Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University, Graduate School of Health Sciences, Aichi, 470-1192, Japan; Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University, Graduate School of Health Sciences, Aichi, 470-1192, Japan; Japanese Drug Organization of Appropriate Use and Research, Aichi, 468-0069, Japan.
Behav Brain Res. 2019 Oct 17;372:112053. doi: 10.1016/j.bbr.2019.112053. Epub 2019 Jul 6.
Accumulating evidence shows that stressful events evoke molecular alterations in the brain, considered a pathology in major depressive disorder (MDD). However, the abnormalities of neurotransmissions as well as intracellular signaling pathways affected by chronic stress in brain have not been fully explored. We investigated the effect of chronic unpredictable mild stress (CUMS) on the emotional behaviors, dopaminergic and serotoninergic function, and intracellular signaling in the nucleus accumbens, hippocampus and prefrontal cortex. Male C57BL/6J mice were exposed to CUMS for 4 weeks. CUMS was shown to induce hyperactivity in a novel environment, decrease interaction time in the social interaction test, prolong feeding latency in the novelty suppressed feeding test and enhance immobility in the forced swimming test. The levels of dopamine, its metabolites and turnover, and protein level of tyrosine hydroxylase (TH) were increased by CUMS in the nucleus accumbens (NAc). The level of serotonin and protein levels of tryptophan hydroxylase (TPH) and TH were decreased by CUMS in the hippocampus (HPC) and prefrontal cortex (PFC). Accompanying the increase in dopaminergic function, phosphorylation levels of extracellular signal-regulated kinases (ERK), protein kinase B (Akt) and cAMP response element-binding protein (CREB) were increased by CUMS in the NAc. Administration of fluoxetine (selective serotonin re-uptake inhibitor: 20 mg/kg i.p.) and aripiprazole (dopamine D receptor partial agonist: 0.1 mg/kg i.p.) during CUMS, prevented behavioral changes and increase of dopamine level in the NAc. These data suggest that CUMS-induced depression-like behaviors are coupled with dopaminergic hyperfunction in the NAc and serotonergic hypofunction in the HPC and PFC.
越来越多的证据表明，应激事件会引起大脑的分子改变，这被认为是重度抑郁症（MDD）的一种病理。然而，慢性应激对大脑中神经递质传递和细胞内信号通路的异常尚未得到充分探索。我们研究了慢性不可预测轻度应激（CUMS）对伏隔核、海马和前额叶皮质中情绪行为、多巴胺能和血清素能功能以及细胞内信号的影响。雄性 C57BL/6J 小鼠接受 CUMS 处理 4 周。结果显示，CUMS 诱导了新环境中的多动行为，减少了社交互动测试中的互动时间，延长了新奇抑制进食测试中的进食潜伏期，增强了强迫游泳测试中的不动性。CUMS 增加了伏隔核（NAc）中多巴胺、其代谢产物和周转率，以及酪氨酸羟化酶（TH）的蛋白水平。CUMS 降低了海马（HPC）和前额叶皮质（PFC）中的血清素和色氨酸羟化酶（TPH）和 TH 的蛋白水平。伴随着多巴胺能功能的增加，CUMS 增加了 NAc 中细胞外信号调节激酶（ERK）、蛋白激酶 B（Akt）和 cAMP 反应元件结合蛋白（CREB）的磷酸化水平。CUMS 期间给予氟西汀（选择性 5-羟色胺再摄取抑制剂：20mg/kg i.p.）和阿立哌唑（多巴胺 D 受体部分激动剂：0.1mg/kg i.p.），可预防行为改变和 NAc 中多巴胺水平的升高。这些数据表明，CUMS 诱导的抑郁样行为与 NAc 中的多巴胺能功能亢进和 HPC 和 PFC 中的血清素能功能低下有关。
