小剂量氯胺酮保护抑郁大鼠电休克后学习记忆中Ⅱ组促代谢型谷氨酸受体的作用

摘要

目的 探讨小剂量氯胺酮保护抑郁大鼠电休克(modified electroconvulsive shock,MECS)后学习记忆中Ⅱ组促代谢型谷氨酸受体(metabotropic glutamate receptors,mGluR)的作用.方法2~3月健康雄性Sprague Dawley(SD)大鼠,采用慢性轻度不可预见性应激(chronic unpredictable mild stress,CUMS)建立抑郁大鼠模型.选取30只建模成功的抑郁大鼠随机分为D组、M组、KM组,另取10只正常大鼠作为对照组(C组),腹腔注射给药,D组给予生理盐水后行伪电休克处理,M组和KM组分别给予丙泊酚及丙泊酚+氯胺酮(10 mg/kg)后行电休克处理,C组不做任何处理,行糖水偏好实验和水迷宫实验评价行为学变化,并检测海马mGluR2和mGluR3表达水平.另取12只抑郁大鼠进行电生理实验,将其随机分为对照组(P组)和ⅡmGluR阻断剂组(L组),制备海马脑片后分别予以正常人工脑脊液和含有ⅡmGluR阻断剂的人工脑脊液灌流,应用电生理技术记录海马Schaffer侧枝-CA1神经通路(SC-CA1)长时程增强(long-term potentiation, LTP).结果 实验处理后,与D组相比,M组和KM组糖水偏好百分比升高(P<0.01),M组逃避潜伏期延长(P<0.01),目标象限探索时间缩短(P<0.01),KM组逃避潜伏期缩短,目标象限探索时间延长(P<0.01).与C组相比,D组、M组、KM组mGluR2、mGluR3蛋白表达水平降低(P<0.05);与M组相比,D组、KM组蛋白表达升高(P<0.05);D组与KM组之间差异无统计学意义(P>0.05).P组海马SC-CA1神经通路LTP高于L组(P<0.05).结论 小剂量氯胺酮可改善抑郁大鼠电休克后学习记忆功能损害,其机制可能与上调海马mGluR2和mGluR3表达有关.%Objective To explore the effect of low-dose ketamine on IImGluR and learning and memory function impairment in depression rats undergoing electroconvulsive shock. Methods In behavioral and molecular biology experiments, thirty depressed rats were randomly divided into 3 groups(n=10): depression group (group D), MECS group (group M) and MECT+Ket group (group KM). Ten healthy rats served as control group (group C). Control group received no treatment. Group D received intraperitoneal injection of normal saline plus sham ECS. Group M received intraperitoneal injection of propofol and group KM received propofol plus ketamine. Both group M and group KM received ECS once a day for 7 consecutive days.Sucrose preference test and Morris water maze were performed to assess depressed behavior and learning and memory function before and after treatment. Western-blot assay was used to detect the expression of mGluR2 and mGluR3. Another 12 depressed rats were divided into control group (group P) and IImGluR antagonist group (group L), brain slices were perfused with artificial cerebrospinal fluid and artificial cerebrospinal fluid containing IImGluR antagonist respectively. LTP in hippocampus SC-CA1 were measured using electrophysiological techniques. Results After MECS,compared with group D,SPP was obviously increased in group M and group KM (P<0.01). Group M showed prolonged escape latency and shortened space exploration time. On the contrary,group KM showed shortened escape latency and prolonged space exploration time(P<0.01).Compared with group C,the expression of mGluR2 and mGluR3 were significantly lower in group D,group M,and group KM (P<0.05)and was the lowest in group M among the four groups (P<0.05).Compared with group P,group L showed a significantly lower LTP in hippocampus SC-CA1 (P<0.05). Conclusion Low-dose ketamine reduces learning and memory function impairment after electroconvulsive shock in depression rats possibly through up-regulation the expression of mGluR2 and mGluR3.