Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, 31-343, Kraków, Smętna Street 12, Poland.
Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, 31-343, Kraków, Smętna Street 12, Poland.
Neuropharmacology. 2017 Oct;125:333-342. doi: 10.1016/j.neuropharm.2017.08.006. Epub 2017 Aug 9.
Short and long acting NMDA receptor (NMDAR) antagonists exert their antidepressant-like effects by activating signaling pathways involved in the synthesis of synaptic proteins and formation of new synaptic connections in the prefrontal cortex (PFC) of rats. The blockade of the ERK pathway abolishes ketamine and Ro 25-6981 antidepressant potency. However, the role of ERK in the antidepressant-like activity of short acting NMDAR antagonists is still unclear. More puzzling is the fact that the precise role of ERK in the short and long lasting effects of long-acting NMDAR antagonists is unknown. In this study, we show that zinc, (Zn) a short-acting NMDAR antagonist evokes only transient ERK activation, which is observed 7 min after its administration in the PFC of rats. In contrast to Zn, the long acting NMDAR antagonist Ro 25-6981 produces persistent ERK activation lasting up to 24 h. Pretreatment with the MAPK/ERK inhibitor (U0126) totally abolished Zn and Ro 25-6981 antidepressant-like activities in the forced swim test in rats. However, when U0126 is administered 15 min after Zn or Ro 25-6981 both compounds maintain their short-lasting antidepressant-like activity. On the other hand, posttreatment with U0126 significantly attenuated the long lasting antidepressant-like activity of Ro 25-6981. These results indicate that the activation of ERK is crucial for the short- and long lasting antidepressant-like activity observed in the FST in rats.
短时间和长时间作用的 NMDA 受体 (NMDAR) 拮抗剂通过激活参与大鼠前额叶皮质 (PFC) 中突触蛋白合成和新突触连接形成的信号通路发挥其抗抑郁作用。ERK 通路的阻断会消除氯胺酮和 Ro 25-6981 的抗抑郁作用。然而，ERK 在短时间作用的 NMDAR 拮抗剂的抗抑郁样活性中的作用尚不清楚。更令人困惑的是，ERK 在长效 NMDAR 拮抗剂的短时间和长时间作用中的确切作用尚不清楚。在这项研究中，我们表明锌（Zn），一种短时间作用的 NMDAR 拮抗剂，仅引起短暂的 ERK 激活，在大鼠 PFC 中给予后 7 分钟即可观察到。与 Zn 相反，长效 NMDAR 拮抗剂 Ro 25-6981 产生持续的 ERK 激活，持续长达 24 小时。在大鼠强迫游泳试验中，MAPK/ERK 抑制剂 (U0126) 的预处理完全消除了 Zn 和 Ro 25-6981 的抗抑郁样活性。然而，当 U0126 在给予 Zn 或 Ro 25-6981 15 分钟后给予时，这两种化合物都保持其短时间的抗抑郁样活性。另一方面，U0126 的后期处理显著减弱了 Ro 25-6981 的长效抗抑郁样活性。这些结果表明，ERK 的激活对于大鼠 FST 中观察到的短时间和长时间的抗抑郁样活性至关重要。
