Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599-7178, United States.
Pharmacol Biochem Behav. 2010 Aug;96(2):206-10. doi: 10.1016/j.pbb.2010.05.006. Epub 2010 May 12.
Previous work established that saredutant, an NK2 receptor antagonist, has antidepressant and anxiolytic-antistress effects in a variety of rodent models. The purpose of the present investigation was two-fold: to confirm the antidepressant-like effects of saredutant using a genetic animal model of depression, the Flinders Sensitive Line (FSL) rat, and to assess whether saredutant might synergize with desipramine to produce antidepressant-like effects at doses not seen with the individual compounds. For the main study the FSL rats and the control Flinders Resistant Line (FRL) rats were treated with various doses of saredutant (1, 3, and 10mg/kg in FSL, 3mg/kg in the FRL), the tricyclic desipramine (5mg/kg) as a positive control, or vehicle for 14 consecutive days and then tested in the social interaction and forced swim tests about 22h later. For the synergism study, the FSL rats were treated with subeffective doses of saredutant (1mg/kg) or desipramine (2.5mg/kg) or both for 14 consecutive days and then the behavior tests were performed. Saredutant, like desipramine, increased social interaction (at 10mg/kg) reduced immobility (at 3 and 10mg/kg), and had no effect on locomotor activity in the FSL rats, but did not affect any of these variables in the FRL rat. Neither saredutant (1mg/kg) nor desipramine (2.5mg/kg) affected any variable by themselves; however, their combination significantly lowered swim test immobility. These findings confirm the antidepressant-like effects of saredutant in a genetic animal model of depression. Moreover, they suggest that saredutant might also act as an add-on therapy for individuals who are not fully responding to their antidepressant treatment.
先前的工作已经证实，NK2 受体拮抗剂沙雷肽胺在多种啮齿动物模型中具有抗抑郁和抗焦虑-抗应激作用。本研究的目的有两个：一是通过抑郁的遗传动物模型——弗林德斯敏感系（FSL）大鼠，证实沙雷肽胺的抗抑郁样作用；二是评估沙雷肽胺是否可以与去甲丙咪嗪协同作用，产生在单独使用这些化合物时未见的抗抑郁样效果。在主要研究中，FSL 大鼠和对照弗林德斯抗性系（FRL）大鼠连续 14 天接受不同剂量的沙雷肽胺（FSL 中为 1、3 和 10mg/kg，FRL 中为 3mg/kg）、三环类去甲丙咪嗪（5mg/kg）作为阳性对照或载体处理，然后约 22 小时后在社会互动和强迫游泳测试中进行测试。在协同作用研究中，FSL 大鼠连续 14 天接受沙雷肽胺（1mg/kg）或去甲丙咪嗪（2.5mg/kg）或两者的亚有效剂量治疗，然后进行行为测试。沙雷肽胺与去甲丙咪嗪一样，增加了社会互动（10mg/kg），减少了不动性（3mg/kg 和 10mg/kg），但对 FSL 大鼠的运动活动没有影响，但对 FRL 大鼠没有影响。沙雷肽胺（1mg/kg）或去甲丙咪嗪（2.5mg/kg）本身均不影响任何变量；然而，它们的组合显著降低了游泳测试中的不动性。这些发现证实了沙雷肽胺在抑郁的遗传动物模型中的抗抑郁样作用。此外，它们表明沙雷肽胺也可能作为一种附加疗法，用于那些对抗抑郁治疗反应不完全的个体。
