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应激性抑郁样行为发生中海马喹啉酸对谷氨酸及其受体的调节

陈慧彬, 李菲, 吴帅, 安书成^*

陕西师范大学生命科学学院，西安 710062

摘要

为了探讨慢性应激性抑郁样行为发生过程中海马胶质细胞释放的喹啉酸(quinolinic acid, QUIN)的作用，以及与谷氨酸(glutamic acid, Glu)及其受体的关系，通过建立慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)性抑郁模型，海马单侧微量注射QUIN、QUIN抑制剂Ro61-8048、N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体拮抗剂MK-801和谷氨酸代谢型受体1 (group 1 metabotropic glutamate receptor, mGluR1)拮抗剂AIDA，观察大鼠体重变化率，采用糖水偏爱测试、旷场实验和悬尾实验等检测行为表现，采用高效液相色谱法(high-performance liquid chromatography, HPLC)和酶联免疫吸附(enzyme linked immunosorbent assay, ELISA)法分别检测海马内Glu水平及其QUIN含量，运用Western blot方法检测NMDA受体关键亚基和mGluR1的变化。结果显示：CUMS诱发大鼠表现出明显的抑郁样行为，且海马Glu和QUIN含量、NMDA受体的NR2B亚基和mGluR1表达水平显著升高；正常大鼠海马微量注射QUIN也表现出明显抑郁样行为，且海马Glu含量、NMDA受体的NR2B亚基和mGluR1表达水平显著升高；CUMS诱发的抑郁样行为可被QUIN抑制剂Ro61-8048显著改善，且海马中Glu含量也显著降低，同时NMDA受体的NR2B亚基和mGluR1表达水平与CUMS相比也明显降低；CUMS引起的抑郁样行为可被海马注射NMDA受体拮抗剂MK-801和mGluR1拮抗剂AIDA显著改善，且其海马中Glu含量也明显降低，同时MK-801和AIDA对海马注射QUIN所引起的抑郁样行为也起到改善作用，并能降低由QUIN引起的Glu含量的升高。以上结果表明，CUMS引起海马小胶质细胞产生和释放QUIN增加，QUIN既可提高NR2B和mGluR1表达，也可以通过NMDA受体和mGluR1途径使Glu含量增多，产生神经兴奋性毒，导致抑郁样行为发生。

关键词： 抑郁; 海马; 应激; 喹啉酸; NMDA受体; 谷氨酸代谢型受体

分类号：Q189;R749.4

[Hippocampus quinolinic acid modulates glutamate and NMDAR/mGluR1 in chronic unpredictable mild stress-induced depression.] [Article in Chinese]

CHEN Hui-Bin, LI Fei, WU Shuai, AN Shu-Cheng^*

College of Life Sciences, Shaanxi Normal University, Xi'an 710062, China

Abstract

The present study was to investigate the role of the quinolinic acid (QUIN) and its relationship with N-methyl-D-aspartic acid (NMDA) receptor and metabotropic glutamate receptor 1 (mGluR1) in depression induced by chronic unpredictable mild stress (CUMS) in hippocampus. CUMS-induced depression model was established in Sprague-Dawley rats. Intrahippocampal injections of QUIN, QUIN antagonist Ro61-8048, non-competitive NMDA receptor antagonist MK-801 and mGluR1 antagonist AIDA were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by measurement of weight changes, sucrose preference test, open-field test and tail suspension test. The concentration of glutamic acid (Glu) and the expression of its receptor subunits in hippocampus were detected by HPLC and Western blot, respectively. The QUIN content in hippocampus was determined by enzyme linked immunosorbent assay (ELISA). The result showed that CUMS significantly induced the depressive-like behaviors in rats, increased the contents of QUIN and Glu, and upregulated the expression of NMDA receptor subunits NR2B and mGluR1 in hippocampus. Microinjection of QUIN into hippocampus resulted in animal depressive-like behaviors, and increased the content of Glu and the expression of NR2B and mGluR1 significantly. QUIN antagonist Ro61-8048 effectively restrained the depression-like behaviors induced by CUMS, and decreased the content of Glu and the expression of NR2B and mGluR1 significantly. Intrahippocampal injections of MK-801 and AIDA effectively improved the depression-like behaviors induced by CUMS and decreased the Glu content. The results suggest that CUMS may contribute to the production and release of QUIN in hippocampal microglia. QUIN results in elevation of Glu level via NMDA receptor and mGluR1, and the increase of expression of NR2B and mGluR1 in hippocampus, which leads to depression-like behaviors in the end.

Key words: depression; hippocampus; stress; quinolinic acid; NMDA receptor; metabotropic glutamate receptor 1

收稿日期：2013-04-28　　录用日期：2013-08-28

通讯作者：安书成　　E-mail: shuchengan@snnu.edu.cn

引用本文：

陈慧彬, 李菲, 吴帅, 安书成. 应激性抑郁样行为发生中海马喹啉酸对谷氨酸及其受体的调节[J]. 生理学报 2013; 65 (6): 577-585.

CHEN Hui-Bin, LI Fei, WU Shuai, AN Shu-Cheng. [Hippocampus quinolinic acid modulates glutamate and NMDAR/mGluR1 in chronic unpredictable mild stress-induced depression.] [Article in Chinese]. Acta Physiol Sin 2013; 65 (6): 577-585 (in Chinese with English abstract).