ISSN 0439-755X
CN 11-1911/B

心理学报 ›› 2012, Vol. 44 ›› Issue (10): 1318-1328.doi: 10.3724/SP.J.1041.2012.01318

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  1. (陕西师范大学生命科学学院, 西安 710062)
  • 收稿日期:2012-02-20 出版日期:2012-10-25 发布日期:2012-10-23
  • 通讯作者: 安书成
  • 基金资助:


Role of Hippocampal 5-HT1A Receptor and Its Modulation to NMDA Receptor and AMPA Receptor in Depression Induced by Chronic Unpredictable Mild Stress

WEN Li-Min;AN Shu-Cheng;LIU Hui   

  1. (College of Life Science, Shaanxi Normal University, Xi’an 710062, China)
  • Received:2012-02-20 Online:2012-10-25 Published:2012-10-23
  • Contact: AN Shu-Cheng

摘要: 为探讨慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)诱发抑郁样行为发生中海马5-羟色胺1A受体(5-hydroxytryptamine receptor 1A, 5-HT1AR)表达与作用, 及其对谷氨酸N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体和α-氨基羟甲基异恶唑丙酸(α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid, AMPA)受体的影响。通过建立CUMS动物模型, 给应激抑郁模型大鼠海马微量注射5-HT1A受体激动剂、给正常大鼠海马微量注射5-HT1A受体拮抗剂, 测量大鼠体重变化率, 并采用糖水偏爱测试、旷场实验和悬尾实验等方法对大鼠进行行为学检测, 运用Western blot和ELISA方法检测大鼠海马组织中5-HT1AR和NMDAR和AMPAR的关键亚基的表达以及磷酸化水平。结果显示, 与对照组相比, CUMS组大鼠表现出抑郁样行为, 海马5-HT1AR、AMPA受体的GluR2/3亚基表达及磷酸化明显降低, NMDA受体的NR1和NR2B亚基表达及磷酸化显著增加; 正常大鼠海马微量注射5-HT1A受体拮抗剂WAY100635, 动物行为学表现及AMPA受体、NMDA受体表达及磷酸化水平均与CUMS组相同; 注射5-HT1A受体激动剂8-OH-DPAT能逆转应激诱导的上述改变。以上结果表明, CUMS诱发抑郁样行为与海马5-HT1AR表达下降, AMPAR表达量及磷酸化水平降低, NMDAR表达量及磷酸化水平升高有关。5-HT通过5-HT1AR产生抗抑郁作用。5-HT1AR激动剂抗抑郁作用与降低NMDAR表达量及磷酸化水平, 提高AMPAR表达量及磷酸化水平密切相关。

关键词: 慢性不可预见性温和应激, 抑郁症, 海马, 5-HT1A受体, NMDA受体, AMPA受体

Abstract: Stressors markedly influence central neurochemical and hormonal processes and thus play a pivotal role in the occurrence of depressive illnesses. As the center for stress response and the potential target for stressful provocation, the hippocampus is becoming a focus in depression research. Although a large number of behavioral paradigms have been proposed as animal models of depression, only a few are considered potentially useful research tools with sufficient validity. The most accepted one is the chronic unpredictable mild stress (CUMS) rodent model, in which rats are chronically and unpredictably subjected to a variety of stressors including immersion in cold water, tail pinch, day and night reversal, and so on. There are several theoretical mechanisms for depression, such as the monoamine neurotransmitter imbalance theory and the neural plasticity theory, but none of them can fully elucidate the formation of depression. Due to the weak and irregular anti-depressant effects of monoamines, glutamate (Glu) and its receptors, especially N-methyl-D-aspartic acid (NMDA) receptors and α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid (AMPA) receptors, have gained more attention in recent years. As an important isoform of the 5-hydroxytryptamine (5-HT) receptor, the 1A receptor is highly expressed in the hippocampus. Numerous pharmacological and clinical studies show that the 1A receptor is correlated with the development and therapy of major depressive disorder, anxiety, and drug addiction. The present study investigates the expression and role of the 5-HT receptor 1A (5-HT1AR) and its relationship with NMDA and AMPA receptors in depression induced by CUMS. The CUMS induced depression model was done using Sprague-Dawley rats that were given intra-hippocampal microinjections of drugs. The location of injections was determined 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 expression of 5-HT1AR was detected by Western blot, and the expression and phosphorylation of the NMDA and AMPA receptor’s subunits were detected by Western blot and ELISA, respectively. The results showed that CUMS rats had depressive-like behavior, lower expression of 5-HT1AR, lower expression and phosphorylation of AMPA receptor subunits (GluR2/3), and higher expression and phosphorylation of NMDA receptor subunits (NR1and NR2B) in the hippocampus in comparison with the CON/SAL group. Microinjection of WAY100635 (an antagonist of 5-HT1AR) into the hippocampus of CON/SAL animals resulted in similar animal depressive-like behaviors, as well as similar expression levels and phosphorylation of NMDA and AMPA receptor subunits observed in CUMS/SAL animals. Pretreatment with microinjection of 8-OH-DPAT (an agonist of 5-HT1AR) could rescue CUMS-induced depressive behavior, decrease expression of AMPA receptor subunits (GluR2/3), and increase expression of NMDA receptor subunits (NR1 and NR2B) in the hippocampus. The results suggest that 5-HT may contribute to CUMS-induced depressive-like behaviors via 5-HT1AR, and the antidepressant effect of 5-HT1AR agonists may be mediated by NMDA and AMPA receptors.

Key words: chronic unpredictable mild stress, depression, hippocampus, 5-HT1A receptor, NMDA receptor, AMPA receptor