Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Neuroscience. 2013 Aug 29;246:160-9. doi: 10.1016/j.neuroscience.2013.04.057. Epub 2013 May 2.
Our prior research has shown that the transcription of endoplasmic reticulum (ER) stress transcription factors activating transcription factor 3 (ATF3) and ATF4 are induced by amphetamine and restraint stress in rat striatum. However, presently the full extent of ER stress responses to psychological stress or cocaine, and which of the three ER stress pathways is activated is unknown. The current study examines transcriptional responses of key ER stress target genes subsequent to psychological stress or cocaine. Rats were subjected to acute or repeated restraint stress or cocaine treatment and mRNA was isolated from dorsal striatum, medial prefrontal cortex and nucleus accumbens brain tissue. ER stress gene mRNA expression was measured using quantitative polymerase chain reaction (PCR) and RNA sequencing. Restraint stress and cocaine-induced transcription of the classic ER stress-induced genes (BIP, CHOP, ATF3 and GADD34) and of two other ER stress components x-box binding protein 1 (XBP1) and ATF6. In addition, rats living in an enriched environment (large group cage with novel toys changed daily) exhibited rapid induction of GADD34 and ATF3 after 30 min of exploring novel toys, suggesting these genes are also involved in normal non-pathological signaling. However, environmental enrichment, a paradigm that produces protective addiction and depression phenotypes in rats, attenuated the rapid induction of ATF3 and GADD34 after restraint stress. These experiments provide a sensitive measure of ER stress and, more importantly, these results offer good evidence of the activation of ER stress mechanisms from psychological stress, cocaine and natural reward. Thus, ER stress genes may be targets for novel therapeutic targets for depression and addiction.
我们之前的研究表明,在大鼠纹状体中,安非他命和束缚应激会诱导内质网(ER)应激转录因子激活转录因子 3(ATF3)和 ATF4 的转录。然而,目前对于心理应激或可卡因引起的 ER 应激反应的全貌,以及哪条 ER 应激途径被激活尚不清楚。本研究检测了心理应激或可卡因处理后关键 ER 应激靶基因的转录反应。大鼠接受急性或重复束缚应激或可卡因处理,并从背侧纹状体、内侧前额叶皮质和伏隔核脑组织中分离 mRNA。使用定量聚合酶链反应(PCR)和 RNA 测序测量 ER 应激基因 mRNA 的表达。束缚应激和可卡因诱导经典 ER 应激诱导基因(BIP、CHOP、ATF3 和 GADD34)以及另外两个 ER 应激成分 X 盒结合蛋白 1(XBP1)和 ATF6 的转录。此外,生活在丰富环境(有新奇玩具且每天更换的大组笼)中的大鼠在探索新奇玩具 30 分钟后,快速诱导 GADD34 和 ATF3 的表达,这表明这些基因也参与了正常的非病理信号转导。然而,环境丰富,一种在大鼠中产生保护性成瘾和抑郁表型的范式,减弱了束缚应激后 ATF3 和 GADD34 的快速诱导。这些实验提供了 ER 应激的敏感测量方法,更重要的是,这些结果为心理应激、可卡因和自然奖赏引起的 ER 应激机制的激活提供了很好的证据。因此,ER 应激基因可能是抑郁和成瘾的新型治疗靶点。