Utilising the sub-chronic phencyclidine model to further understand positive and cognitive schizophrenia symptomatology and treatment

Abstract

Schizophrenia is an extremely complex, heterogenous disease affecting approximately 1% of the population. Dysregulation of the dopamine system, particularly in the striatum is a key player in the pathophysiology and current treatment of schizophrenia. As such these treatment options are limited as they mainly target the positive symptoms of disease and even then, are not efficacious for all patients, often causing unpleasant side effects. Animal models are useful in furthering understanding of disease pathophysiology and identifying novel treatments. The sub-chronic phencyclidine model (scPCP) has been widely used to investigate the cognitive impairments associated with schizophrenia with a lack of focus on the function of dopamine within this model. This project set out to utilise the scPCP animal model to better understand both cognitive and positive symptomatology, to investigate the underlying pathology and investigate / identify novel treatment targets. The behavioural studies presented in the thesis demonstrate that scPCP treated animals display a deficit in the novel object recognition test (NOR), a behavioural test used to evaluate recognition memory in rodents. scPCP animals also display an increase in locomotor activity (LMA) when acutely challenged with phencyclidine or amphetamine. Pharmacological studies found that both haloperidol and clozapine prevented the increase in LMA following acute amphetamine challenge in scVehicle treated animals. Interestingly only clozapine but not haloperidol had the same efficacy in scPCP treated animals. Acute treatment with the novel Kv3 channel modulator, AUT00206, was able to reverse the NOR deficits but had no effect on LMA activity induced by acute PCP or acute amphetamine challenge in either scVehicle or scPCP treated animals. Post-mortem studies revealed that scPCP animals display altered inflammatory, synaptic, GABAergic and dopaminergic markers across multiple brain regions of relevance to schizophrenia symptomatology. Taken together the findings suggest that the scPCP model is able to replicate a range of schizophrenia related behavioural deficits of relevance to both cognitive and positive schizophrenia symptomatology. A number of post-mortem correlates with schizophrenia were also observed in relation to altered inflammatory, synaptic, GABAergic and dopaminergic markers. Pharmacological studies highlight a potential role for targeting GABAergic deficits for treating cognitive deficits. The changes in the dopaminergic markers reported may have relevance to treatment resistant schizophrenia and this coupled with the ability of clozapine and not haloperidol to prevent LMA in scPCP animals may allow further insights into the superior efficacy of clozapine in TRS in the clinic.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Joanna Neill (Supervisor) & Michael Harte (Supervisor)