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Investigation into effects of chronic treatment with antipsychotics using a combination of behavioural and electrophysiological techniques
[Thesis]. Manchester, UK: The University of Manchester; 2019.
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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 measure of cognition. Tests were repeated at 6 time points throughout the study (1 dNOR and cNOR assessment prior to osmotic minipump implant and 2 other dNOR and cNOR testing sessions post minipump implant). In addition to dNOR, the effectiveness of scPCP treatment in this study was also examined by assessment of its locomotor activity response to an acute dose of amphetamine (1mg/kg) administered intraperitoneally (i.p.). While results of the dNOR test (prior to implant) could not confidently confirm the effectiveness of scPCP treatment, findings of the locomotor activity in response to amphetamine suggested that the scPCP treatment had been effective. Overall, the behavioural findings of this study were also inconclusive due to performance variability. By limiting the number of NOR testing sessions, Chapter 6, following the same treatment plan as Chapter 4, showed that 28 days of treatment with haloperidol did not impair cognitive performance in the cNOR task in scPCP and control rats. Investigations into the synaptic properties of the vHipp-mPFC pathway (Chapter 5), showed a significant reduction in strength of glutamatergic synaptic connectivity from vHipp to the mPFC in scPCP treated rats, although the vHipp-mPFC pathway was still able to support synaptic facilitation and long-term potentiation in scPCP treated rats. The general pattern of the results points towards compromised inhibitory mechanisms manifested as hyper excitability/plasticity in this pathway in the scPCP model, which is consistent with studies in other animal models of the disease. Investigations in this chapter further suggested a significant reduction in the excitability threshold in the scPCP treated rats, an effect which might also involve disturbances in β-adrenoceptor-mediated effects. As presented in Chapter 6, 28 days of treatment with haloperidol appeared to have reduced the strength of synaptic connectivity in the sub-chronic Vehicle (0.9% saline; scVeh) treated rats. This effect did not reach statistical significance in comparison to the scVeh-control treatment group. This trend was absent in the haloperidol treated scPCP rats in comparison to its control. The amplitude of synaptic connectivity was, however, appeared to have been reduced (also not statistically significant) to the same extent in both scVeh and scPCP treatment groups in response to long-term haloperidol treatment. This may point towards the effect of haloperidol in increasing the activity of a subset of inhibitory mechanisms, which may be involved in regulating response strength and size. Interestingly, investigations into short- and long-term synaptic plasticity showed that long-term haloperidol treatment induced a state of hyper excitability/plasticity in the vHipp-mPFC pathway in both scVeh and scPCP rats, which was significantly more robust in the scPCP treatment groups. These results suggest that the observed hyper-excitability may be due to disruptions in GABAB-D2-NMDA receptor interaction. Collectively, these results suggest that different inhibitory mechanisms may be involved in regulating the vHipp-mPFC responses, which may be differentially affected by haloperidol. In conclusion, the behavioural studies presented in this thesis highlighted that the scPCP model is susceptible to the effects of handling, which can interfere with study outcome. In addition, these studies suggested, that repeated administration of dNOR and cNOR tests, results in pronounced performance variability, which leads to ambiguous findings. In spite of these challenges, the behavioural studies presented in this thesis were able to demonstrate that, for the duration studied, haloperidol did not impair performance on the cNOR task in the scPCP and scVeh treatment groups. Through the use of electrophysiological techniques, the studies presented in this thesis were able to investigate previously unexplored aspects of the scPCP model, which contributes to its validity with relevance to cognitive impairments associated with schizophrenia. Results of these studies demonstrated deficits in synaptic connectivity and highlighted a general reduction in inhibitory tone, manifested as hyper excitability/plasticity in the vHipp-mPFC pathway in scPCP-treated rats. These disturbances, which may be responsible for cognitive impairments in schizophrenia, were further exacerbated by long-term haloperidol treatment. Functional consequences of these disturbances were not reflected in the behavioural paradigms employed, as these tests do not depend on vHipp-mPFC interaction for successful performance. Further studies are required to determine the behavioural and cognitive impact of these synaptic alterations using more complex and sensitive behavioural paradigms, which engage the vHipp-mPFC pathway. In addition to its role in mediating cognitive processes, disruptions in the activity of the vHipp-mPFC pathway, specifically the hyperactivity of the vHipp, are also thought to be involved in psychosis. The hyper-excitability in the vHipp-mPFC pathway following long-term treatment with haloperidol may be indicative of the processes of dopamine super-sensitivity and AP-induced psychosis, instances of which are observed in the clinic. Therefore, investigations into synaptic properties of the vHipp-mPFC pathway may provide a platform for better understanding of disease processes and contribute to advancements in novel drug development with improved efficacy in treating positive symptoms and cognitive impairments associated with schizophrenia.
Keyword(s)
Antipsychotics; Chronic; Cognition; Electrophysiology; Haloperidol; Medial prefrontal cortex; Ventral Hippocampus; sub-chronic Phencyclidine Model