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dc.contributor.advisorWolmarans, P.D.
dc.contributor.advisorSteyn, S.F.
dc.contributor.advisorMograbi, Daniel
dc.contributor.authorEngelbrecht, J.P.
dc.date.accessioned2021-11-03T10:56:10Z
dc.date.available2021-11-03T10:56:10Z
dc.date.issued2021
dc.identifier.urihttps://orcid.org/0000-0002-9129-271X
dc.identifier.urihttp://hdl.handle.net/10394/37633
dc.descriptionMSc (Pharmacology), North-West University, Potchefstroom Campusen_US
dc.description.abstractObsessive-compulsive disorder (OCD)1 is a phenotypically heterogeneous psychiatric disorder characterised by repetitive and ritualised behaviours (compulsions), that are purportedly enacted to attenuate the level of distress induced by persistent intrusive thoughts, images, or urges (obsessions). From a neurobiological perspective, OCD is associated with cortico-striatal-thalamic-cortical (CSTC)2 dysfunction. The cortex, striatum and thalamus play important roles in goal directed behaviour and is pivotal for normal executive functioning. The CSTC circuit comprises both a direct, behaviourally activating, and an indirect, behaviourally inactivating pathway. As such, one proposed mechanism for the symptomology observed in OCD is believed to be related to a bias in favour of the dopamine 1 (D1) receptor expressing direct pathway, over that of the indirect, D2 receptor expressing neurons. Further, considering the behavioural opponency known to exist between dopamine and serotonin, OCD is believed to be associated with hyposerotonergic signalling in the CSTC pathways. In fact, an associative, albeit not causal link between OCD and serotonin was first made approximately 50 years ago when the serotonin reuptake inhibitor, clomipramine, demonstrated moderate efficacy in treating the symptoms of OCD, a finding which has informed the treatment of the disorder ever since. In line with the above, chronic (10-12 weeks or longer) high dose selective serotonin reuptake inhibitor (SSRI)3 treatment delivers therapeutic response in 40-60% of patients and is regarded as the first line pharmacological treatment for OCD. However, treatment resistance remains a profound clinical dilemma. Common strategies to improve the therapeutic response in OCD include the use of low-dose neuroleptic drugs, e.g. risperidone, in combination with SSRIs. That said, such therapy is also only effective in a third of SSRI non-responders. In line with this, new advances in OCD research are pointing to potentially unique perturbations in the psychobiological processes that may underlie treatment resistance. Indeed, it has been demonstrated that certain symptom dimensions are associated with higher treatment resistance rates, which may be related to unique impairments in specific psychobiological processes, i.e. shifting ability, working memory, and an overreliance on habitual responding which potentially contributes to the degree of cognitive impairment shown. Therefore, an improved understanding of the psychobiological mechanisms that may underlie certain obsessive-compulsive symptom dimensions would be valuable for our continued development of novel pharmacological interventions. Although not as well studied in OCD1 as serotonin and dopamine, adenosine may be of potential clinical relevance in OCD as it modulates the neurotransmission of both serotonin and dopamine within the CSTC2 circuits, hippocampus, and amygdala. More specifically the A2A receptor subtype is of interest in this investigation, since A2A antagonism has been shown to improve the motor and cognitive deficits in Parkinson’s disease patients. Further, striatal and extra-striatal A2A receptor expression are differentially involved in motor control, context appraisal and anxiogenic processes, all of which are implicated to varying degrees in OCD. Deer mice (Peromyscus maniculatus bairdii) present researchers with a unique avenue to study the potential relationships between and mechanisms underlying naturally occurring and compulsive-like inflexible behaviour (stereotypy) and cognitive deficits. Briefly, 40-45% of adult deer mice of both sexes present with seemingly purposeless and highly repetitive vertical and horizontal motor behaviours, i.e. high stereotypy (H)3 that manifests in a waxing and waning nature throughout the dark cycle. Further, in line with the hyposerotonergic theory of OCD, H deer mice present with significant reductions in striatal serotonin transporter (SERT)4 density compared to their normal (N)5 behavioural counterparts. Last, H but not N behaviour is moderately sensitive to chronic, high-dose (50 mg/kg/day) intervention with the SSRI6, escitalopram. Here, we aimed to employ the deer mouse model of compulsive-like spontaneous stereotypy to explore the effects of anti-adenosinergic (i.e. the selective A2A receptor antagonist, istradefylline), as opposed to serotonergic (i.e. escitalopram) intervention on the expression of H behaviour. We further aimed to investigate the potential relationship between H stereotypy and cognitive flexibility as assessed in the T-maze continuous alternation task (T-CAT)1 and determine how any differences in cognitive flexibility between N2 and H3 animals would respond to istradefylline and escitalopram. Briefly, 182 deer mice of both sexes, aged 10 – 12 weeks at the onset of investigation, were screened for vertical and horizontal stereotypical behaviour (pre-exposure phase) and subsequently divided into two behavioural cohorts i.e. N and H (n = 40 per group). Each cohort was then further divided into four subgroups (n = 10 per exposure group; however, final end-point group sizes varied between 8 and 10) based on the type of intervention received (vehicle control; escitalopram 50 mg/kg/d; istradefylline 10 mg/kg/d and istradefylline 20 mg/kg/d) making for a total of eight groups. Since istradefylline is insoluble in water, all drugs were constituted for oral administration via a drinking solution (vehicle) which consisted of a 2% sucrose solution containing 2% dimethyl sulfoxide, 1.5% polyethoxylated castor oil (Kolliphor® EL) and ≤1.5% mineral oil. All drugs were administered for 28 days before mice were subjected for the first time to T-CAT testing and a single round of post-exposure stereotypy testing the subsequent day. Prior to the onset of experimentation, the study was approved by the AnimCare Research Ethics Committee of the North-West University (approval number: NWU-00575-19-A5). The main findings of this work are that 1) istradefylline broadly reduced the expression of stereotypical behaviour in deer mice of both cohorts, 2) no correlation seems to exist between the time spent engaging in H behaviour, and spontaneous alternating behaviour, and 3) istradefylline significantly improved the alternating behaviour of H expressing animals. In terms of our first main finding, chronic istradefylline exposure, irrespective of dose, not only reduced the time that H animals spent engaging in H stereotypical behaviour, but also significantly increased the time during which no stereotypy was expressed. Further, istradefylline also reduced the whole-night average and the highest intensity of stereotypical expression. While we showed that the effect of escitalopram on the expression of stereotypy is less pronounced than previously reported, it is likely that a different methodological framework applied here, i.e. by making use of a pre- and post-exposure stereotypy screen instead of weekly screens, could have contributed to this result. That said, a definitive role for adenosinergic signalling in the manifestation of H2 behaviour is highlighted in this work which should be explored further. Although we found no correlation between the expression of stereotypy and cognitive flexibility as assessed in the T-CAT1, it is important to note that H2, but not N3 animals did present with drug-sensitive alterations in alternation behaviour. Here, istradefylline increased the alternation behaviour of H, but not N animals, a finding that implicates adenosinergic signalling in the processes that may underlie cognitive flexibility. That said, continued investigation is needed, since it is unclear how istradefylline contributed to this improvement. In fact, considering its attenuating effects on fear processing, anxiety, motor control and contextual appraisal, any or more of these processes could likely have contributed to the reported result. In conclusion, we have presented evidence for adenosine signalling in the manifestation of both repetitive OC4-like behaviour as well as potential cognitive impairment. That istradefylline improved both stereotypy and alternation behaviour, putatively links these two constructs on the level of adenosinergic involvement and provides a much-needed platform for future pharmacotherapeuticen_US
dc.language.isoenen_US
dc.publisherNorth-West University (South-Africa)en_US
dc.subjectObsessive-compulsive disorderen_US
dc.subjectIstradefyllineen_US
dc.subjectEscitalopramen_US
dc.subjectT maze continuous alternation task (T-CAT)en_US
dc.subjectCognitive flexibilityen_US
dc.subjectAdenosineen_US
dc.subjectDeer mouseen_US
dc.subjectSpontaneous alternationen_US
dc.titleCognitive flexibility in the deer mouse model of obsessive-compulsive disorder and its response to serotonin and adenosine modulationen_US
dc.typeThesisen_US
dc.description.thesistypeMastersen_US
dc.contributor.researchID12324515 - Wolmarans, Petrus De Wet (Supervisor)
dc.contributor.researchID20267398 - Steyn, Stephanus Frederik (Supervisor)


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