PDF(Sci-hub)
Abstract：
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.
摘要：
我们证明了谷胱甘肽过氧化物酶-1（GPx-1）的基因，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爱的潜在保护剂。因为σ（σ）-1受体与可卡因诱导的药物依赖有关，我们调查了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过表达的转基因（GPx-1TG）中比非TG小鼠更不明显。可卡因治疗显着增强了WT纹状体的氧化负荷并降低了GSH水平，GPx-1KO,和非TG小鼠，但不在GPx-1TG小鼠中。此外,可卡因显著增加了核易位，核因子-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的遗传耗竭抑制了Nrf2相关的谷胱甘肽系统，而GPx-1的遗传过表达激活了该系统的行为致敏作用。BD1047，一种σ-1受体拮抗剂，和U0126,一种ERK抑制剂显著诱导Nrf2相关的抗氧化潜能对抗行为致敏。与BD1047不同，U0126不影响可卡因诱导的σ-1受体免疫反应性，这表明σ-1受体是ERK信号的上游分子。重要的是,BD1047和U0126未能影响可卡因在GPx-1TG小鼠中诱导的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。
