中央杏仁核中促肾上腺皮质激素释放激素神经元调控吗啡戒断诱发的负性情绪
王雪颖¹, 余敏², 马兰¹, 王菲菲¹, 江长优^1,*
1复旦大学基础医学院医学神经生物学国家重点实验室，药理研究中心，上海 200032；²复旦大学基础医学院临床医学八年制，上海 200032
摘要
成瘾药物戒断诱发负性情绪并伴有脑内应激系统的激活，是导致负性强化并使成瘾个体持续觅药和复吸的重要因素。促肾上腺皮质激素释放激素(corticotrophin-releasing hormone, CRH)是应激系统发挥生理作用的重要递质，在介导焦虑、恐惧等负性情绪的重要核团——中央杏仁核(central amygdala, CeA)中广泛分布。然而在CeA中这类表达CRH的神经元在成瘾药物戒断引发的负性情绪中作用还并不清楚。本研究采用CRH-Cre转基因小鼠，通过依赖Cre-LoxP系统的化学遗传学方法特异性激活或抑制小鼠CeA中的CRH神经元，结合条件性位置厌恶(conditioned place aversion, CPA)、高架十字迷宫、自主活动能力测试等行为学实验，探究CeA中CRH神经元对小鼠吗啡戒断产生的厌恶、焦虑等负性情绪的影响。结果显示，抑制CeA中CRH神经元可抑制小鼠吗啡戒断诱导的CPA形成，并降低小鼠焦虑水平。直接激活CeA中CRH神经元可使未经历吗啡暴露的小鼠产生CPA和焦虑。吗啡自然戒断和CRH神经元的活性改变对小鼠的自主活动能力都没有显著影响。以上结果提示，CeA中CRH神经元参与调控小鼠吗啡戒断诱导的负性情绪。本研究为药物成瘾与复吸机制提供了理论依据。


关键词： 中央杏仁核; 促肾上腺皮质激素释放激素; 吗啡戒断; 负性情绪
分类号：R964

Corticotrophin-releasing hormone neurons in the central amygdala mediate morphine withdrawal-induced negative emotions
WANG Xue-Ying¹, YU Min², MA Lan¹, WANG Fei-Fei¹, JIANG Chang-You^1,*
1The State Key Laboratory of Medical Neurobiology and Pharmacology Research Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China；²Clinic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
Abstract
Drugs of abuse leads to adaptive changes in the brain stress system, and produces negative affective states including aversion and anxiety after drug use is terminated. Corticotrophin-releasing hormone (CRH) is the main transmitter in control of response to stressors and is neuronal enriched in the central amygdala (CeA), a sub-region of the extended amygdala playing an important role in integrating emotional information and modulating stress response. The effect of CRH neurons in CeA on the negative emotions on morphine na?ve and withdrawal mice is unclear. Thus, we utilized CRH-Cre transgenic mice injected with AAV-mediated Designer Receptors Exclusively Activated By Designer Drugs (DREADDs) to chemogenetically manipulate CRH neurons in CeA. And methods of behavior analysis, including conditioned place aversion (CPA), elevated plus maze and locomotor activity tests, were used to investigate morphine withdrawal-induced negative emotions in mice. The results showed that, inhibiting CRH neurons of CeA decreased the formation of morphine withdrawal-induced CPA, as well as the anxiety level of CRH-Cre mice. Furthermore, specifically activating CRH neurons in CeA evoked CPA and anxiety of morphine na?ve mice. Neither inhibiting nor activating CRH neurons had effects on their locomotor activity. These results suggest that CRH neurons in CeA are involved in the mediation of morphine withdrawal-induced negative emotion in mice, providing a theoretical basis for drug addiction and relapse mechanism.
Key words: central amygdala; corticotrophin-releasing hormone; morphine withdrawal; negative emotion

收稿日期：2019-03-03　　录用日期：2019-04-23
通讯作者：江长优　　E-mail: jiangcy@fudan.edu.cn
DOI: 10.13294/j.aps.2019.0078
引用本文：
王雪颖, 余敏, 马兰, 王菲菲, 江长优. 中央杏仁核中促肾上腺皮质激素释放激素神经元调控吗啡戒断诱发的负性情绪[J]. 生理学报 2019; 71 (6): 824-832.
WANG Xue-Ying, YU Min, MA Lan, WANG Fei-Fei, JIANG Chang-You. Corticotrophin-releasing hormone neurons in the central amygdala mediate morphine withdrawal-induced negative emotions. Acta Physiol Sin 2019; 71 (6): 824-832 (in Chinese with English abstract).



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