Research has demonstrated that chronic stress experienced early in life can lead to impairments in memory and learning. These deficits are attributed to an imbalance in the interaction between glucocorticoids, the end product of the hypothalamic-pituitary-adrenal (HPA) axis, and glucocorticoid receptors in brain regions responsible for mediating memory, such as the hippocampus. This imbalance can result in detrimental conditions like neuroinflammation. The aim of this study was to assess the impact of sumatriptan, a selective agonist for 5-HT 1B/1D receptors, on fear learning capabilities in a chronic social isolation stress model in mice, with a particular focus on the role of the HPA axis. Mice were assigned to two opposing conditions, including social condition (SC) and isolated condition (IC) for a duration of five weeks. All mice underwent passive avoidance test, with their subsequent freezing behavior serving as an indicator of fear retrieval. Mice in the IC group were administered either a vehicle, sumatriptan, GR-127935 (a selective antagonist for 5-HT 1B/1D receptors), or a combination of sumatriptan and GR-127935 during the testing sessions. At the end, all mice were sacrificed and samples of their serum and hippocampus were collected for further analysis. Isolation was found to significantly reduce freezing behavior (p<0.001). An increase in the freezing response among IC mice was observed following the administration of varying doses of sumatriptan, as indicated by a one-way ANOVA analysis (p<0.001). However, the mitigating effects of sumatriptan were reversed upon the administration of GR-127935. An ELISA assay conducted before and after the passive avoidance test revealed no significant change in serum corticosterone levels among SC mice. In contrast, a significant increase was observed among IC mice, suggesting hyper-responsiveness of the HPA axis in isolated animals. This hyper-responsiveness was ameliorated following the administration of sumatriptan. Furthermore, both the sumatriptan and SC groups exhibited a similar trend, showing a significant increase in the expression of hippocampal glucocorticoid receptors following the stress of the passive avoidance test. Lastly, the elevated production of inflammatory cytokines (TNF-α, IL-1β) observed following social isolation was attenuated in the sumatriptan group. Sumatriptan improved fear learning probably through modulation of HPA axis and hippocampus neuroinflammation.

中文翻译：

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舒马曲坦减轻小鼠社会孤立应激引起的恐惧学习绝望：下丘脑-垂体-肾上腺轴的中介作用

研究表明，生命早期经历的慢性压力会导致记忆和学习障碍。这些缺陷归因于糖皮质激素（下丘脑-垂体-肾上腺（HPA）轴的最终产物）与负责调节记忆的大脑区域（例如海马体）中的糖皮质激素受体之间相互作用的不平衡。这种不平衡可能会导致神经炎症等有害疾病。本研究的目的是评估舒马曲坦（5-HT 1B/1D 受体的选择性激动剂）对小鼠慢性社会孤立应激模型中恐惧学习能力的影响，特别关注 HPA 轴的作用。小鼠被分配到两种相反的条件下，包括社交条件（SC）和隔离条件（IC），持续五周。所有小鼠都接受了被动回避测试，随后的冻结行为作为恐惧恢复的指标。在测试过程中，IC 组的小鼠被给予载体、舒马曲坦、GR-127935（5-HT 1B/1D 受体的选择性拮抗剂）或舒马曲坦和 GR-127935 的组合。最后，处死所有小鼠并收集其血清和海马样本用于进一步分析。研究发现，隔离可以显着减少冻结行为（p<0.001）。单向方差分析表明，给予不同剂量的舒马普坦后，观察到 IC 小鼠的冻结反应有所增加（p<0.001）。然而，给予 GR-127935 后舒马曲坦的缓解作用被逆转。在被动回避测试之前和之后进行的 ELISA 测定显示 SC 小鼠的血清皮质酮水平没有显着变化。相比之下，在 IC 小鼠中观察到显着增加，表明离体动物的 HPA 轴反应过度。服用舒马普坦后，这种过度反应得到改善。此外，舒马曲坦组和 SC 组都表现出相似的趋势，显示在被动回避测试的压力后海马糖皮质激素受体的表达显着增加。最后，在舒马普坦组中，社交隔离后观察到的炎症细胞因子（TNF-α、IL-1β）的产生增加有所减弱。舒马曲坦可能通过调节 HPA 轴和海马神经炎症来改善恐惧学习。