| dc.description.abstract | Obsessive-compulsive disorder (OCD)1 is a debilitating neuropsychiatric condition that notably infringes on an individual’s quality of life. The condition is characterised by two primary symptoms, namely obsessions (intrusive thoughts or images) and compulsions (persistent behavioural routines). The proposed neurobiology associated with OCD is founded upon a hyperactive cortico-striatal circuit together with altered serotonergic, dopaminergic and glutamatergic neurotransmission. Importantly, the mostly positive response of OCD patients to first-line selective serotonin reuptake inhibitor (SSRI)2 treatment provides the theoretical basis for the description of OCD as a condition of hyposerotonergic signalling. However, since only 40 - 60% of SSRI treated patients demonstrate an improvement of symptoms, treatment resistance remains a clinical dilemma and thus a wider understanding of the underlying neurobiological mechanisms is needed to improve therapeutic approaches.
The essential amino acid, tryptophan (TRP)3, is metabolised along two pathways, i.e. the serotonin (5-HT)4 and kynurenine (KYN)5 pathways. Enhanced TRP metabolism towards the KYN pathway may further diminish the already limited central TRP availability, which is required for 5-HT synthesis. Further, with respect to the KYN pathway, an altered ratio between neuroprotective kynurenic acid (KYNA)6 and neurotoxic quinolinic acid (QA)7, two neuroactive glutamatergic KYN metabolites, may be associated with atypical glutamatergic signalling within the cortico-striatal circuit, and in turn underlie OC8 symptom expression. Resultantly, a focal point of this investigation was to investigate TRP metabolism as well as the said ratio, in the deer mouse model (Peromyscus maniculatus bairdii) of OCD. Importantly, the initial conversion of TRP to KYN is enzymatically mediated by two unique, inducible enzymes - tryptophan-2,3-dioxygenase (TDO)9 and indoleamine-2,3-dioxygenase (IDO). IDO activity is induced under conditions of inflammation, i.e. alterations in the gut microbiota or infection, both of which are associated with the systemic presence of lipopolysaccharide (LPS)10 and pro-inflammatory cytokines. Bolstered IDO11 activation—thereby facilitating KYN pathway metabolism—has been shown in OCD patients. Prior
findings from our laboratory, which demonstrated potentially pro-inflammatory alterations in the gut microbiota composition of large nest building (LNB)
1 deer mice provided the foundation for this work.
Considering the above, we aimed to investigate TRP2 metabolism and potential markers of inflammation in naturalistically normal nest building (NNB)3, the behavioural control, and LNB expressing deer mice. Approximately 30% of laboratory-housed and cage-reared deer mice spontaneously present with compulsive-like, i.e. persistent LNB behaviour which is attenuated by high-dose oral escitalopram treatment. As such this investigation sought to determine whether LNB vs. NNB would associate with unique cortico-striatal TRP and TRP metabolite concentrations. In addition, plasma LPS4 and lipopolysaccharide binding protein (LBP)5 concentrations, both markers of inflammatory processes, were investigated as possible indicators that could partially explain any potential differences in TRP metabolites profiles between the two nesting phenotypes. Last, we wanted to determine the potential effects of escitalopram exposure on the various TRP metabolites and plasma LPS and LBP concentrations of NNB and LNB expressing animals.
Eighty deer mice of both sexes were initially screened for nest building behaviour and subsequently separated into two behavioural cohorts i.e. NNB and LNB (n = 24 per group), which were further divided in half. One group of each cohort were exposed to either normal water (n = 12 per group), or escitalopram (50 mg/kg/day) (n = 12 per group), for 35-days, after which nest building expression was once again analysed after the said intervention. After completion of the second behavioural assessment, animals were euthanised and brain (frontal-cortical and striatal) plasma samples collected. Brain TRP metabolites were analysed by means of a newly developed liquid chromatography-mass spectrometry (LC/MS)6 method (see Chapter 3), while plasma LPS and LBP levels were analysed using enzyme-linked immunosorbent assay (ELISA)7 kits. The behavioural and neurobiological results of this work are contained in Chapter 4.
The main findings arising from this investigation were that 1) LNB, but not NNB behaviour responds to high-dose chronic escitalopram administration, 2) LNB is associated with hyposerotonergia, rather than altered KYN8 metabolism, and 3) that the behaviour of LNB animals is associated with escitalopram-responsive differences in plasma LPS and LBP concentrations
Briefly, we showed that LNB1 is associated with reduced frontal-cortical serotonin concentrations compared to the same region in NNB2 animals and that escitalopram failed to replenish such noted deficits. Thus, although escitalopram exposure attenuated LNB-expression and prevented nesting exacerbation over time, such an effect could not be ascribed directly to a serotonergic effect, a finding that rather indicates a therapeutic association with increased frontal-cortical and striatal TRP3 concentration. Further, the treatment response in LNB mice was associated with decreasing plasma LPS4 levels, pointing to a potential underlying SSRI5-dependant mechanism linked in some manner to unique interactions with alterations in the gut microbiota. However, this assertion requires further investigation. Further, the similar KYNA6/QA7 profiles in LNB and NNB animals showed that altered KYN8 metabolism is likely not involved in the manifestation of LNB. However, to derive a comprehensive view of the association between compulsive-like behaviour and TRP metabolism on the one hand and the gut microbiota and immune activation, on the other hand, further investigation into inflammatory cytokines, the microbiota profiles of NNB and LNB animals, as well as IDO9 enzyme activity may be useful. | en_US |
