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A Study of the WKY As a Rat Model of Depression

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A Study of the WKY As a Rat Model of Depression A study of the WKY as a rat model of depression Thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the University of Cape Town by Petrus Jurgens van Zyl University of Cape Town Promoter: Prof. V.A. Russell Department of Human Biology February 2015 The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgement of the source. The thesis is to be used for private study or non- commercial research purposes only. Published by the University of Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University of Cape Town Declaration I, the undersigned, hereby declare that the work contained in this thesis is my own original work and has not previously in its entirety or in part been submitted to any university for a degree ________________ ________________ Signature Date Dedicated to my parents who supported me through my study and God who gave me the opportunities to pursue my interest in research. Abstract 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 less active 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 evidenced 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, i MOR and KOR, respectively), and tyrosine hydroxylase in the nucleus accumbens (NAc) or prefrontal cortex (PFC) of WKY rats. Since MS is a well-accepted animal model of depression, the aim of the second study was to create a more robust model of depression by subjecting WKY rats to MS and determining their depression-like behaviour, as well as its reversal with chronic desipramine treatment and the accompanying neurochemical changes following treatment. Depression-like behaviour was recorded in the OFT, FST, and isolation-induced ultrasonic vocalizations (USVs), in WKY/NCrl and MS (removal of the pups from the dam for 3 h per day from P2 to P14) WKY/NCrl rats. Wistar rats served as the reference strain. The normally reared WKY/NCrl, MS WKY/NCrl and Wistar rats were injected intraperitoneally with either saline or desipramine (15 mg/kg/day) for 15 days and their behaviour recorded. Similar to the first study, WKY/NCrl and MS WKY/NCrl rats displayed increased immobility and decreased active swimming and struggling behaviours in the FST, and decreased activity in the OFT compared to Wistar rats. In addition, MS WKY/NCrl spent more time in the closed arms of the EPM than normally reared WKY/NCrl, and WKY rats emitted more USVs than Wistar rats in response to removal of cage mate(s). Desipramine treatment decreased immobility and increased active swimming and struggling behaviour of WKY/NCrl in the FST and also decreased their USVs in response to removal of cage mate(s). Furthermore, MS WKY/NCrl responded to the anxiolytic effects of desipramine as evidenced by the increased amount of time spent in the open arms of the EPM. Therefore, MS WKY/NCrl rats displayed depression- and anxiety-like behaviour that responded to the antidepressant and anxiolytic effect of desipramine in the FST and EPM. This therefore implied that MS WKY/NCrl rats provided a more robust model of depression and anxiety. The increased number of USVs emitted by WKY/ NCrl compared to Wistar rats and decreased number of USVs after desipramine treatment, suggest that USVs occurred in response to an aversive situation (social isolation) that, in accordance with its communication function, may represent social signalling to re-establish social contact with the cage mate(s). In this study, USVs served as a useful marker of depression-/anxiety-like behaviour, with the rats responding to antidepressant treatment. To determine the effect of chronic desipramine treatment on the neurochemistry in the brain of MS WKY rats, changes in dopamine, serotonin (determined by enzyme-linked immunosorbent assay (ELISA)), opioid receptor density (MOR and KOR), phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated glycogen synthase kinase 3β (p-GSK3β) (determined by polyacrylamide gel electrophoresis and western blotting) were measured in MS WKY/NCrl and normally ii reared WKY/NCrl rats. Desipramine treatment increased the density of p-GSK3β in the PFC of normally reared WKY/NCrl rats but did not affect MS WKY/NCrl rats. This study provides novel evidence for the mechanism of action of desipramine and the possible role of p-GSK3β in mediating the reduction of depression-/anxiety-like behaviour of WKY/NCrl rats. However, desipramine had no effect on serotonin and p-ERK levels in the PFC or dopamine and opioid receptors in the NAc. The aim of the third study was to determine if stress during adulthood can exaggerate the depression-/anxiety-like behaviour in the widely used MS SD rat model. Furthermore, to determine changes in brain-derived neurotrophic factor (BDNF) levels in the ventral hippocampus and protein profile in the PFC of MS SD rats subjected to stress in adulthood. Depression-like behaviour was measured in the EPM, OFT and FST in the MS SD rats exposed to chronic restraint stress (4 h per day for 5 days) in adulthood. Changes in BDNF concentration (measured with an ELISA) was measured in the ventral hippocampus in SD rats subjected to MS and restraint stress followed by proteomic analysis of the PFC. As expected, MS increased immobility of SD rats in the FST but restraint stress did not enhance the effect of MS on SD rats. MS on its own induced depression-like behaviour but restraint stress was unable to further potentiate the depression-like behaviour. It is suggested that since MS during early development causes a disruption in the hypothalamic‐pituitary‐adrenal axis (HPA axis) and long-term changes in the response to subsequent stress, it may have prevented restraint stress from exerting its depression-like behavioural effect. Furthermore, MS and restraint stress had no effect on BDNF levels in the ventral hippocampus but proteomic analysis of the PFC in SD rats revealed a decrease in actin-related proteins in MS rats and non-separated rats subjected to restraint stress as well as a general decrease in mitochondrial energy-related proteins in MS rats with or without subsequent exposure to restraint stress and non-separated rats subjected to restraint stress. Furthermore, a decrease in proteins involved in protein synthesis and an increase in proteins involved in protein degradation were found in rats subjected to both MS and restraint stress. The aim of the final study was to determine whether the depression-like behaviour of the rodent models of depression could also be reversed by acute treatment with ketamine. The WKY/NCrl and Wistar rats as well as non-separated SD and MS SD rats were injected intraperitoneally with a single dose of either saline or ketamine (5, 10 or 15 mg/kg). Isolation-induced USVs (4 days before and 5 h and 29 h after injection of ketamine/saline) were recorded as well as their behaviour in the OFT (22 h and 46 h after injection of ketamine/saline) and FST (2 h, 48 h and 72 h after injection of ketamine/saline).
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