艾司西酞普兰对抑郁模型大鼠脑内抑制性氨基酸变化的作用

doi:10.12114/j.issn.1007-9572.2021.00.469

中国全科医学 ›› 2021, Vol. 24 ›› Issue (20): 2547-2554.DOI: 10.12114/j.issn.1007-9572.2021.00.469

所属专题：精神卫生最新文章合集

艾司西酞普兰对抑郁模型大鼠脑内抑制性氨基酸变化的作用

丁楷模1，2，3，李冰玥3，4，张咪咪3，5，6，李国海1，2*，李素霞3*

1.212013 江苏省镇江市，江苏大学医学院　2.212021 江苏省镇江市精神卫生中心　3.100191 北京市，北京大学中国药物依赖性研究所　4.100083 北京市，北京科技大学化学与生物工程学院　5.361101 福建省厦门市，厦门大学附属翔安医院妇产科　6.361102 福建省厦门市，厦门大学医学院
*通信作者：李国海，主任医师；E-mail：liguohai744@163.com　李素霞，副研究员；E-mail：li313@bjmu.edu.cn

出版日期:2021-07-15 发布日期:2021-07-15
基金资助:
基金项目：国家自然科学基金面上项目（81871071）

Changes of Inhibitory Amino Acids in the Brain of Depression Model Rats before and after Escitalopram Treatment　

DING Kaimo1，2，3，LI Bingyue3，4，ZHANG Mimi3，5，6，LI Guohai1，2*，LI Suxia3*

1.School of Medicine，Jiangsu University，Zhenjiang 212013，China
2.Zhenjiang Mental Health Center，Zhenjiang 212021，China
3.National Institute on Drug Dependence，Peking University，Beijing 100191，China
4.School of Chemistry and Biological Engineering，University of Science and Technology Beijing，Beijing 100083，China
5.Department of Obstetrics and Gynecology，Xiang'an Hospital of Xiamen University，Xiamen 361101，China
6.School of Medicine，Xiamen University，Xiamen 361102，China
*Corresponding authors：LI Guohai，Chief physician；E-mail：liguohai744@163.com
LI Suxia，Associate professor；E-mail：li313@bjmu.edu.cn

Published:2021-07-15 Online:2021-07-15

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摘要/Abstract

摘要： 背景　抑郁症是一种常见的慢性易复发疾病，给全球经济带来巨大负担，虽然数十年来对抑郁症发病机制的研究一直未中断，但抑郁症发生的具体机制仍然不详。目的　研究抑郁样大鼠脑内抑制性氨基酸的变化及艾司西酞普兰对其变化的作用。方法　于2016年6月—2017年3月，选取雄性成年SD大鼠38只，其中18只给予28 d慢性不可预见性应激（CUS）处理为CUS组，20只正常饲养不予CUS处理为对照组，根据干预方法不同将CUS组和对照组各分出两亚组，CUS+艾司西酞普兰组（9只）和对照+艾司西酞普兰组（12只）于第15天开始腹腔注射艾司西酞普兰，CUS+溶媒组（9只）和对照+溶媒组（8只）于第15天开始腹腔注射0.9%氯化钠溶液。以体质量增加量、蔗糖偏好测试（SPT）中蔗糖偏好值、旷场测试（OFT）中水平运动距离和中央区停留时间、高架十字迷宫测试（EPM）中开臂停留时间、黑白盒测试（BWT）中白盒停留时间评估大鼠行为学的变化；采用高效液相色谱-质谱联用（LC-MS）方法检测大鼠前额叶皮质及海马中氨基酸代谢变化。结果　行为学影响：CUS与艾司西酞普兰对体质量增加量、蔗糖偏好值、水平运动距离、中央区停留时间均无交互作用（P>0.05），而CUS对体质量增加量、蔗糖偏好值、水平运动距离主效应均显著（P<0.05），CUS对中央区停留时间主效应不显著（P>0.05），艾司西酞普兰对蔗糖偏好值、水平运动距离主效应均显著（P<0.05），艾司西酞普兰对体质量增加量、中央区停留时间主效应均不显著（P>0.05）。CUS与艾司西酞普兰对开臂停留时间、白盒停留时间存在交互作用（P<0.05），但CUS和艾司西酞普兰对开臂停留时间主效应不显著（P>0.05），对白盒停留时间主效应显著（P<0.05），进一步分析发现，给予溶媒处理，CUS组大鼠开臂停留时间及白盒停留时间较对照组大鼠均缩短（P<0.05），而给予艾司西酞普兰处理可以逆转CUS引起开臂停留时间及白盒停留时间的缩短（P<0.05）。LC-MS结果：在前额叶皮质中，CUS与艾司西酞普兰对γ-氨基丁酸（GABA）浓度及谷氨酸（Glu）/GABA存在交互作用（P<0.05），CUS对GABA浓度、Glu/GABA主效应均不显著（P>0.05），艾司西酞普兰对GABA浓度、Glu/GABA主效应均显著（P<0.05）。进一步分析显示，给予溶媒处理，CUS组前额叶皮质中GABA浓度较对照组下降（P<0.05），Glu/GABA较对照组升高（P<0.05），而给予艾司西酞普兰处理可以逆转GABA浓度下降和Glu/GABA升高（P=0.005）。在海马中未发现氨基酸代谢改变。结论　前额叶皮质GABA可能参与慢性应激诱导的抑郁样行为发生，艾司西酞普兰可显著逆转抑郁模型大鼠出现的抑郁样及焦虑样行为，并可改善前额叶皮质GABA浓度的异常。

关键词: 抑郁症；&gamma, -氨基丁酸；艾司西酞普兰；额叶前皮质；慢性不可预见性应激

Abstract: Background　Major depressive disorder（MDD）is a common chronic and recurrent illness，causing enormous global economic burden.Its pathogenesis remains unclear although relevant studies have been continuing for decades.Objective　To investigate the changes of inhibitory amino acids in the brain of depression-like rats model before and after escitalopram treatment.Methods　 This study was implemented from June 2016 to March 2017.Thirty-eight adult male SD rats were selected，and 18 of them were treated with chronic unpredictable stress（CUS）for 28 days（CUS group），other 20 were normally reared without CUS（control group）.Since the 15th day of intervention，21 rats〔9 in CUS group（CUS+escitalopram subgroup） and 12 in control group（control + escitalopram subgroup〕 were intraperitoneally injected with escitalopram，while other 17 rats〔9 in CUS group（CUS + vehicle subgroup） and 8 in control group（control + vehicle subgroup）〕 were intraperitoneally injected with 0.9% normal saline solution.Body weight gain，sucrose preference value measured by sucrose preference test（SPT），horizontal movement distance and time spent in the central area measured by the open field test（OFT），time used for exploring the open arms in the elevated plus-maze test（EPM），and time consumed in white box in the black box and white box testing（BWT）were used to assess the changes of depression-and anxiety-like behaviors.A high performance liquid chromatography-mass spectrometry（LC-MS）was used to investigate the changes of amino acid metabolism in the prefrontal cortex and hippocampus in rats.Results　Behavioral results：there was no interaction effect between CUS and escitalopram on the weight gain，sucrose preference percentage value，horizontal movement distance and time spent in the central area in OFT（P>0.05）.A significant main effect of CUS on the weight gain，sucrose preference value，and the horizontal movement distance in OFT was found（P<0.05），while no significant main effect of CUS on time spent in the central area in OFT was found（P>0.05）.A significant main effect of escitalopram on the sucrose preference value，and the horizontal movement distance in OFT was found（P<0.05），while no significant main effect of escitalopram on the weight gain，and time spent in the central area in OFT was found（P>0.05）.There was an interaction effect between CUS and escitalopram on the time spent on exploring open arms in EPM and on the time consumed in white box in BWT（P<0.05）.A significant main effect of CUS and escitalopram on the time consumed in white box in BWT was found（P<0.05），but no such effect was found on the time spent on exploring open arms in EPM（P>0.05）.The post hoc analysis showed that the mean time spent on exploring open arms in EPM and that consumed in white box in BWT in CUS group were both significantly decreased compared with control group（P<0.05）and escitalopram shortened the time spent on exploring open arms in EPM and that consumed in white box in BWT（P<0.05）.LC-MS results: there was an interaction effect between CUS and escitalopram on the concentration of γ-aminobutyric acid（GABA）and the ratio of glutamate（Glu）/GABA in the prefrontal cortex（P<0.05）.There was no significant main effect of CUS on the concentration of GABA and Glu / GABA（P>0.05）.A significant main effect of escitalopram on the concentration of GABA and Glu/GABA was found（P<0.05）.The post hoc analysis showed that the concentration of GABA was significantly decreased and Glu/GABA was significantly increased in the prefrontal cortex in CUS group compared with control group（P<0.05）and escitalopram rescued the concentration of GABA and Glu/GABA（P=0.005）.However，no changes in amino acid metabolism were found in the hippocampus.Conclusion　GABA in the prefrontal cortex may be involved in the occurrence of depression-like behaviors induced by CUS.escitalopram may significantly rescue depression-like and anxiety-like behaviors and improve the abnormal concentration of GABA in the prefrontal cortex induced by CUS.

Key words: Depressive disorder, GABA, Escitalopram, Prefrontal cortex, Chronic unpredictable mild stress

丁楷模,李冰玥,张咪咪,等. 艾司西酞普兰对抑郁模型大鼠脑内抑制性氨基酸变化的作用[J]. 中国全科医学, 2021, 24(20): 2547-2554. DOI: 10.12114/j.issn.1007-9572.2021.00.469.
DING Kaimo,LI Bingyue,ZHANG Mimi, et al. Changes of Inhibitory Amino Acids in the Brain of Depression Model Rats before and after Escitalopram Treatment　[J]. Chinese General Practice, 2021, 24(20): 2547-2554. DOI: 10.12114/j.issn.1007-9572.2021.00.469.

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艾司西酞普兰对抑郁模型大鼠脑内抑制性氨基酸变化的作用

Changes of Inhibitory Amino Acids in the Brain of Depression Model Rats before and after Escitalopram Treatment

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