氯胺酮、丙咪嗪以及两者联合用药对Wistar Kyoto大鼠抑郁样行为的作用

Effects of ketamine,imipramine,and their combination on depression-like behaviors in Wistar Kyoto rats

本文旨在研究氯胺酮、丙咪嗪或两者联合用药对Wistar Kyoto(WKY)大鼠抑郁样行为的治疗效果和机制。取6周龄Wistar大鼠作为正常对照,给同龄WKY大鼠(抑郁症模型)腹腔注氯胺酮(给药1周,停药1周)、丙咪嗪(给药2周)或氯胺酮联合丙咪嗪。行糖水偏好及强迫游泳实验观察各组大鼠抑郁样行为的变化,用Western blot检测大鼠缰核β钙/钙调素依赖蛋白激酶II(βform of calcium/calmodulin-dependent protein kinase type II,βCa MKII)和膜谷氨酸受体1(glutamate receptor 1,Glu R1)蛋白表达,以及前额叶皮质的膜Glu R1蛋白表达。结果显示,与Wistar大鼠相比,WKY大鼠糖水偏好程度显著降低,强迫游泳实验中不动时间显著增加;单独氯胺酮治疗对WKY大鼠的抑郁样行为没有显著作用,而丙咪嗪或氯胺酮联合丙咪嗪治疗可显著减少WKY大鼠不动时间。与Wistar大鼠相比,WKY大鼠缰核βCa MKII和膜Glu R1蛋白表达显著上调,前额叶皮质的膜Glu R1蛋白表达显著下调;单独氯胺酮治疗对WKY大鼠缰核βCa MKII和膜Glu R1蛋白表达没有显著作用,但可上调前额叶皮质的膜GluR1蛋白表达;丙咪嗪或氯胺酮联合丙咪嗪治疗均可显著下调WKY大鼠缰核βCa MKII和膜Glu R1蛋白表达,上调前额叶皮质的膜Glu R1蛋白表达,丙咪嗪对上述蛋白表达的作用和联合用药之间无显著差异。以上结果提示,丙咪嗪治疗2周显著改善了WKY大鼠的抑郁样行为,联合使用氯胺酮不能增强丙咪嗪的疗效;丙咪嗪的抗抑郁机制可能与缰核中βCa MKII及膜Glu R1表达下调以及前额叶皮质的膜GluR1表达上调有关。

The aim of the present study was to investigate the effects of ketamine,imipramine,and ketamine plus imipramine on chronic depression-like behaviors of Wistar Kyoto（WKY） rats and underlying mechanism. Six-week-old Wistar rats were used as normal control. WKY rats,depression model animal,were injected intraperitoneally with ketamine（1 week,replaced with saline in 2nd week）,imipramine（2 weeks）,or ketamine in combination with imipramine. The depression-like behaviors were assessed by sucrose preference and forced swimming tests. Protein expressions of β form of calcium/calmodulin-dependent protein kinase type II（βCa MKII） and membrane fraction of glutamate receptor 1（Glu R1） were measured in corresponding brain tissue with Western blot. The results showed that,compared with Wistar rats,WKY rats exhibited decreased sucrose preference and extended immobility time. Ketamine alone did not affect depression-like behaviors of WKY,whereas imipramine or its combination with ketamine could significantly decrease the immobility time. Compared with Wistar rats,WKY rats showed up-regulated levels of βCa MKII and membrane Glu R1 protein expressions in habenula,and down-regulated level of membrane Glu R1 protein expressions in the prefrontal cortex. Imipramine or its combination with ketamine could reverse these changes of protein expressions in WKY rats. There was no difference in reversing effect between imipramine and its combination with ketamine. Ketamine alone did not affect the βCa MKII and membrane Glu R1 protein expressions in the habenula,but increased membrane Glu R1 protein expression in the prefrontal cortex of WKY rats. These results suggest 2-week imipramine treatment significantly improves depressive behavior in WKY rats; however,the addition of ketamine in the first week fails to enhance the effect of imipramine. The underlying mechanisms of imipramine＇s anti-depressive effect may be associated with the down-regulation of βCa MKII and membrane Glu R1 in the habenula,as well as the up-regulation of membrane Glu R1 in the prefrontal cortex.