A study of the WKY as a rat model of depression

Doctoral Thesis


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University of Cape Town

Major depression is a heterogeneous neuropsychiatric disorder with a significant genetic - stress interaction. The Wistar - Kyoto (WKY) rat displays hypersensitivity to stress and depression - like behaviour and is used as a genetic model of major depression. However, the depression - and anxiety - like behaviour of WKY has not yet been compared between the WKY/NCrl and WKY/NHsd substrains when characterizing WKY as a rat model of depression. WKY rats respond to noradrenergic and dopaminergic drugs but not to selective serotonin reuptake inhibitors (SSRIs) and are therefore suggested to model treatment resistant depression. The early life stress of maternal separation (MS) has been used to produce a rodent model of depression in Sprague - Dawley (SD) rats but results have been variable. It was therefore considered that WKY subjected to MS might produce a more robust model of depression than either WKY or MS alone. The widely used MS SD rat model of depression, as well as MS SD rats subjected to restraint stress in adult life, were evaluated as appropriate comparator models of depression. Furthermore, changes in the biochemistry in relevant brain areas of MS SD rats exposed to restraint stress in adulthood is still elusive and was further explored. The glutamate N - methyl - D - aspartate (NMDA) receptor antagonist, ketamine, has been found to be clinically useful. The acute effects of ketamine have not been previously tested in male WKY or MS SD rats and it was therefore decided to study the behavioural effects of ketamine in these rat models of depression. The aim of the first study was to characterize the WKY rat model of depression and to select the appropriate substrain of WKY best suited as a model of depression. The WKY/NCrl and WKY/NHsd substrains of WKY were tested for optimal depression - /anxiety - like behaviour in the forced swim test (FST), open field test (OFT) and elevated plus maze (EPM) and compared to the Wistar reference strain. Both WKY/NCrl and WKY/NHsd were less active than Wistar rats in the OFT and FST and WKY/NCrl were les s activ e than WKY/ NHsd. Therefore, the initial study identified WKY/NCrl as the appropriate substrain of WKY to model depression. The WKY/NCrl rats were further characterized in terms of their response to an optimal dose of the antidepressant drug, desipramine in the FST. Desipramine has been shown to be effective in reducing the depression - like behaviour of WKY and was therefore chosen as the antidepressant drug for this study. A dose of 15 mg/kg desipramine attenuated the depression - like behaviour as evide nced by decreased immobility in the FST and was therefore used for subsequent experiments. Desipramine had no effect on opioid receptors (μ - and κ - opioid receptors, MOR and KOR, respectively) , and tyrosine hydroxylase in the nucleus accumbens ( NAc ) or prefrontal cortex ( PFC ) of WKY rats.

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