Investigation into effects of chronic treatment with antipsychotics using a combination of behavioural and electrophysiological techniques

Abstract

Schizophrenia is a chronic and severe psychiatric disorder that follows a remitting and relapsing course of action. Impaired cognitive functions are a core feature of schizophrenia, which persist throughout the patients’ life despite life-long treatment with antipsychotics (APs). While the neurocognitive effects of long-term AP treatment remain unclear, several lines of evidence point towards its detrimental impact on cognition, accompanied by structural brain alterations in patients with schizophrenia. Pre-clinical models provide a platform for systematic investigation into the neurocognitive effects of long-term AP treatment. However, model results so far lack translational validity due to methodological limitations. Substantial evidence suggests that disruptions in the functional interaction between the hippocampal formation (HF) and medial prefrontal cortex (mPFC) contributes to the cognitive impairments associated with the disease. In particular, pre-clinical investigations emphasise a key role for the direct pathway from the ventral hippocampus (vHipp) to the mPFC in mediating higher-order cognitive functions; these include episodic memory, executive function and goal-directed behaviour, deficits in which are well documented in patients with schizophrenia. Timely transfer and accurate processing of information between brain regions is governed by processes of synaptic plasticity which are thought to be modulated by AP treatments. Modulations of synaptic plasticity in this pathway in response to long-term treatment with APs could advance current understanding of APs’ mechanism of action on cognition and its neural correlates. Since studying processes of synaptic plasticity are challenging in humans, their examination in pre-clinical models is essential. Using the well-validated sub-chronic (sc) phencyclidine (PCP; scPCP) model for cognitive impairments associated with schizophrenia, this project investigated the neurocognitive effects of long-term treatment with haloperidol and olanzapine to address some of the methodological issues associated with pre-clinical research in this field. Performance in two variations of the novel object recognition (NOR) task formed the primary measure of cognition in the studies reported here (Chapters 3, 4 and 6). The disrupted NOR (dNOR; classic one-trial NOR test) test was employed to examine the ability of long-term AP treatment to rescue scPCP-induced memory deficits. In contrast to dNOR, performance of scPCP-treated rats is intact in the continuous NOR (cNOR). Therefore, cNOR was employed to examine potentially negative effects of long-term treatment with APs. Furthermore, through in vivo electrophysiological recordings under anaesthetised conditions, this project characterised the synaptic properties (synaptic connectivity, short- and long-term synaptic plasticity) of the vHipp-mPFC pathway in the scPCP model for the first time (Chapter 5). This was followed by an investigation into the impact of long-term haloperidol treatment on synaptic properties of the vHipp-mPFC pathway in the scPCP model (Chapter 6). Results presented in Chapter 3 were inconclusive in determining the influence of 22 days of treatment with haloperidol (0.1 mg/kg/day, oral administration; p.o.) and olanzapine (1.5 mg/kg/day; p.o.) on dNOR performance. Performance was assessed once weekly on days 1, 8, 15 and 22 of AP treatment and at two other time points during treatment washout period. In this study, the presence of a robust scPCP-induced dNOR deficit could not be confirmed. It was reasoned that this could have been caused by excess handling prior to scPCP dosing and during AP treatment period. Furthermore, high variability in the dNOR outcome rendered the findings of this study inconclusive. In Chapter 4, investigations were limited to haloperidol (0.5mg/kg/day), which was delivered via subcutaneous osmotic minipumps over 28 days. In addition to the dNOR test, the cNOR test was also introduced as a measur

Date of Award	1 Aug 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Gigg (Supervisor), Joanna Neill (Supervisor) & Michael Harte (Supervisor)