Background

The precise mechanism governing the antidepressant effects of tianeptine is unknown. Modulation of brain glutamatergic neurotransmission has been however implicated, suggesting potential shared features with rapid-acting antidepressants targeting N-methyl-D-aspartate receptors (NMDAR). Our recent studies suggest that a single subanesthetic dose of NMDAR antagonists ketamine or nitrous oxide (N₂O) gradually evoke 1–4 Hz electrophysiological activity (delta-rhythm) of cerebral cortex that is accompanied by molecular signaling associated with synaptic plasticity (e.g. activation of tropomyosin receptor kinase B (TrkB) and inhibition of glycogen synthase kinase 3β (GSK3β)).

Methods

We have here investigated the time-dependent effects of tianeptine (30 mg/kg, i.p.) on electrocorticogram, focusing on potential biphasic regulation of the delta-rhythm. Selected molecular markers associated with ketamine's antidepressant effects were analyzed in the medial prefrontal cortex after the treatment using quantitative polymerase chain reaction and western blotting.

Results

An acute tianeptine treatment induced changes of electrocorticogram typical for active wakefulness that lasted for 2–2.5 h, which was followed by high amplitude delta-activity rebound. The levels of Arc and Homer1a, but not c-Fos, BdnfIV and Zif268, were increased by tianeptine. Phosphorylation of mitogen-activated protein kinase (MAPK), TrkB and GSK3β remained unaltered at 2-hours and at 3-hours post-treatment. Notably, tianeptine also increased the level of mRNA of several dual specificity phosphatases (Duspss) – negative regulators of MAPK.

Conclusion

Tianeptine produces acute changes of electrocorticogram resembling rapid-acting antidepressants ketamine and N₂O. Concomitant regulation of Dusps may hamper the effects of tianeptine on MAPK pathway and influence the magnitude of homeostatic emergence of delta-activity and TrkB-GSK3β signaling.

中文翻译：

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噻奈普汀诱导双特异性磷酸酶的表达并引起皮质慢波电生理活动的反弹出现

背景

噻奈普汀抗抑郁作用的确切机制尚不清楚。然而，脑谷氨酸能神经传递的调节已被牵连，这表明与靶向N-甲基-D-天冬氨酸受体 (NMDAR)的速效抗抑郁药具有潜在的共同特征。我们最近的研究表明，单次亚麻醉剂量的 NMDAR 拮抗剂氯胺酮或一氧化二氮 (N ₂ O) 逐渐引起大脑皮层的 1-4 Hz 电生理活动（δ 节律），伴随着与突触可塑性相关的分子信号传导（例如激活原肌球蛋白受体激酶 B (TrkB) 和糖原合酶激酶 3β (GSK3β) 的抑制作用。

方法

我们在此研究了噻奈普汀 (30 mg/kg, ip) 对脑电图的时间依赖性影响，重点关注 delta 节律的潜在双相调节。在使用定量聚合酶链反应和蛋白质印迹治疗后，在内侧前额叶皮质中分析了与氯胺酮抗抑郁作用相关的选定分子标记。

结果

急性噻奈普汀治疗诱发了持续 2-2.5 小时的典型活跃觉醒的皮层电图变化，随后出现高幅度 delta 活动反弹。tianeptine 增加了 Arc 和 Homer1a 的水平，但不增加 c-Fos、BdnfIV 和 Zif268。丝裂原活化蛋白激酶 (MAPK)、TrkB 和 GSK3β 的磷酸化在治疗后 2 小时和 3 小时保持不变。值得注意的是，噻奈普汀还增加了几种双特异性磷酸酶 ( Dusps s)的 mRNA 水平——MAPK的负调节剂。

结论

Tianeptine 产生类似于速效抗抑郁药氯胺酮和 N _{2 O 的皮层电图急性变化。} Dusp s 的伴随调节可能会阻碍 tianeptine 对 MAPK 通路的影响，并影响 delta 活性和 TrkB-GSK3β 信号的稳态出现幅度。