Animal Models of Depression

拟议中的项目将检查葛兰素史克公司提供的一些药物的效果， 评估这些药物潜在的抗抑郁能力。将进行评估 主要使用两种新的动物模型。其中之一是一种新的筛选技术， 抗抑郁治疗，这似乎是更有选择性的检测有效的抗抑郁药物比以前开发的筛选技术。该模型使用了一种选择性繁殖的大鼠品系，即游泳测试易感大鼠（Swim-test Susceptible rat，或Susceptible rat），当其在游泳测试之前暴露于轻度应激情况下时，其在游泳测试中的主动行为减少的脆弱性增加。抗抑郁药物的长期治疗被发现可以阻止这种脆弱性;其他精神活性药物的长期治疗没有效果。因此，该测试似乎可用于检测抗抑郁药物，并将其与其他精神活性药物区分开来。第二个模型是一种新的抑郁症啮齿动物模型，其中动物显示出持久的抑郁症症状（即，20-35天持续时间）。在先前存在的啮齿动物模型中，抑郁样症状是暂时的（即，持续2-4天）;因此，先前的模型不允许在抑郁症状发作后施用药物，以便可以观察到在人类中发生的恢复。这种新模式允许这样做。出现长期症状的模型使用另一种选择性繁殖的大鼠-多动大鼠。除了在这些模型中测试药物外，还将在标准Porsolt游泳测试中测试药物。最后，提出了进一步发展动物模型的建议。在这方面，我们将（a）尝试进一步完善多动大鼠作为研究双相情感障碍的潜在模型，和（B）使我们选择性繁殖的大鼠进行母体分离，作为产生情感障碍的改进模型的可能手段。

The proposed project will examine effects of a number of drugs supplied by GlaxoSmithKline, assessing these drugs for their potential antidepressant capability. Assessment will be made primarily using two new animal models. One of these is a new screening technique for effective antidepressant treatments that appears to be more selective for detecting effective antidepressant drugs than is previously-developed screening techniques. This model uses a selectively-bred line of rats, the Swim-test Susceptible rat (or Susceptible rat), that shows heightened vulnerability to having its active behavior in a swim test reduced when it is exposed to a mild stress situation prior to the swim test. Chronic treatment with antidepressant drugs has been found to block this vulnerability; chronic treatment with other psychoactive drugs is without effect. Thus, this test appears usable to detect antidepressant drugs, and to discriminate these from other psychoactive drugs. The second model is a new rodent model of depression in which the animals show long-lasting symptoms of depression (i.e., 20-35 days duration) following a single exposure to a stressful situation. In previously-existing rodent models, depression-like symptoms have been transitory (i.e., lasted 2-4 days); thus, previous models did not allow drugs to be administered after onset of depressive symptoms so that recovery could be observed as it occurs in humans. This new model permits this to be done. The model in which long-lasting symptoms occur uses another selectively-bred rat- the Hyperactive rat. In addition to testing of drugs in these models, drugs also will be tested in a standard Porsolt swim test. Finally, additional development of animal models is proposed. In this regard, we will (a) attempt to further perfect the Hyperactive rat as a potential model for study of bipolar disorder, and (b) subject our selectively-bred rats to maternal separation as a possible means of producing improved models of affective disorders.