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.

中文翻译：

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TREK1受体阻滞剂和氟西汀对慢性不可预测的轻度应激敏感大鼠的治疗作用比较。

由于慢性不可预测的轻度应激（CUMS）而导致的抑郁行为动物模型通常用于评估抗抑郁药的治疗方法。由于行为效应的异质性，CUMS模型面临一些批评。Spadin和SID1900是TREK1阻滞剂，具有快速的抗抑郁作用。然而，迄今为止，它们的有效性和长期治疗机制尚不清楚。我们假设对TREK1受体阻滞剂的早期干预可以完全逆转抑郁样行为，TREK1受体阻滞剂的长期给药比SSRI氟西汀具有更明显的作用，并且其长期治疗作用可能是由受损的神经发生改善所介导的。此外，我们通过筛选CUMS诱导程序后的大鼠，优化了CUMS模型的使用，以提高同质性。通过强迫游泳测试，蔗糖偏爱和野外测试来评估抑郁症样行为。为了评估神经发生，在海马齿状回中测量了细胞增殖和新产生的细胞凋亡。在接受CUMS程序的32只大鼠中，有26例表现出抑郁样行为的大鼠被归类为CUMS敏感大鼠（CUMSS），而没有归类的6只大鼠被归类为CUMS抗性大鼠（CUMSR）。CUMSR大鼠表现出较小的神经发生损伤，而CUMSS大鼠具有更明显的作用。TREK1阻滞剂的治疗可比氟西汀提前至少1周逆转抑郁样行为。长期服用TREK1受体阻滞剂和氟西汀可以恢复神经发生损伤。这项研究强调了通过确定CUMS敏感性进行模型验证的重要性。发现TREK1阻滞剂比氟西汀具有更快，更明显的作用。长期给药后的治疗益处与受损神经发生的恢复有关。