1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India.
2 Neuroscience Biology, Bristol-Myers Squibb Company, Wallingford, CT, USA.
J Psychopharmacol. 2019 Jan;33(1):25-36. doi: 10.1177/0269881118812102. Epub 2018 Nov 28.
A significant proportion of patients suffering from major depression fail to remit following treatment and develop treatment-resistant depression. Developing novel treatments requires animal models with good predictive validity. MRL/lpr mice, an established model of systemic lupus erythematosus, show depression-like behavior.
We evaluated responses to classical antidepressants, and associated immunological and biochemical changes in MRL/lpr mice.
MRL/lpr mice showed increased immobility in the forced swim test, decreased wheel running and sucrose preference when compared with the controls, MRL/MpJ mice. In MRL/lpr mice, acute fluoxetine (30 mg/kg, intraperitoneally (i.p.)), imipramine (10 mg/kg, i.p.) or duloxetine (10 mg/kg, i.p.) did not decrease the immobility time in the Forced Swim Test. Interestingly, acute administration of combinations of olanzapine (0.03 mg/kg, subcutaneously)+fluoxetine (30 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.)+fluoxetine (30 mg/kg, i.p.) retained efficacy. A single dose of ketamine but not three weeks of imipramine (10 mg/kg, i.p.) or escitalopram (5 mg/kg, i.p.) treatment in MRL/lpr mice restored sucrose preference. Further, we evaluated inflammatory, immune-mediated and neuronal mechanisms. In MRL/lpr mice, there was an increase in autoantibodies' titers, [3H]PK11195 binding and immune complex deposition. There was a significant infiltration of the brain by macrophages, neutrophils and T-lymphocytes. p11 mRNA expression was decreased in the prefrontal cortex. Further, there was an increase in the 5-HTR expression, plasma corticosterone and indoleamine 2,3-dioxygenase activity.
In summary, the MRL/lpr mice could be a useful model for Treatment Resistant Depression associated with immune dysfunction with potential to expedite antidepressant drug discovery.
相当一部分患有重度抑郁症的患者在治疗后未能缓解，并发展为治疗抵抗性抑郁症。开发新的治疗方法需要具有良好预测有效性的动物模型。MRL/lpr 小鼠是系统性红斑狼疮的一种已建立的模型，表现出类似抑郁的行为。
我们评估了经典抗抑郁药在 MRL/lpr 小鼠中的反应以及相关的免疫和生化变化。
与对照的 MRL/MpJ 小鼠相比，MRL/lpr 小鼠在强迫游泳试验中表现出更高的不动性，轮跑和蔗糖偏好减少。在 MRL/lpr 小鼠中，急性氟西汀（30mg/kg，腹腔内（i.p.）），丙咪嗪（10mg/kg，i.p.）或度洛西汀（10mg/kg，i.p.）不能减少强迫游泳试验中的不动时间。有趣的是，奥氮平（0.03mg/kg，皮下注射）+氟西汀（30mg/kg，i.p.）或安非他酮（10mg/kg，i.p.）+氟西汀（30mg/kg，i.p.）的急性联合给药仍保留疗效。单次给予氯胺酮但不是 3 周的丙咪嗪（10mg/kg，i.p.）或依地普仑（5mg/kg，i.p.）治疗可恢复蔗糖偏好。此外，我们评估了炎症，免疫介导和神经元机制。在 MRL/lpr 小鼠中，自身抗体滴度，[3H]PK11195 结合和免疫复合物沉积增加。大脑中有巨噬细胞，中性粒细胞和 T 淋巴细胞浸润。前额叶皮质中的 p11mRNA 表达减少。此外，5-HTR 表达，血浆皮质酮和吲哚胺 2,3-双加氧酶活性增加。
总之，MRL/lpr 小鼠可能是一种有用的模型，用于与免疫功能障碍相关的治疗抵抗性抑郁症，具有加速抗抑郁药物发现的潜力。
