Willner Paul, Gruca Piotr, Lason Magdalena, Tota-Glowczyk Katarzyna, Litwa Ewa, Niemczyk Monika, Papp Mariusz
Department of Psychology, Swansea University, Swansea, UK.
Department of Pharmacology, Polish Academy of Sciences, Institute of Pharmacology, Krakow, Poland.
Behav Pharmacol. 2019 Apr;30(2 and 3-Spec Issue):239-250. doi: 10.1097/FBP.0000000000000431.
A recent review proposed four criteria for an animal model of treatment-resistant depression (TRD): a phenotypic resemblance to a risk factor for depression; enhanced response to stress; nonresponse to antidepressant drugs and response to treatments effective in TRD, such as deep brain stimulation (DBS) of the prefrontal cortex or ketamine. Chronic mild stress (CMS) provides a valid model of depression; the Wistar-Kyoto (WKY) rat is considered to be nonresponsive to antidepressant drugs. Here, we applied CMS to WKY rats. WKY and Wistar rats were exposed to CMS, then treated with saline, imipramine, citalopram or venlafaxine. After 5 weeks of CMS and 3 weeks of drug treatment, all WKY groups were implanted unilaterally with DBS electrodes in the prefrontal cortex, and examined in sucrose intake, elevated plus maze (EPM; decreased entries and time in the open arms) and novel object recognition (decreased exploration) tests, following 2×2 h of DBS. CMS decreased sucrose intake, open arm entries on the EPM, and object recognition. Relative to Wistars, WKY rats showed evidence of increased emotionality in the EPM and novel object recognition tests, and a greater impact of CMS on body weight gain and open arm entries. Wistars responded to drug treatment with an increase in sucrose intake but WKY were nonresponsive to drug treatment on all three behavioural tests. With one exception, DBS reversed the anhedonic, anxiogenic and dyscognitive effects of CMS in all groups of WKY rats. In a further experiment, subacute ketamine (10 mg/kg) also normalized behaviour on all three tests. We conclude that WKY rats subjected to CMS meet all four criteria for a valid model of TRD, and provide a basis for studying the mechanism of action of DBS.
最近的一项综述提出了难治性抑郁症（TRD）动物模型的四个标准：与抑郁症风险因素的表型相似性；对应激的反应增强；对抗抑郁药物无反应以及对TRD有效治疗的反应，如前额叶皮质的深部脑刺激（DBS）或氯胺酮。慢性轻度应激（CMS）提供了一个有效的抑郁症模型；Wistar-Kyoto（WKY）大鼠被认为对抗抑郁药物无反应。在此，我们将CMS应用于WKY大鼠。将WKY和Wistar大鼠暴露于CMS，然后用生理盐水、丙咪嗪、西酞普兰或文拉法辛进行治疗。在进行5周的CMS和3周的药物治疗后，所有WKY组均单侧植入前额叶皮质的DBS电极，并在2×2小时的DBS后，进行蔗糖摄取、高架十字迷宫（EPM；开放臂进入次数和停留时间减少）和新物体识别（探索减少）测试。CMS降低了蔗糖摄取、EPM上的开放臂进入次数和物体识别能力。相对于Wistar大鼠，WKY大鼠在EPM和新物体识别测试中表现出情绪增加的迹象，并且CMS对体重增加和开放臂进入次数的影响更大。Wistar大鼠对药物治疗的反应是蔗糖摄取增加，但WKY大鼠在所有三项行为测试中对药物治疗均无反应。除一个例外，DBS逆转了所有WKY大鼠组中CMS的快感缺失、焦虑和认知障碍效应。在进一步的实验中，亚急性氯胺酮（10mg/kg）也使所有三项测试中的行为恢复正常。我们得出结论，接受CMS的WKY大鼠符合TRD有效模型的所有四个标准，并为研究DBS的作用机制提供了基础。
