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UBC Theses and Dissertations

The development of an animal model of depression : a focus on anhedonia Barr, Alasdair McMillan

Abstract

Depression is one of the more frequent psychiatric disorders, that continues to exact a tremendous cost to society, in both human and financial terms. Novel therapies for the treatment of this disorder will originate from preclinical research, which is based upon the use of animal models. In the current dissertation, we describe the development of two animal models of depression. The first three experiments describe in detail a series of studies that were conducted to provide further validation of the Chronic Mild Stress (CMS) model of depression. Despite initially promising results in Experiment 1, in which CMS-treated rats exhibited significant decreases in appetitive investigations for a sucrose solution, the finding of Experiments 2 signified that there were fundamental flaws in this model, as CMS-treated rats failed to display reduced motivation to obtain a similar solution under a progressive ratio schedule of reinforcement. In Experiment 3, in vivo microdialysis in the ventral striatum was used to demonstrate that CMS-treated rats failed to exhibit the hypodopaminergia that is hypothesized to lead to depressogenic behaviours in these animals. The results of Experiments 2 and 3 rendered the CMS paradigm unsuitable for further research and questioned its validity as a legitimate model of depression. In Experiments 4-7, we describe the extensive research that we undertook to validate an alternate rodent model of depression, namely the Psychostimulant Withdrawal model. The results of Experiments 4 indicated a reduced motivation of rats to obtain a sucrose solution under a progressive ratio schedule, while Experiment 5 indicated that this model induced sexual deficits in rats comparable to those seen in unipolar depression; Experiment 6 demonstrated protracted negative contrast effects in drug withdrawn animals, hence suggesting this paradigm is amenable to modeling subtle psychological processes. In Experiment 7, we demonstrate that the model responds to an appropriate therapeutic strategy as rats exhibited an earlier recovery of rewarding brain self-stimulation following repeated electroconvulsive shock. The dissertation commences with a general review of depression and animal models of this disorder; it concludes with an evaluation of the Psychostimulant Withdrawal model of depression, integrated with the findings of the current dissertation.

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