Department of Neonatal Intensive Care Unit, Xi'an Children's Hospital (The Affiliated Children's Hospital of Xi'an Jiaotong University), Xi'an, Shaanxi, 86-710003, P.R. China.
Shaanxi Institute of Pediatric Diseases, Xi'an Key Laboratory of Children's Health and Diseases, Xi'an Children's Hospital (The Affiliated Children's Hospital of Xi'an Jiaotong University), Xi'an, Shaanxi, 86-710003, P.R. China.
J Affect Disord. 2020 Jul 1;272:398-408. doi: 10.1016/j.jad.2020.03.104. Epub 2020 May 1.
New insights have recently been gained into ketamine's potential anti-depressive effects. However, the mechanisms that underlie ketamine's rapid antidepressant activity still remain a mystery.
We used a rat prenatal stress (PS) model of depression to explore the functional role of mGluR5 in ketamine's rapidly induced antidepressant activity. Effects of the antidepressants imipramine, escitalopram, ketamine, and fluoxetine were compared. AAV-mGluR5 and AAV-shRNA-mGluR5 were constructed to overexpress and knockdown hippocampal mGluR5 respectively.
This study shows that mGluR5, which is associated with depression-like behaviors, is increased in susceptible rats exposed to prenatal stress, and that ketamine could significantly alleviate these stress-induced effects. RU-38486 down-regulated expression of mGluR5 and up-regulated NR1. MPEP and CHPG also altered expression of both mGluR5 and NR1. Notably, hippocampal overexpression of mGluR5 in wild type rats changed NR1 and PSD-95 expression and induced depression-like behavior that could be blocked by ketamine activity. Further, knockdown of hippocampal mGluR5 in PS-S rats restored normal levels of mGluR5, NR1, and PSD-95, and alleviated depression-like behavior.
The entire rat hippocampus was used for this study, but the role of mGluR5 may vary by sub-region.
These results suggest that hippocampal mGluR5 may play a key role in mediating the rapid antidepressant effects of ketamine in a prenatal stress model of depression. This provides a novel therapeutic target in clinical treatment of depression.
最近人们对氯胺酮的潜在抗抑郁作用有了新的认识。然而，氯胺酮快速抗抑郁作用的机制仍然是个谜。
我们使用大鼠产前应激（PS）抑郁模型来探讨 mGluR5 在氯胺酮快速诱导抗抑郁活性中的功能作用。比较了抗抑郁药丙咪嗪、艾司西酞普兰、氯胺酮和氟西汀的作用。构建了 AAV-mGluR5 和 AAV-shRNA-mGluR5 分别过表达和敲低海马 mGluR5。
本研究表明，与抑郁样行为相关的 mGluR5 在易感性大鼠暴露于产前应激时增加，而氯胺酮可显著减轻这些应激诱导的作用。RU-38486 下调 mGluR5 的表达并上调 NR1。MPEP 和 CHPG 也改变了 mGluR5 和 NR1 的表达。值得注意的是，野生型大鼠海马 mGluR5 的过表达改变了 NR1 和 PSD-95 的表达，并诱导了抑郁样行为，这种行为可被氯胺酮的活性阻断。此外，PS-S 大鼠海马 mGluR5 的敲低恢复了正常的 mGluR5、NR1 和 PSD-95 水平，并缓解了抑郁样行为。
本研究使用了整个大鼠海马，但 mGluR5 的作用可能因亚区而异。
这些结果表明，海马 mGluR5 可能在介导氯胺酮在产前应激抑郁模型中的快速抗抑郁作用中起关键作用。这为临床治疗抑郁症提供了一个新的治疗靶点。
