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氯胺酮可逆转应激诱导的抑郁样行为并增加前扣带回中的γ-氨基丁酸水平:一项在大鼠中进行的11.7 T氢质子磁共振波谱研究

Ketamine reverses stress-induced depression-like behavior and increased GABA levels in the anterior cingulate: an 11.7 T 1H-MRS study in rats.

作者信息

Perrine Shane A, Ghoddoussi Farhad, Michaels Mark S, Sheikh Imran S, McKelvey George, Galloway Matthew P

机构信息

Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.

Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA.

出版信息

Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jun 3;51:9-15. doi: 10.1016/j.pnpbp.2013.11.003. Epub 2013 Nov 15.

Abstract

Gamma-aminobutyric acid (GABA) is the major inhibitory amino acid neurotransmitter in the brain and is primarily responsible for modulating excitatory tone. Clinical neuroimaging studies show decreased GABA levels in the anterior cingulate of patients with mood disorders, including major depressive disorder. Chronic unpredictable stress (CUS) is an animal model thought to mimic the stressful events that may precipitate clinical depression in humans. In this study male Sprague-Dawley rats were subjected to a modified CUS paradigm that used a random pattern of unpredictable stressors twice daily for 10 days to explore the early developmental stages of depression-like endophenotypes. Control rats were handled daily for 10 days. Some rats from each treatment group received an injection of ketamine (40 mg/kg) after the final stressor. One day following the final stressor rats were tested for behavioral effects in the forced swim test and then euthanized to collect trunk blood and anterior cingulate brain samples. GABA levels were measured in anterior cingulate samples ex vivo using proton magnetic resonance spectroscopy ((1)H-MRS) at 11.7 T. Animals subjected to CUS had lower body weights, higher levels of blood corticosterone, and increased immobility in the forced swim test; all of which suggest that the stress paradigm induced a depression-like phenotype. GABA levels in the anterior cingulate were significantly increased in the stressed animals compared to controls. Administration of ketamine on the last day of treatment blunted the depression-like behavior and increased GABA levels in the anterior cingulate following CUS. These data indicate that stress disrupts GABAergic signaling, which may over time lead to symptoms of depression and ultimately lower basal levels of cortical (1)H-MRS GABA that are seen in humans with depression. Furthermore, the data suggests that ketamine modulates cortical GABA levels as a mechanism of its antidepressant activity.

摘要

γ-氨基丁酸(GABA)是大脑中主要的抑制性氨基酸神经递质,主要负责调节兴奋性神经冲动。临床神经影像学研究表明,患有情绪障碍(包括重度抑郁症)的患者前扣带回中的GABA水平降低。慢性不可预测应激(CUS)是一种动物模型,被认为可模拟可能促使人类临床抑郁症发作的应激事件。在本研究中,雄性斯普拉格-道利大鼠接受了改良的CUS范式,即每天两次采用随机模式施加不可预测的应激源,持续10天,以探究类似抑郁的内表型的早期发育阶段。对照大鼠每天接受处理,持续10天。每个处理组的一些大鼠在最后一次应激源刺激后注射氯胺酮(40 mg/kg)。在最后一次应激源刺激后的一天,对大鼠进行强迫游泳试验以检测行为效应,然后实施安乐死以采集躯干血液和前扣带回脑样本。使用11.7 T的质子磁共振波谱((1)H-MRS)在体外测量前扣带回样本中的GABA水平。遭受CUS的动物体重较低、血液皮质酮水平较高,并且在强迫游泳试验中的不动时间增加;所有这些都表明应激范式诱发了类似抑郁的表型。与对照组相比,应激动物前扣带回中的GABA水平显著升高。在处理的最后一天给予氯胺酮可减轻类似抑郁的行为,并增加CUS后前扣带回中的GABA水平。这些数据表明,应激会破坏GABA能信号传导,随着时间的推移可能导致抑郁症状,并最终降低抑郁症患者中所见的皮质(1)H-MRS GABA的基础水平。此外,数据表明氯胺酮通过调节皮质GABA水平作为其抗抑郁活性的一种机制。

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