Kokras Nikolaos, Antoniou Katerina, Mikail Hudu G, Kafetzopoulos Vasilios, Papadopoulou-Daifoti Zeta, Dalla Christina
Department of Pharmacology, Medical School, University of Athens, Greece; First Department of Psychiatry, Eginition Hospital, Medical School, University of Athens, Greece.
Department of Pharmacology, Medical School, University of Ioannina, Greece.
Neuropharmacology. 2015 Dec;99:408-21. doi: 10.1016/j.neuropharm.2015.03.016. Epub 2015 Apr 1.
In preclinical studies screening for novel antidepressants, male and female animals should be used. However, in a widely used antidepressant test, the forced swim test (FST), sex differences between males and females are not consistent. These discrepancies may discourage the inclusion of females in FST studies. In order to overcome this problem and provide a detailed insight regarding the use of female animals in the FST, we designed the following experiment and we performed a thorough analysis of the relevant literature. Male and female Wistar adult rats were subjected to the FST and sertraline was used as an antidepressant in two doses (10 mg/kg and 40 mg/kg, 3 injections in 24 h). Rodents were subjected in the two FST sessions during all possible combinations of the estrous cycle stages. We found that females exhibited higher levels of immobility than males and this sex difference was alleviated following antidepressant treatment. Sertraline at both doses enhanced swimming in both sexes, but females appeared more responsive to lower sertraline doses regarding immobility levels. Surprisingly, the high sertraline dose enhanced climbing particularly in proestrous and diestrous. Marked sex differences were also observed in the frequency of head swinging, with females exhibiting lower counts than males. Conclusively, when screening for new antidepressants, it is recommended to use standard FST procedures and if possible to include females in all phases of the cycle. Using only one dose of an investigational drug in females in certain phases of the cycle could result to false negative results.
在筛选新型抗抑郁药的临床前研究中，应使用雄性和雌性动物。然而，在一种广泛使用的抗抑郁药测试即强迫游泳测试（FST）中，雄性和雌性之间的性别差异并不一致。这些差异可能会阻碍在FST研究中纳入雌性动物。为了克服这个问题并深入了解在FST中使用雌性动物的情况，我们设计了以下实验，并对相关文献进行了全面分析。成年雄性和雌性Wistar大鼠接受FST，舍曲林作为抗抑郁药使用两种剂量（10毫克/千克和40毫克/千克，在24小时内注射3次）。啮齿动物在发情周期各阶段的所有可能组合期间接受两次FST测试。我们发现，雌性比雄性表现出更高的不动水平，并且这种性别差异在抗抑郁药治疗后得到缓解。两种剂量的舍曲林均增强了两性的游泳能力，但就不动水平而言，雌性似乎对较低剂量的舍曲林更敏感。令人惊讶的是，高剂量舍曲林尤其在发情前期和动情间期增强了攀爬能力。在摆头频率方面也观察到明显的性别差异，雌性的次数低于雄性。总之，在筛选新的抗抑郁药时，建议使用标准的FST程序，并且如果可能的话，在周期的所有阶段都纳入雌性动物。在周期的某些阶段仅对雌性使用一种剂量的研究药物可能会导致假阴性结果。
