慢性应激性抑郁发生与海马Glu和GABA水平变化及其受体机制
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摘要
抑郁症是一种以显著而持久的情绪低落和快感缺失为主要特征的综合征。近十几年来,随着社会的快速发展,竞争也日益激烈,各种生活、学习、工作的压力越来越大,致使抑郁症的发病率呈现出逐年升高的趋势。由于其高患病率、高自杀率、高负担、易复发、易自残的患病特点,抑郁症已经成为严重危害人类身心健康的常见情感障碍性疾病。但抑郁症的发病机制非常复杂,至今尚未完全阐明。
γ-氨基丁酸(y-aminobutyric acid,GABA)是哺乳动物中枢神经系统中最重要的抑制性神经递质,在脑中GABA几乎对所有的神经元都有抑制作用。近年来的研究表明,GABA能系统功能障碍是精神分裂及焦虑症、双相情感障碍(bipolar disorder)等疾病的重要特症,在情感障碍类疾病的发生中起非常重要的作用。研究表明抑郁症患者的脑脊液、血浆中GABA含量下降。慢性应激(chronic mild stress, CMS)或强迫游泳(forced swimming)等抑郁模型动物脑中的GABA也显著降低,给予GABA则可有效缓解抑郁样行为表现。但也有研究表明,抑郁模型动物大脑海马的GABA水平不变或升高。这可能和抑郁模型建造时应激因子、应激时间、应激强度的差异有关。GABA受体有促离子型和促代谢型两类：离子通道型受体包括GABA GABAC受体,GABAB受体为G-蛋白偶联受体。其中GABAA、GABAB型受体广泛存在于海马组织,与抑郁的关系非常密切。GABAA型受体的研究较多,大量的临床和临床前研究显示,GABAA受体功能障碍是抑郁和焦虑症的特征。激活GABAA型受体有明显的抗抑郁、抗焦虑的作用。GABAB型受体在抑郁发生中的作用目前说法不一。而最近的研究表明,GABAB受体拮抗剂是新型抗抑郁药的潜在靶点,而非GABAB受体激动剂。
谷氨酸(glutamic acid, Glu)是哺乳动物脑内最重要兴奋性神经递质,对脑中几乎所有的神经元都具有兴奋作用。海马组织内的神经元,无论是传入、传出还是中间神经元,几乎都属于Glu能神经元,它对突触可塑性、情绪行为、学习记忆等有非常重要的作用。早期的研究资料就显示,抑郁症病人的谷氨酸代谢水平与正常人不同,而抗抑郁药治疗则可缓解这种现象。动物模型研究也显示,慢性应激会使大鼠海马内Glu水平长期显著高于正常值,高水平的Glu会过度激活NMDA受体而产生兴奋性神经毒性作用,从而使神经元损伤导致抑郁,NMDA受体拮抗剂及其类似药物具有抗抑郁作用。
现在的研究越来越明确的显示,大脑兴奋系统和抑制系统之间的平衡是避免病态发生的一个重要途径。而以兴奋作用为主的Glu和以抑制作用为主的GABA在脑的正常功能活动中起着十分重要的作用。适度应激只所以不会引起精神情感障碍,其重要原因之一是当应激导致这种平衡被破坏时,通过Glu能突触和GABA能突触之间互相调节使兴奋和抑制保持平衡。当这一平衡不能维持时,就会导致神经与精神性疾病。为了证明Glu及NMDA受体和GABA及GABAA和GABAB型受体在慢性应激性抑郁发生中的作用,尤其是二者的平衡及其相互调节的受体机制,本实验通过建立慢性不可预见性温和应激(chronic unpredicped mild stress, CUMS)CUMS抑郁模型,海马微量注射NMDA拮抗剂MK-801、GABAA型受体激动剂、GABAB型受体的激动剂和拮抗剂,应用高效液相色谱技术测量GABA和Glu的含量,通过糖水偏爱测试、体重测量、旷场实验、悬尾实验、强迫游泳实验检测动物的行为变化,探讨在慢性应激性抑郁发生中,GABA和Glu水平变化及其相关受体机制。实验结果如下：
1、慢性不可预见性温和应激能引起大鼠抑郁样行为表现,海马组织中Glu水平均显著增高(P<0.05),GABA含量极显著性降低(P<0.01)。
2、NMDA受体拮抗剂MK-801能缓解CUMS诱导的抑郁行为,使海马GABA含量上调,Glu下调。
3、GABAA受体激动剂Muscimol能抑制CUMS诱导的抑郁行为,使海马中的Glu水平下调,GABA上调。GABAB受体激动剂Balofen能引起抑郁样行为的发生,且海马Glu水平稍有减少,GABA显著下调。GABAB受体拮抗剂CGP35348则能有效缓解CUMS诱导的抑郁行为,海马中Glu含量下调,GABA的含量有所增加。
分析以上实验结果可以看出,海马中Glu和GABA的平衡失调,Glu水平升高,GABA水平下降是慢性应激性抑郁发生的原因之一。NMDA受体拮抗剂MK-801抗抑郁作用一是限制NMDA受体被过度激活而导致的神经元损伤,同时通过突触前调节Glu和GABA的释放,使其达到平衡。GABAA受体激活起到抗抑郁作用,而GABAb受体激活则产生抑郁样行为,其作用也是通过调节Glu和GABA水平与平衡实现的。
Depression is a syndrome mainly characterized by long-lasting low mood and anhedonia. Along with fast development, fierce competition and much more pressure from life and work in recent years, the incidence of depression is increasing year by year. Own to its high incidence, high suicide ratio, heavy economical load, easy palindromia and automutiation, depression has become one of the most harmful psych-emotion disorders.However, the pathogenesis mechanism of depression is still complex and uncovered.
y-aminobutyric acid (GABA) is the most crucial inhibitory neurotransmitter in mammal central nervous system, which almost inhibits all the neurons. Recent researches demonstrate the dysfunction of GABA-ergic system is the principal feature in schizophrenia, anxiety disorder and bipolar disorder etc, indicating that GABA play an important role in emotion disorders. And also, GABA decreases in cerebrospinal fluid and blood plasma in depression disorders. Chronic mild stress (CMS) and forced swimming, which can be used as animal model for depression, significantly decline GABA in central nervous system, while administration of GABA effectively ameliorates depression-like behaviors. However, other researches showed that GABA unchanged, even rose in hippocampus in depression animals, which was probably to do with discrepancies of stress factors, duration and intensity in the course of depression modeling. There are two types of GABA receptors, that is, ion receptors and metabolism receptors. The ion receptor consists of GABAAR, GABABR, and GABACR. There into, GABAAR and GABABR extensively distribute in hippocampus, and have close connection with depression. Many clinical studies manifested GABAAR dysfunction was linked to depression and anxiety disorders. Activating GABAAR apparently resist depression and anxiety disorders. But, different statements are about GABABR in depression. Recent studies showed that it was not GABABR inhibitor but GABABR agonist that had potential to antidepression.
Glutamic acid (Glu) is the most important excitatory neurotransmitter in mammal central nervous system, having an exciting action on almost all the neurons in brain. Most of hippocampal neurons are Glu-ergic, no matter afferent neurons, internuncial neurons and efferent neurons. Glu contributes importantly to neuron-plasticity, emotional behavior and learning-memory. References showed that metabolic level of Glu was different in depression, but antidepressant normalized this phenomenon. Also, researches on pattern animal displayed that chronic stress increased Glu in hippocampus, and high level of Glu excessively activated NMDA receptor and induced excitatory neurotoxicity, thus causing damage to neurons. However, antagonist to NMDA receptor, including its analogue, has antidepressant functions.
More and more studies declared that it was an important way of make a balance between excitatory neuro-system and inhibitory neuro-system in brain to avoid disease. Therefore, GABA and Glu become the key point in researching brain function. Appropriate stress does not lead to psych-emotion disorders, since it does not disrupt the balance between the excitatory system and the inhibitory system, which mainly arise from Glu and GABA.
In order to prove of Glu, GABA and their receptors in the CUMS-induced depression, especially the mechanism of the regulation and balance between the two systems, we used the CUMS (chronic unpredictable mild stress, CUMS), intra-hippocampal microinjection of agonists and antagonist of Glu receptor and GABA receptor, and HPLC to investigate the variation of Glu and GABA, and the pathogenesis of the involved Glu and GABA receptors.
Results are in the following:
1. CUMS resulted in depression-like behaviors, significantly increased Glu (P<0.05) and decreased GABA (P<0.01) in hippocampus.
2. MK-801, NMDAR antagonist, relieved CUMS-induced depression-like behaviors, up-regulated GABA and down-regulated Glu in hippocampus.
3.Muscimol, GABAAR agonist, ameliorated CUMS-induced depression-like behaviors, decreased Glu and increased GABA in hippocampus. Balofen, GABABR agonist, induced depression-like behaviors, and reduced hippocampal Glu slightly and GABA distinctly. GP35348, GABABR antagonist, effectively ameliorated CUMS-induced depression-like behaviors, declined hippocampal Glu and raised hippocampal GABA.
Analysis from the above results show disequilibrium between hippocampal Glu and GABA, that is, Glu increase and GABA decrease, is one of pathological mechanisms involved in CUMS-induced depression. The antidepression function of NMDAR antagonist MK-801 is via two ways:preventing damages to neurons from NMDAR excessive activation, and regulating presynaptic release of Glu and GABA to maintain the equilibrium. The activation of GABAAR induces antidepression, while the activation of GABABR produces despression-like behaviors, which are also achieved by balancing Glu and GABA.
γ-氨基丁酸(y-aminobutyric acid,GABA)是哺乳动物中枢神经系统中最重要的抑制性神经递质,在脑中GABA几乎对所有的神经元都有抑制作用。近年来的研究表明,GABA能系统功能障碍是精神分裂及焦虑症、双相情感障碍(bipolar disorder)等疾病的重要特症,在情感障碍类疾病的发生中起非常重要的作用。研究表明抑郁症患者的脑脊液、血浆中GABA含量下降。慢性应激(chronic mild stress, CMS)或强迫游泳(forced swimming)等抑郁模型动物脑中的GABA也显著降低,给予GABA则可有效缓解抑郁样行为表现。但也有研究表明,抑郁模型动物大脑海马的GABA水平不变或升高。这可能和抑郁模型建造时应激因子、应激时间、应激强度的差异有关。GABA受体有促离子型和促代谢型两类：离子通道型受体包括GABA GABAC受体,GABAB受体为G-蛋白偶联受体。其中GABAA、GABAB型受体广泛存在于海马组织,与抑郁的关系非常密切。GABAA型受体的研究较多,大量的临床和临床前研究显示,GABAA受体功能障碍是抑郁和焦虑症的特征。激活GABAA型受体有明显的抗抑郁、抗焦虑的作用。GABAB型受体在抑郁发生中的作用目前说法不一。而最近的研究表明,GABAB受体拮抗剂是新型抗抑郁药的潜在靶点,而非GABAB受体激动剂。
谷氨酸(glutamic acid, Glu)是哺乳动物脑内最重要兴奋性神经递质,对脑中几乎所有的神经元都具有兴奋作用。海马组织内的神经元,无论是传入、传出还是中间神经元,几乎都属于Glu能神经元,它对突触可塑性、情绪行为、学习记忆等有非常重要的作用。早期的研究资料就显示,抑郁症病人的谷氨酸代谢水平与正常人不同,而抗抑郁药治疗则可缓解这种现象。动物模型研究也显示,慢性应激会使大鼠海马内Glu水平长期显著高于正常值,高水平的Glu会过度激活NMDA受体而产生兴奋性神经毒性作用,从而使神经元损伤导致抑郁,NMDA受体拮抗剂及其类似药物具有抗抑郁作用。
现在的研究越来越明确的显示,大脑兴奋系统和抑制系统之间的平衡是避免病态发生的一个重要途径。而以兴奋作用为主的Glu和以抑制作用为主的GABA在脑的正常功能活动中起着十分重要的作用。适度应激只所以不会引起精神情感障碍,其重要原因之一是当应激导致这种平衡被破坏时,通过Glu能突触和GABA能突触之间互相调节使兴奋和抑制保持平衡。当这一平衡不能维持时,就会导致神经与精神性疾病。为了证明Glu及NMDA受体和GABA及GABAA和GABAB型受体在慢性应激性抑郁发生中的作用,尤其是二者的平衡及其相互调节的受体机制,本实验通过建立慢性不可预见性温和应激(chronic unpredicped mild stress, CUMS)CUMS抑郁模型,海马微量注射NMDA拮抗剂MK-801、GABAA型受体激动剂、GABAB型受体的激动剂和拮抗剂,应用高效液相色谱技术测量GABA和Glu的含量,通过糖水偏爱测试、体重测量、旷场实验、悬尾实验、强迫游泳实验检测动物的行为变化,探讨在慢性应激性抑郁发生中,GABA和Glu水平变化及其相关受体机制。实验结果如下：
1、慢性不可预见性温和应激能引起大鼠抑郁样行为表现,海马组织中Glu水平均显著增高(P<0.05),GABA含量极显著性降低(P<0.01)。
2、NMDA受体拮抗剂MK-801能缓解CUMS诱导的抑郁行为,使海马GABA含量上调,Glu下调。
3、GABAA受体激动剂Muscimol能抑制CUMS诱导的抑郁行为,使海马中的Glu水平下调,GABA上调。GABAB受体激动剂Balofen能引起抑郁样行为的发生,且海马Glu水平稍有减少,GABA显著下调。GABAB受体拮抗剂CGP35348则能有效缓解CUMS诱导的抑郁行为,海马中Glu含量下调,GABA的含量有所增加。
分析以上实验结果可以看出,海马中Glu和GABA的平衡失调,Glu水平升高,GABA水平下降是慢性应激性抑郁发生的原因之一。NMDA受体拮抗剂MK-801抗抑郁作用一是限制NMDA受体被过度激活而导致的神经元损伤,同时通过突触前调节Glu和GABA的释放,使其达到平衡。GABAA受体激活起到抗抑郁作用,而GABAb受体激活则产生抑郁样行为,其作用也是通过调节Glu和GABA水平与平衡实现的。
Depression is a syndrome mainly characterized by long-lasting low mood and anhedonia. Along with fast development, fierce competition and much more pressure from life and work in recent years, the incidence of depression is increasing year by year. Own to its high incidence, high suicide ratio, heavy economical load, easy palindromia and automutiation, depression has become one of the most harmful psych-emotion disorders.However, the pathogenesis mechanism of depression is still complex and uncovered.
y-aminobutyric acid (GABA) is the most crucial inhibitory neurotransmitter in mammal central nervous system, which almost inhibits all the neurons. Recent researches demonstrate the dysfunction of GABA-ergic system is the principal feature in schizophrenia, anxiety disorder and bipolar disorder etc, indicating that GABA play an important role in emotion disorders. And also, GABA decreases in cerebrospinal fluid and blood plasma in depression disorders. Chronic mild stress (CMS) and forced swimming, which can be used as animal model for depression, significantly decline GABA in central nervous system, while administration of GABA effectively ameliorates depression-like behaviors. However, other researches showed that GABA unchanged, even rose in hippocampus in depression animals, which was probably to do with discrepancies of stress factors, duration and intensity in the course of depression modeling. There are two types of GABA receptors, that is, ion receptors and metabolism receptors. The ion receptor consists of GABAAR, GABABR, and GABACR. There into, GABAAR and GABABR extensively distribute in hippocampus, and have close connection with depression. Many clinical studies manifested GABAAR dysfunction was linked to depression and anxiety disorders. Activating GABAAR apparently resist depression and anxiety disorders. But, different statements are about GABABR in depression. Recent studies showed that it was not GABABR inhibitor but GABABR agonist that had potential to antidepression.
Glutamic acid (Glu) is the most important excitatory neurotransmitter in mammal central nervous system, having an exciting action on almost all the neurons in brain. Most of hippocampal neurons are Glu-ergic, no matter afferent neurons, internuncial neurons and efferent neurons. Glu contributes importantly to neuron-plasticity, emotional behavior and learning-memory. References showed that metabolic level of Glu was different in depression, but antidepressant normalized this phenomenon. Also, researches on pattern animal displayed that chronic stress increased Glu in hippocampus, and high level of Glu excessively activated NMDA receptor and induced excitatory neurotoxicity, thus causing damage to neurons. However, antagonist to NMDA receptor, including its analogue, has antidepressant functions.
More and more studies declared that it was an important way of make a balance between excitatory neuro-system and inhibitory neuro-system in brain to avoid disease. Therefore, GABA and Glu become the key point in researching brain function. Appropriate stress does not lead to psych-emotion disorders, since it does not disrupt the balance between the excitatory system and the inhibitory system, which mainly arise from Glu and GABA.
In order to prove of Glu, GABA and their receptors in the CUMS-induced depression, especially the mechanism of the regulation and balance between the two systems, we used the CUMS (chronic unpredictable mild stress, CUMS), intra-hippocampal microinjection of agonists and antagonist of Glu receptor and GABA receptor, and HPLC to investigate the variation of Glu and GABA, and the pathogenesis of the involved Glu and GABA receptors.
Results are in the following:
1. CUMS resulted in depression-like behaviors, significantly increased Glu (P<0.05) and decreased GABA (P<0.01) in hippocampus.
2. MK-801, NMDAR antagonist, relieved CUMS-induced depression-like behaviors, up-regulated GABA and down-regulated Glu in hippocampus.
3.Muscimol, GABAAR agonist, ameliorated CUMS-induced depression-like behaviors, decreased Glu and increased GABA in hippocampus. Balofen, GABABR agonist, induced depression-like behaviors, and reduced hippocampal Glu slightly and GABA distinctly. GP35348, GABABR antagonist, effectively ameliorated CUMS-induced depression-like behaviors, declined hippocampal Glu and raised hippocampal GABA.
Analysis from the above results show disequilibrium between hippocampal Glu and GABA, that is, Glu increase and GABA decrease, is one of pathological mechanisms involved in CUMS-induced depression. The antidepression function of NMDAR antagonist MK-801 is via two ways:preventing damages to neurons from NMDAR excessive activation, and regulating presynaptic release of Glu and GABA to maintain the equilibrium. The activation of GABAAR induces antidepression, while the activation of GABABR produces despression-like behaviors, which are also achieved by balancing Glu and GABA.
引文
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