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Exploration of cognitive and neurochemical deficits in an animal model of schizophrenia. Investigation into sub-chronic PCP-induced cognitive deficits using behavioural, neurochemical and electrophysiological techniques; and use of receptor-selective agents to study the pharmacology of antipsychotics in female rats. Item Type Thesis Authors McLean, Samantha L. Rights <a rel="license" href="http://creativecommons.org/licenses/ by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by- nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http:// creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. Download date 02/10/2021 14:22:57 Link to Item http://hdl.handle.net/10454/4451 University of Bradford eThesis This thesis is hosted in Bradford Scholars – The University of Bradford Open Access repository. Visit the repository for full metadata or to contact the repository team © University of Bradford. This work is licenced for reuse under a Creative Commons Licence. EXPLORATION OF COGNITIVE AND NEUROCHEMICAL DEFICITS IN AN ANIMAL MODEL OF SCHIZOPHRENIA Investigation into sub-chronic PCP-induced cognitive deficits using behavioural, neurochemical and electrophysiological techniques; and use of receptor-selective agents to study the pharmacology of antipsychotics in female rats Samantha Louise MCLEAN submitted for the degree of Doctor of Philosophy School of Pharmacy University of Bradford 2010 i ABSTRACT Keywords: Rat; Phencyclidine; Antipsychotics; Cognition; Dopamine; 5-HT; GABA Cognitive dysfunction is a core characteristic of schizophrenia, which can often persist when other symptoms, particularly positive symptoms, may be improved with drug treatment. The non- competitive NMDA receptor antagonist, phencyclidine (PCP), is a psychomotor stimulant drug that has been shown to induce symptoms characteristic of schizophrenia in humans and animals. The aim of these studies was to use the sub-chronic PCP model in rats to investigate cognitive dysfunction in behavioural tests which have been highlighted as relevance by the MATRICS initiative (MATRICS.ucla.edu). The main tests used were attentional set-shifting, operant reversal learning, and novel object recognition tasks. The pharmacology of antipsychotics was studied in the reversal learning task using receptor selective compounds. Following this, experiments were carried out using in vitro electrophysiology and in vivo microdialysis in an attempt to investigate the mechanisms underpinning the PCP-induced cognitive deficits. The attentional set-shifting task is a test of executive function, the extra-dimensional shift (EDS) phase relates to the ability to shift attention to a different stimulus dimension; this is impaired in patients with schizophrenia. The studies presented in chapter 2 showed that sub-chronic PCP administration impaired attentional set-shifting performance selectively in the EDS phase, a deficit which was significantly attenuated by sub-chronic administration of clozapine and risperidone, but not haloperidol. The effect of PCP was also shown to be more robust in female rats compared to males. A deficit in set-shifting ability was also observed in isolation reared rats. However, the deficits produced by PCP were more robust than the deficit produced by isolation rearing. The reversal learning task is another test of executive function. Chapter 3 reported that sub- chronic PCP administration impairs reversal learning ability in an operant task, as demonstrated by reduced percent correct responding in the reversal phase of the reversal learning task. It was found that a D1 agonist (SKF-38398), a 5-HT1A partial agonist (buspirone), a 5-HT2C antagonist (SB- 243213A) and an agonist and positive allosteric modulator of the alpha 7 nACh receptor (PNU- 282987 and PheTQS respectively) are able to reverse the sub-chronic PCP-induced deficit in reversal learning. Although many antipsychotics have affinity for muscarinic M1 and histamine H1 receptors, selective agents at these receptors were not able to improve the PCP-induced deficit. In chapter 4, the atypical antipsychotics, clozapine and risperidone, when given alone to naïve rats had no effect on reversal learning. Haloperidol when given to naïve rats impaired performance at the highest dose. Sub-chronic PCP was again found to impair reversal learning performance. Investigative experiments revealed that the 2 min time-out could be important as a cue. Following a double reversal, olanzapine-treated rats lost the ability to switch between the rules, whereas clozapine and risperidone-treated rats could perform the double reversal. Experiments with the extended (15 min) reversal phase could allow the investigation of the time-course effects of antipsychotics or selective compounds. The studies presented in chapter 5 found a reduction in gamma oscillations in the CA3 region of the hippocampus, following sub-chronic PCP treatment (2-5 weeks post treatment) that was paralleled by a deficit in parvalbumin immunoreactive (IR) cell density, at a similar time point (2 weeks post treatment). In contrast, a time-dependent increase in gamma oscillations was observed (6-8 weeks post treatment), at which point parvalbumin IR cell density was unchanged (8 weeks post treatment). Gamma oscillations were unchanged in the prefrontal cortex (PFC) following the PCP treatment regime. Locomotor activity tests were also carried out to ensure that the sub-chronic PCP treatment was successful. In-vivo microdialysis revealed that vehicle-treated rats show an increase in dopamine in the PFC which is selective for the retention trial of the novel object recognition task. PCP-treated rats were unable to distinguish between the novel and familiar objects and the increase in dopamine observed in vehicle rats was absent. As a control experiment it was also shown that sub-chronic PCP did not induce anxiety-like symptoms in the elevated plus maze and open field tests. These studies suggest that sub-chronic PCP induces cognitive deficits in behavioural tasks, and these deficits may be due to GABAergic mediated processes in the hippocampus and dopaminergic dysfunction in the PFC. These behavioural and neurochemical results are concurrent to findings observed in schizophrenia. ii TABLE OF CONTENTS Abstract………………………………………………………………………………....ii Table of contents...…………………………………………………………………..…iii Acknowledgements………………………………………………………………...…..ix Publications arising from this thesis………………………………………………......x Chapter 1 General Introduction……….…………………………………………..….1 1.1 Schizophrenia…………………………………………………………………………….2 1.2 Symptoms of schizophrenia…………………………………………………………….2 1.2.1 Positive symptoms of schizophrenia………………………………………3 1.2.2 Negative symptoms of schizophrenia……………………………………...3 1.2.3 Cognitive dysfunction in schizophrenia………………………………...…4 1.3 Behavioural tests of cognition……………………………………………………….…5 1.3.1 Novel object recognition…………………………………………………..7 1.3.2 Reversal learning…………………………………………………………..7 1.3.3 Attentional set-shifting…………………………………………………….8 1.3.4 Pre-pulse inhibition (PPI)………………………………………………….8 1.4 Aetiology of schizophrenia…………………………………………………………...…9 1.5 Neurochemical hypotheses of schizophrenia……………………………………….10 1.5.1 Dopamine…………………………………………………………………10 1.5.2 Serotonin (5-HT)…………………………………………………………12 1.5.3 Glutamate…………………………………………………………………12 1.5.4 GABA…………………………………………………………………….15 1.5.5 Involvement of other neurotransmitter systems in schizophrenia………..16 1.6 Animal models of schizophrenia…………………………………………………...…17 1.6.1 Use of pharmacological agents to mimic schizophrenia…………………18 1.6.2 Non-pharmacological models of schizophrenia………………………….20 1.6.3 Pathophysiological changes observed in schizophrenia and similarities with PCP and isolation rearing models………………………………………....24 1.6.4 Genetic models of schizophrenia………………………………………....26 1.7 Antipsychotics…………………………………………………………………………..27 1.7.1 Typical antipsychotics…………………………………………………....27 iii 1.7.2 Atypical antipsychotics…………………………………………………...28 1.7.3 Pharmacology of antipsychotics and receptor targets for cognition….…..29 1.8 Experimental aims……………………………………………………………………...34 Chapter 2 Attentional set-shifting……………………………………………………36 2.1 Introduction……………………………………………………………………………..37 2.2 Materials and methods………………………………………………………………...42 2.2.1 Subjects…………………………………………………………………...42 2.2.2 Locomotor activity……………………………………………………….43 2.2.3 Set-shifting apparatus…………………………………………………….44 2.2.4 Habituation and training………………………………………………….45 2.2.5 Testing paradigm…………………………………………………………47 2.2.6 Drugs……………………………………………………………………..51 2.2.7 Pilot antipsychotic study………………………………………………….52 2.2.8 Data and statistical analysis………………………………………………52 2.3 Results……………………………………………………………………………………54 2.3.1 Effects of sub-chronic PCP in female and male rats in attentional set- shifting………………………………………………………………………….54 2.3.2 Effects of clozapine, risperidone and haloperidol on sub-chronic PCP- induced deficits in attentional set-shifting…………………………………...…58 2.3.3 Effects of isolation rearing on attentional set-shifting…………………....63 2.3.4 Effects of sub-chronic PCP in a counterbalanced attentional set-shifting study, and the effect of discovery trials………………………………………...68 2.4 Discussion……………………………………………………………………………….73 2.4.1 Effects of sub-chronic PCP in female and male rats in attentional set- shifting………………………………………………………………………….73 2.4.2 Effects of clozapine, risperidone and haloperidol on sub-chronic PCP- induced
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