Investigation of the central serotonergic system in the olfactory bulbectomized rat model of depression

Depression is a devastating heterogeneous disease that has a high lifetime prevalence. Despite over 50 years of research, the aetiology of depression is still largely undetermined but the improper functioning of the central serotonergic system is believed to play a considerable role. The olfactory bulbectomized (OB) rat model of depression is well validated, exhibiting behavioural, physiological and neurochemical alterations that are reflective of the clinical condition; open field hyperactivity is the primary behavioural hallmark, which is attenuated by chronic and not acute antidepressant treatment, reflective of the clinical condition. To date there is an absence of a comprehensive evaluation of the central serotonergic system in this model, encompassing multiple parameters of central serotonergic transmission as well as an assessment of its functionality. The work presented aims to address these limitations, assessing a time course of changes and effect of chronic antidepressant treatment (fluoxetine, venlafaxine and imipramine) on the following parameters: tryptophan hydroxylase expression (DRN, striatum, substantia nigra and amygdala), 5-HT1A and 5-HT2A functionality (via an acute agonist challenge of 8-OH-DPAT and DOI respectively) and mRNA expression (prefrontal cortex, hippocampus and amygdala) measurement of 5-HT, 5-HIAA and 5-HIAA/5-HT (amygdala) and finally expression of SERT (DRN, prefrontal cortex, hippocampus and amygdala). Initially a time course characterisation of the serotonergic system was carried out, determining that neither lesion nor time following lesion had an impact on the serotonergic parameters assessed. Functionality of the 5-HT1A and 5-HT2A revealed an enhanced dose dependent increase in locomotor activity in OB rats, with altered OB responsiveness to components of the panel of behaviours. Assessment of chronic fluoxetine, venlafaxine or imipramine treatment resulted in limited effects on the serotonergic parameters investigated. Functionality of the receptors, exhibited by increased locomotor activity, was unaffected by antidepressant treatment, whilst imipramine increased rearing in assessment of 8-OH-DPAT in stereotyped behaviours, whilst fluoxetine reduced flat body posture and increased forepaw treading but had no effect on DOI-induced stereotyped behaviours. Fluoxetine increased PFC 5-HT1A mRNA in sham-lesion rats, whilst also reducing 5-HIAA levels in the amygdala regardless of lesion type and further potentiating the reduction in OB rats. Venlafaxine increased 5-HIAA/5-HT ratio in sham lesioned rats. Alteration of behaviour in the open field was not observed with the OB model due habituation occurring upon re-exposure. Nocturnal homecage hyperactivity in the OB rat was evident from 1 week following lesion and remained significantly elevated for 2 weeks before waning thereafter. However this raises the possibility of a window of opportunity for detecting antidepressant responses. In conclusion, this work demonstrates that although limited central serotonergic structural changes were found, there is evidence of altered functionality, an area worthy of further investigation to help complete the picture.2021-11-0