Bacillus Calmette-Guerin vaccine induces a selective serotonin reuptake inhibitor (SSRI)-resistant depression like phenotype in mice
Bacillus Calmette-Guerin vaccine induces a selective serotonin reuptake inhibitor (SSRI)-resistant depression like phenotype in mice
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DOI：
10.1016/j.bbi.2014.06.205
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发表时间：
2014-11-01
影响因子：
15.1
通讯作者：
Vikramadithyan, Reeba Kannimel
中科院分区：
文献类型：
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作者：
Kumar, K. Vijaya;Rudra, Anjuman;Vikramadithyan, Reeba Kannimel
临床前研究表明，注射卡介苗（BCG）疫苗会诱导小鼠出现抑郁样行为；然而，抗抑郁药物治疗的效果此前尚未有报道。在本研究中，我们通过给 BALB/c 小鼠注射卡介苗疫苗来诱导抑郁样行为。卡介苗治疗产生了严重的血清病，表现为体重减轻、自发运动活动减少和自愿轮跑活动减少。 BCG 治疗还提高了血浆 IL6 和 IFN γ 水平，并显着激活了肺 IDO 活性。在血清疾病相关行为完全恢复的时间点（即第 14 天），BCG 治疗的小鼠在强迫游泳测试 (FST) 和悬尾测试 (TST) 中表现出不动性显着增加，表明存在促抑郁表型。我们观察到，与盐水治疗的小鼠相比，BGC 治疗的小鼠皮质和海马区域的 [H-3]PK11195 结合显着增加，表明存在明显的神经炎症。对 BCG 治疗小鼠 FST 行为的药理学评估表明，小鼠对选择性血清素再摄取抑制剂 (SSRI) 氟西汀和艾司西酞普兰具有选择性耐药性。相比之下，三环类抗抑郁药丙咪嗪、双重血清素/去甲肾上腺素再摄取抑制剂（SNRI）度洛西汀和双重多巴胺/去甲肾上腺素再摄取抑制剂（DNRI）诺米芬辛在这些小鼠中保留了抗抑郁功效。 SSRIs 急性治疗缺乏疗效不能用药物暴露或血清素转运蛋白 (SERT) 占用率的差异来解释。我们的结果表明，卡介苗疫苗诱导的抑郁样行为对 SSRI 具有选择性耐药性，并且有可能用于评估正在开发的治疗人类 SSRI 耐药性的新型治疗药物。 (C) 2014 Elsevier Inc. 保留所有权利。
Preclinical studies have shown that administration of Bacillus Calmette-Guerin (BCG) vaccine induces depression-like behaviors in mice; however, the effect of antidepressant drug treatment has not been reported earlier. In the present study, we induced depression-like behavior by administering BCG vaccine to BALB/c mice. BCG treatment produced robust serum sickness as shown by a decrease in body weight, reduced spontaneous locomotor activity and reduced voluntary wheel running activity. BCG treatment also elevated plasma IL6 and IFN gamma levels and produced a marked activation of lung IDO activity. At a time point when serum sickness-related behaviors had fully recovered (i.e., day 14) BCG-treated mice showed a significant increase in immobility in the forced swim test (FST) and tail suspension test (TST) indicative of a pro-depressant phenotype. We observed significant increase in [H-3]PK11195 binding in cortex and hippocampus regions of BGC-treated mice in comparison to saline-treated mice indicating prominent neuroinflammation. Pharmacological evaluation of FST behavior in BCG-treated mice demonstrated selective resistance to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and escitalopram. In contrast the tricyclic antidepressant imipramine, the dual serotonin/norepinephrine reuptake inhibitor (SNRI) duloxetine, and the dual dopamine/norepinephrine reuptake inhibitor (DNRI) nomifensine retained antidepressant efficacy in these mice. The lack of efficacy with acute treatment with SSRIs could not be explained either by differences in drug exposure or serotonin transporter (SERT) occupancy. Our results demonstrate that BCG-vaccine induced depression like behavior is selectively resistant to SSRIs and could potentially be employed to evaluate novel therapeutic agents being developed to treat SSRI-resistance in humans. (C) 2014 Elsevier Inc. All rights reserved.