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.
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