Sun H-L, Zhou Z-Q, Zhang G-F, Yang C, Wang X-M, Shen J-C, Hashimoto K, Yang J-J
Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Transl Psychiatry. 2016 Feb 23;6(2):e741. doi: 10.1038/tp.2016.21.
Although ketamine shows a rapid and sustained antidepressant effect, the precise mechanisms underlying its effect are unknown. Recent studies indicate a key role of p11 (also known as S100A10) in depression-like behavior in rodents. The present study aimed to investigate the role of p11 in the antidepressant-like action of ketamine in chronic unpredictable mild stress (CUMS) rat model. The open-field test, forced swimming test and sucrose preference test were performed after administration of ketamine (10 mg kg(-1)) or a combination of ketamine and ANA-12 (a tropomyosin-related kinase B (TrkB) antagonist; 0.5 mg kg(-1)). The lentivirus vector for p11 was constructed to knock down the hippocampal expression of p11. In the CUMS rats, ketamine showed a rapid (0.5 h) and sustained (72 h) antidepressant effect, and its effect was significantly blocked by co-administration of ANA-12. Furthermore, ketamine significantly increased the reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of CUMS rats, whereas ketamine did not affect the expression of p11 in CUMS rats 0.5 h after administration. In addition, ketamine significantly increased the reduced ratio of p-TrkB/TrkB in the hippocampus by CUMS rats, and its effect was also blocked by ANA-12. Moreover, the reduced expression of BDNF and p11 in the hippocampus of CUMS rats was significantly recovered to control levels 72 h after ketamine administration. Interestingly, knockdown of hippocampal p11 caused increased immobility time and decreased sucrose preference, which were not improved by ketamine administration. These results suggest that p11 in the hippocampus may have a key role in the sustained antidepressant effect of ketamine in the CUMS model of depression.
尽管氯胺酮显示出快速且持续的抗抑郁作用，但其作用的精确机制尚不清楚。最近的研究表明，p11（也称为S100A10）在啮齿动物的抑郁样行为中起关键作用。本研究旨在探讨p11在慢性不可预测轻度应激（CUMS）大鼠模型中氯胺酮抗抑郁样作用中的作用。在给予氯胺酮（10 mg·kg⁻¹）或氯胺酮与ANA - 12（一种原肌球蛋白相关激酶B（TrkB）拮抗剂；0.5 mg·kg⁻¹）组合后，进行旷场试验、强迫游泳试验和蔗糖偏好试验。构建了p11的慢病毒载体以敲低海马中p11的表达。在CUMS大鼠中，氯胺酮显示出快速（0.5小时）且持续（72小时）的抗抑郁作用，并且其作用被联合给予ANA - 12显著阻断。此外，氯胺酮显著增加了CUMS大鼠海马中脑源性神经营养因子（BDNF）降低的表达，而氯胺酮在给药后0.5小时不影响CUMS大鼠中p11的表达。另外，氯胺酮显著增加了CUMS大鼠海马中p - TrkB/TrkB降低的比例，并且其作用也被ANA - 12阻断。而且，氯胺酮给药72小时后，CUMS大鼠海马中BDNF和p11降低的表达显著恢复到对照水平。有趣的是，海马p11的敲低导致不动时间增加和蔗糖偏好降低，氯胺酮给药并未改善这些情况。这些结果表明，海马中的p11可能在CUMS抑郁模型中氯胺酮的持续抗抑郁作用中起关键作用。
