1 Medical Faculty, Kunming University of Science and Technology, Kunming, China.
2 Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, China.
J Psychopharmacol. 2018 Sep;32(9):1037-1046. doi: 10.1177/0269881118791523. Epub 2018 Aug 23.
Drug addiction is characterized by compulsive drug use and relapse. Thioredoxin-1 is emerging as an important modulator involved in the cellular protective response against a variety of toxic stressors. Previous study has reported that thioredoxin-1 overexpression prevents the acquisition of methamphetamine-conditioned place preference. Here, we aimed to investigate the effect of thioredoxin-1 on methamphetamine-conditioned place preference extinction and the possible mechanism.
(a) An extinction procedure in mice was employed to investigate the effect of thioredoxin-1 on the extinction of methamphetamine-conditioned place preference. After the acquisition of methamphetamine-conditioned place preference, mice underwent the following procedures: the injection of thioredoxin-1 small interfering RNA in the ventral tegmental area followed by the post-conditioned place preference test, four days of extinction training followed by four days of recovery after surgery. (b) The levels of thioredoxin-1, dopamine D1 receptor, tyrosine hydroxylase, phosphorylated extracellular regulated kinase, and phosphorylated cyclic adenosine monophosphate response element binding protein were examined by using Western blot analysis.
Thioredoxin-1 downregulation in the ventral tegmental area delayed methamphetamine-conditioned place preference extinction. The expression of thioredoxin-1 was decreased in the ventral tegmental area of mice in control and negative groups after methamphetamine-conditioned place preference extinction, but not in the thioredoxin-1 siRNA group. The levels of dopamine D1 receptor, tyrosine hydroxylase, phosphorylated extracellular regulated kinase, and phosphorylated cyclic adenosine monophosphate response element binding protein were decreased in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of mice in the control and negative groups after methamphetamine-conditioned place preference extinction, but were inversely increased in thioredoxin-1 siRNA group.
The results suggest that downregulation of thioredoxin-1 in the ventral tegmental area may delay methamphetamine-conditioned place preference extinction by regulating the mesocorticolimbic dopaminergic signaling pathway.
药物成瘾的特征是强迫性药物使用和复发。硫氧还蛋白-1 作为一种重要的调节剂，参与细胞对各种毒性应激的保护反应。先前的研究报告称，硫氧还蛋白-1 的过表达可防止甲基苯丙胺条件性位置偏好的获得。在这里，我们旨在研究硫氧还蛋白-1 对甲基苯丙胺条件性位置偏好消退的影响及其可能的机制。
（a）在小鼠中采用消退程序来研究硫氧还蛋白-1 对甲基苯丙胺条件性位置偏好消退的影响。在获得甲基苯丙胺条件性位置偏好后，小鼠进行以下程序：硫氧还蛋白-1 小干扰 RNA 在腹侧被盖区注射，然后进行后条件性位置偏好测试，进行四天的消退训练，然后在手术后进行四天的恢复。（b）通过 Western blot 分析检测硫氧还蛋白-1、多巴胺 D1 受体、酪氨酸羟化酶、磷酸化细胞外调节激酶和磷酸化环腺苷酸反应元件结合蛋白的水平。
腹侧被盖区的硫氧还蛋白-1 下调延迟了甲基苯丙胺条件性位置偏好的消退。在控制组和阴性对照组的小鼠腹侧被盖区，甲基苯丙胺条件性位置偏好消退后硫氧还蛋白-1 的表达降低，但在硫氧还蛋白-1 siRNA 组中没有降低。在控制组和阴性对照组的小鼠腹侧被盖区、伏隔核和前额叶皮质中，多巴胺 D1 受体、酪氨酸羟化酶、磷酸化细胞外调节激酶和磷酸化环腺苷酸反应元件结合蛋白的水平在甲基苯丙胺条件性位置偏好消退后降低，但在硫氧还蛋白-1 siRNA 组中则相反。
结果表明，腹侧被盖区的硫氧还蛋白-1 下调可能通过调节中脑边缘多巴胺能信号通路来延迟甲基苯丙胺条件性位置偏好的消退。
