Major Depressive Disorder (clinical depression) is a severe and potentially incapacitating mental illness that is common in children and adolescents, with an estimated lifetime prevalence of 15 -20 % in this population. An important difference between clinical depression in children and adolescents, as compared to adults, is its response to antidepressant drugs. Tricyclic antidepressants have not been shown to be effective in treatment of child and adolescent clinical depression. Although antidepressant drugs have numerous neurochemical actions, the therapeutic mechanisms of action of antidepressant drugs in relieving depression remain unknown. In non-depressed persons antidepressant drugs are not euphoriant or stimulant. Therefore, investigations related to which of the many neurochemical effects of antidepressant drugs are functionally related to their therapeutic efficacy in relieving depression requires research using a behavioral animal model of clinical depression. To better understand the neurobiology underlying the differences between children and adolescents, and adults in the response to pharmacological treatment of clinical depression, animal models of childhood and adolescent depression are needed. Currently, there are no established juvenile animal models of clinical depression. Although the models developed in adult animals can serve as a starting point, they must be adapted and validated in juvenile animals due the many differences between juvenile and adult animals. The overall goal of this proposal is to assess the validity and usefulness of two well-established rat animal models of adult clinical depression as models of childhood and adolescent clinical depression. Specifically, we propose to assess the usefulness of the forced-swim test and of learned helplessness as animal models for clinical depression in juvenile rats. The key questions which are addressed by this proposal are: 1) Do juvenile rats respond to antidepressant drugs with decreased immobility in the forced swim? 2) Do juvenile rats develop learned helplessness after inescapable stress in both the acute and persistent paradigms, as demonstrated by shuttlebox testing? 3) Do juvenile rats respond to antidepressant drugs in the both acute and persistent learned helplessness paradigms with decreased escape latencies in shuttlebox testing? Ultimately, the models may facilitate a better understanding of the underlying neurobiology of clinical depression, and serve as predictive measures of antidepressant efficacy in children and adolescents.
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