect the cocaine-induced σ-1 receptor immunoreactivity, suggesting that the σ-1 receptor is an upstream molecule for ERK signaling. Importantly, BD1047 and U0126 failed to affect the σ-1 receptor immunoreactivity and ERK phosphorylation induced by cocaine in GPx-1 TG mice. Our results suggest that GPx-1 is a critical mediator for the attenuation of cocaine-induced behavioral sensitization via modulating σ-1 receptor-mediated ERK activation by the induction of the Nrf2-related system.

我们证明，谷胱甘肽过氧化物酶-1 (GPx-1) 基因（一种主要的抗氧化酶）是对抗可卡因诱导的神经毒性和条件性位置偏好的潜在保护剂。由于 sigma (σ)-1 受体与可卡因诱导的药物依赖有关，因此我们研究了 GPx-1 基因是否在可卡因诱导的行为敏化中调节 σ-1 受体。可卡因诱导的行为敏化在 GPx-1 敲除 (KO) 小鼠中比野生型 (WT) 小鼠更明显，而在 GPx-1 过表达转基因 (GPx-1 TG) 小鼠中比非 TG 小鼠不太明显。可卡因治疗显着增强了 WT、GPx-1 KO 和非 TG 小鼠纹状体的氧化负担并降低了 GSH 水平，但在 GPx-1 TG 小鼠中则不然。此外，可卡因显着增加核易位、核因子红细胞2相关因子2（Nrf2）的DNA结合活性以及γ-谷氨酰半胱氨酸（GCL）的mRNA表达。 GPx-1 的基因缺失会抑制 Nrf2 相关的谷胱甘肽系统，而 GPx-1 的基因过度表达则激活该系统以对抗行为敏化。 BD1047（一种 σ-1 受体拮抗剂）和 U0126（一种 ERK 抑制剂）可显着诱导 Nrf2 相关的抗氧化潜力，以对抗行为敏化。与 BD1047 不同，U0126 不影响可卡因诱导的 σ-1 受体免疫反应性，表明 σ-1 受体是 ERK 信号传导的上游分子。重要的是，BD1047 和 U0126 未能影响 GPx-1 TG 小鼠中可卡因诱导的 σ-1 受体免疫反应性和 ERK 磷酸化。 我们的结果表明，GPx-1 是通过诱导 Nrf2 相关系统调节 σ-1 受体介导的 ERK 激活来减弱可卡因诱导的行为敏化的关键介质。