ISSN 0439-755X
CN 11-1911/B
主办：中国心理学会
　　　中国科学院心理研究所
出版：科学出版社

心理学报 ›› 2015, Vol. 47 ›› Issue (10): 1269-1278.doi: 10.3724/SP.J.1041.2015.01269

• 论文 • 上一篇    下一篇

应激性抑郁样行为发生中眶额叶5-HT1A受体对谷氨酸和γ-氨基丁酸的调节

李江娜;安书成;李珍   

  1. (陕西师范大学生命科学学院, 西安 710119)
  • 收稿日期:2014-08-27 发布日期:2015-10-25 出版日期:2015-10-25
  • 通讯作者: 安书成, E-mail: shuchengan@snnu.edu.cn; 电话：+86-29-85310266
  • 基金资助:

    国家自然科学基金资助项目(81371512)。

Orbitofrontal Cortex 5-HT1A Receptor Modulate Glutamate and GABA in Depression Induced by Chronic Unpredictable Mild Stress

LI Jiangna; AN Shucheng; LI Zhen   

  1. (College of Life Science, Shaanxi Normal University, Xi’an 710119, China)
  • Received:2014-08-27 Online:2015-10-25 Published:2015-10-25
  • Contact: AN Shucheng, E-mail: shuchengan@snnu.edu.cn; 电话：+86-29-85310266

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摘要：

5-羟色胺(5-hydroxytryptamine, 5-HT)在抑郁症的发生及治疗中起着极其重要的作用, 谷氨酸(glutamic acid, Glu)过度释放是应激性抑郁发生的重要原因。为了证明应激性抑郁样行为发生中眶额叶(orbitofrontal cortex, OFC)5-HT1A受体是否通过对Glu和γ-氨基丁酸(gamma-aminobutyric acid, GABA)的调节而发挥作用。本研究通过建立慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)抑郁模型, 结合OFC区分别微量注射5-HT1A受体激动剂8-OH-DPAT和拮抗剂WAY100635, 采用糖水偏爱率测试、旷场测试及悬尾测试检测动物的行为学表现, 并通过高效液相色谱法(high-performance liquid chromatography, HPLC)分别检测了OFC区5-HT、Glu和GABA的含量。结果显示, CUMS组和注射WAY100635组大鼠较对照组表现出明显的抑郁样行为, 且Glu含量显著升高, 但5-HT水平和GABA含量均未有显著性变化。微量注射8-OH-DPAT后, 能够显著改善大鼠的抑郁样行为, 且Glu显著降低, 但5-HT水平和GABA含量仍未发生显著性变化。结果表明, 慢性不可预见性温和应激所引起的抑郁样行为, 并不是由于眶额叶5-HT水平的降低, 而可能是由于5-HT不能满足应激状态下调节Glu能神经的需要, 或可能是OFC区Glu能神经元上5-HT1A受体功能的降低, 导致Glu水平过高所致。眶额叶5-HT1A受体在Glu合成与释放中发挥重要调节作用。

关键词: 5-羟色胺, 谷氨酸, γ-氨基丁酸, 抑郁

Abstract:

 

Stress response and depression have a crucial impact on modern society. Although the symptoms are well characterized, the molecular mechanisms underlying depression are largely unknown. Currently, the monoaminergic systems, especially serotonergic systems, have received the most attention in the research of depression. Accumulating evidence suggests that the glutamatergic and GABAergic system play an important role in the neurobiology and treatment of this disease. Multiple studies have shown that serotonin (5-HT) could modulate the neurotransmission of glutamic acid (Glu) and gamma-aminobutyric acid (GABA). The orbitofrontal cortex (OFC), which is involved in the pathophysiology and treatment of depression, plays a critical role in the control of higher brain functions and it mainly receives a dense 5-HT innervation from the dorsal raphe nucleus. There exist some 5-HT1A receptors on glutamatergic neurons and GABAergic neurons in the OFC. The purpose of this research was to elucidate the modulatory action of 5-HT1A receptor on the functions of Glu and GABA, which are the principal neurotransmitters mediating excitatory and inhibitory signals in the OFC respectively, in a well-established animal model of depression induced by chronic unpredictable mild stress (CUMS).
We used CUMS in rat to mimic the core symptoms in human. Using the pharmacology approaches by microinjecting of 5-HT1A receptor agonist 8-OH-DPAT and its antagonist WAY100635 to the OFC, we detected behavioral changes by using behavior tests including sucrose preference test, open field test and tail suspension test. In addition, high-performance liquid chromatography (HPLC) was used to detect the level of neurotransmitters such as 5-HT, Glu and GABA in the OFC, respectively.
CUMS group showed a variety of behavioral characteristics of depression, including a significant reduction in the sucrose preference, and locomotion, rearing and grooming in the open field test, and a significant increase in immobility time in the tail suspension test compared with control group. In addition, CUMS group showed that a significant increase in the concentration of Glu, but no significant difference in the levels of 5-HT and GABA in the OFC. Depression-like behaviors of CUMS rats were obviously ameliorated after being treated with 8-OH-DPAT, while the concentration of Glu was decreased. Rats received WAY100635 in control group showed similar depression-like behaviors and similar increased Glu levels. However, 5-HT level and GABA concentration were not altered in both groups received 8-OH-DPAT or WAY100635.

These findings indicated that the mechanism through which CUMS could induce depression-like behaviors, probably is not due to the decrease of 5-HT level within the OFC, but because of excessive release of Glu that resulted from that 5-HT could not regulate glutamatergic neurons or the decrease of 5-HT1A receptor function on glutamatergic neurons within the OFC during stress. Our data suggested that 5-HT1A receptor in the OFC plays an important role in modulating the synthesis and release of Glu during CUMS. This study provided insights on modulation of glutamate transmission in depression.

Key words: 5-hydroxytryptamine, glutamic acid, gamma-aminobutyric acid, depression