Methamphetamine (METH) abuse is known to cause executive dysfunction. However, the molecular mechanism underlying METH induced executive dysfunction remains unclear. Go/NoGo experiment was performed in mice to evaluate METH-induced executive dysfunction. Immunoblot analysis of Nuclear factor-E2-related factor 2 (Nrf2), phosphorylated Nrf2 (p-Nrf2), heme-oxygenase-1 (HO-1), Glucose Regulated Protein 78(GRP78), C/EBP homologous protein (CHOP), Bcl-2, Bax and Caspase3 was performed to evaluate the levels of oxidative stress, endoplasmic reticulum (ER) stress and apoptosis in the dorsal striatum (Dstr). Malondialdehyde (MDA) levels and glutathione peroxidase (GSH-Px) activity was conducted to evaluate the level of oxidative stress. TUNEL staining was conducted to detect apoptotic neurons. The animal Go/NoGo testing confirmed that METH abuse impaired the inhibitory control ability of executive function. Meanwhile, METH down-regulated the expression of p-Nrf2, HO-1 and GSH-Px and activated ER stress and apoptosis in the Dstr. Microinjection of Tert-butylhydroxyquinone (TBHQ), an Nrf2 agonist, into the Dstr increased the expression of p-Nrf2, HO-1, and GSH-Px, ameliorated ER stress, apoptosis and executive dysfunction caused by METH. Our results indicated that the p-Nrf2/HO-1 pathway was potentially involved in mediating methamphetamine-induced executive dysfunction by inducing endoplasmic reticulum stress and apoptosis in the dorsal striatum.

已知滥用甲基苯丙胺 (METH) 会导致执行功能障碍。然而，METH 引起执行功能障碍的分子机制仍不清楚。在小鼠中进行 Go/NoGo 实验以评估 METH 引起的执行功能障碍。核因子-E2相关因子2 (Nrf2)、磷酸化Nrf2 (p-Nrf2)、血红素加氧酶-1 (HO-1)、葡萄糖调节蛋白78(GRP78)、C/EBP同源蛋白(CHOP)的免疫印迹分析、Bcl-2、Bax和Caspase3用于评估背侧纹状体（Dstr）的氧化应激、内质网（ER）应激和细胞凋亡的水平。丙二醛（MDA）水平和谷胱甘肽过氧化物酶（GSH-Px）活性用于评估氧化应激水平。进行TUNEL染色以检测凋亡神经元。动物Go/NoGo测试证实，滥用冰毒会损害执行功能的抑制控制能力。同时，METH下调p-Nrf2、HO-1和GSH-Px的表达，并激活Dstr中的ER应激和细胞凋亡。将 Nrf2 激动剂叔丁基羟基醌 (TBHQ) 显微注射到 Dstr 中可增加 p-Nrf2、HO-1 和 GSH-Px 的表达，改善 METH 引起的 ER 应激、细胞凋亡和执行功能障碍。我们的结果表明，p-Nrf2/HO-1 通路可能通过诱导背侧纹状体内质网应激和细胞凋亡来介导甲基苯丙胺诱导的执行功能障碍。