Characterisation of sex differences in behavioural domains and antidepressant response in two rat models of depression

Although the rate of depression is known to be almost twice as high in women compared to men, most evaluation of antidepressant efficacy involved only males until the early 1990s. In pre-clinical depression research male subjects are still preferred over females due to the perception that females’ responses are more variable than those of males. The aim of the this thesis is to characterise two rodent models of depression, the olfactory bulbectomy (OB) model and the Wistar Kyoto (WKY) model, in regards to sex differences in anxiety- and depressive-like behaviours, cognitive ability as well as responsivity to chronic antidepressant treatment, namely fluoxetine, an SSRI, and desipramine, a tricyclic antidepressant. We also aim to evaluate the reproductive ability of these models as well as their maternal and offspring characteristics. Irrespective of sex, a hyperactive response was observed in the elevated plus maze (EPM) in the OB rat, but not in the open field test (OFT) where a hyperactive response is usually associated with this model. However only male OB rats displayed increased open arm entries in the EPM and decreased time in the target zone of the Morris water maze (MWM). In the WKY rats, both sexes displayed a hypoactive phenotype in the EPM and OFT but males exhibited a heightened freezing response compared to females upon exposure to these arenas. Again only males displayed impairments in the MWM and neither sex exhibited increased immobility time in the FST. We were unable to detect an antidepressant response in either male or female OB rats due to habituation to the OFT arena causing an absence of hyperactivity in the vehicle treated groups. As for the WKY rats, we found that both sexes were unresponsive to chronic fluoxetine treatment and desipramine caused a reduction in immobility time in the FST in male WKY rats only. We hypothesised that BDNF mRNA levels could be used as an index associated with antidepressant response however we did not find any effect of drug treatment on hippocampus or frontal cortex levels in either OB or WKY rats. We did not find impaired ix sexual activity in male rats in either model however female OB rats were less likely to give birth following mating compared to their controls. No developmental delays could be detected in pups born to OB mothers although small litter size could have had confounding effects in this regard. Pups born to WKY mothers exhibited delays in somatic and cognitive development however we did not observe any differences in maternal behaviour in WKY dams. From our results we can see that female OB rats exhibit the main behavioural characteristic of the OB syndrome but they fail to display other aspects that have been previously reported in males, including learning and memory deficits and altered behaviour in the EPM. This suggests the need for further evaluation of the OB syndrome in females perhaps with the use of alternative tests to measure different aspects of depressive-like behaviour such as anhedonia. A similar inference could be made for the WKY females; they exhibited the hypoactive, anxious phenotype associated with the WKY model but failed to display cognitive deficits, depressive-like behaviour or antidepressant responsivity. To conclude, these findings highlight the need for investigating sex differences in models of psychiatric disease as such evaluations could shed light on novel therapeutic approaches.2021-04-1