Exploration of the opioidergic system in the olfactory bulbectomized rat model of depression

In recent years, there has been renewed interest in targeting the central opioid system as a novel strategy for the treatment of psychiatric disorders such as depression, due to its involvement in the regulation of mood, stress, social functioning and cognition. The use of preclinical modelling to investigate the role of the opioid system in depression is integral to further our understanding of the potential value of this system as a therapeutic strategy in the treatment of depression. The olfactory bulbectomised (OB) rat has a number of the physiological, endocrine, behavioural, and neuroinflammatory features which are relevant to clinical depression, many of which are attenuated with chronic, but not acute, antidepressant treatment. As such, the aim of this project was to investigate the role of the central opioid system in the OB rat model of depression. The reliability and reproducibility of the behavioural responses in the OB rat model were investigated via a meta-analysis, followed by characterisation of its behavioural effects with particular respect to social cognition and housing. The pharmacological impact on the behavioural deficits in the OB rat were investigated with chronic administration of conventional antidepressants, as well as opioid modulating drugs. Alterations to the central opioid system following exposure to acute (forced swim) and chronic (OB) stressors, alone and in combination, were also investigated. The first results Chapter was a systematic review and meta-analysis of the OB rat which confirmed its value as a model of depression, with robust and reproducible behavioural responses across laboratories in a range of behaviours, in particular the hyperactivity in the open field (OF), the most commonly used behavioural endpoint. The second results chapter was a characterisation of the OB rat model, evaluating the effects of housing and examining for the first time the 3-chamber test of social cognition in the model. There was no effect of housing either singly or in pairs on the behaviour in the OF in sham-operated rats, but the characteristic hyperactivity in the OB rat was blunted when two OB rats were housed together. OB rats were also shown to habituate to the OF on re-exposure, with exposure to prior behavioural tests also affecting the response in OB animals. With regards to the 3-chamber sociability test, OB rats spent less time exploring the novel conspecific animal in the 3-chamber sociability test, with a distinct habituation to the test arena over time being observed, regardless of housing, when compared to sham-operated counterparts; these deficits in social cognitive functioning was not attenuated by chronic administration with the antidepressants desipramine and fluoxetine. Chronic administration with opioid modulating drugs, either that target a single receptor, or using combination regimens, were shown to have differential effects on behaviour but overall also failed to attenuate this social cognitive deficit. Exposure to acute (forced swim) and chronic (olfactory bulbectomy) stressors in the rat caused reductions in expression primarily to the kappa opioid receptor (KOP) and delta opioid receptor (DOP) systems, with the primary regions affected being the hippocampus and prefrontal cortex; two regions involved in the processing of emotion and cognitive function. In conclusion, the OB rat is a robust and well-established animal model, with its behavioural responses shown to be easily replicated across laboratories, and mirror a number of symptoms in MDD. The opioid system has been shown to be altered after removal of the olfactory bulbs, with the KOP and DOP systems being the primary subsystems effected. The impact of an acute stressor, via a forced swim, was also shown to further alter the opioid system in OB rats, delineating that the opioid system in this model is sensitive to additional stressors. The deficit in social cognitive functioning in OB rats in this project contributes a novel feature to the model; a feature which resembles that of the social cognitive dysfunction seen in MDD. This deficit of social cognition in the OB model was refractory to normalisation with both conventional antidepressants, and opioid modulating compounds, suggesting that it is a deeply engrained deficit in the model, representing an important addition to the behavioural alterations associated with this model.

Funder

Science Foundation Ireland
Alkermes Inc

Publisher

NUI Galway

Rights

Attribution-NonCommercial-NoDerivs 3.0 Ireland

cbn

Collections

University of Galway Theses (PhD Theses)