Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute, School of Medicine , Southeast University , Nanjing , Jiangsu 210009 , China.
Shenzhen Key Lab of Neuropsychiatric Modulation and Collaborative Innovation Center for Brain Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Brain Cognition and Brain Disease Institute (BCBDI) for Collaboration Research of SIAT at CAS, and McGovern Institute at MIT, Shenzhen Institutes of Advanced Technology , Chinese Academy of Sciences , Shenzhen 518055 , China.
ACS Chem Neurosci. 2018 Nov 21;9(11):2824-2831. doi: 10.1021/acschemneuro.8b00225. Epub 2018 Jul 12.
The animal model for depressive behavior due to chronic unpredicted mild stress (CUMS) is commonly used to evaluate antidepressant treatments. The CUMS model has faced some criticism because of the heterogeneity of behavioral effects. Spadin and SID1900 are TREK1 blockers with a quick antidepressant effect. However, to date, their effectiveness and the long-term therapeutic mechanisms are not known. We hypothesize that early intervention with TREK1 blockers can fully reverse depressive-like behaviors, that the chronic administration of TREK1 blockers has a more pronounced effect than the SSRI fluoxetine, and that its long-term therapeutic effects may be mediated by improvement of impaired neurogenesis. Furthermore, we optimized the use of the CUMS model for increased homogeneity by screening the rats after the CUMS induction procedure. Depressive-like behavior was assessed by a forced swimming test, sucrose preference, and open field tests. To evaluate neurogenesis, cell proliferation and newly generated cell apoptosis were measured in the hippocampal dentate gyrus. Of 32 rats that underwent the CUMS procedure, 26 rats that exhibited depressive-like behaviors were grouped as CUMS sensitive rats (CUMSS), while six that did not were grouped as CUMS resistant ones (CUMSR). The CUMSR rats exhibited minor neurogenesis impairments, while the CUMSS rats had a more pronounced effect. Treatment with TREK1 blockers could reverse depressive-like behaviors at least 1 week earlier than that of fluoxetine. Chronic administration of both the TREK1 blockers and fluoxetine could restore neurogenesis impairments. This study underlines the importance of model validation by determination of CUMS sensitivity. The TREK1 blockers were found to have an effect that was more rapid and more pronounced than that of fluoxetine. Therapeutic benefits after chronic administration were associated with a restoration of impaired neurogenesis.
慢性不可预测轻度应激（CUMS）导致抑郁行为的动物模型常用于评估抗抑郁治疗。由于行为效应的异质性，CUMS 模型受到了一些批评。Spadin 和 SID1900 是 TREK1 阻断剂，具有快速抗抑郁作用。然而，迄今为止，它们的有效性和长期治疗机制尚不清楚。我们假设 TREK1 阻断剂的早期干预可以完全逆转抑郁样行为，慢性 TREK1 阻断剂的给药比 SSRI 氟西汀更显著，其长期治疗效果可能通过改善受损的神经发生来介导。此外，我们通过在 CUMS 诱导程序后筛选大鼠来优化 CUMS 模型的使用，以提高同质性。通过强迫游泳试验、蔗糖偏好试验和旷场试验评估抑郁样行为。为了评估神经发生，测量海马齿状回中的细胞增殖和新生成细胞的凋亡。在接受 CUMS 程序的 32 只大鼠中，有 26 只表现出抑郁样行为的大鼠被分为 CUMS 敏感型大鼠（CUMSS），而 6 只没有表现出抑郁样行为的大鼠被分为 CUMS 抵抗型大鼠（CUMSR）。CUMSR 大鼠的神经发生损伤较小，而 CUMSS 大鼠的损伤更为明显。TREK1 阻断剂的治疗至少可以比氟西汀早 1 周逆转抑郁样行为。慢性给予 TREK1 阻断剂和氟西汀均可恢复神经发生损伤。这项研究强调了通过确定 CUMS 敏感性来验证模型的重要性。TREK1 阻断剂的作用比氟西汀更快、更明显。慢性给药后的治疗益处与受损神经发生的恢复有关。
