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Comparing the Effects of Subchronic Phencyclidine and Medial Prefrontal Cortex Lesions on Cognitive Tests Relevant to Schizophrenia

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Comparing the Effects of Subchronic Phencyclidine and Medial Prefrontal Cortex Lesions on Cognitive Tests Relevant to Schizophrenia Psychopharmacology Comparing the Effects of Subchronic Phencyclidine and Medial Prefrontal Cortex Lesions on Cognitive Tests Relevant to Schizophrenia Journal: Psychopharmacology Manuscript ID: Psych-2015-00226.R2 Manuscript Type: Original Investigation Date Submitted by the Author: 01-Jul-2015 Complete List of Authors: McAllister, Kathryn; The University of Cambridge, Department of Psychology; The University of Cambridge, MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute Mar, Adam; The University of Cambridge, Department of Psychology; The University of Cambridge, MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute Theobald, David; The University of Cambridge, Department of Psychology; The University of Cambridge, MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute Saksida, Lisa; The University of Cambridge, Department of Psychology; The University of Cambridge, MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute Bussey, Timothy; The University of Cambridge, Department of Psychology; The University of Cambridge, MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute SCHIZOPHRENIA, PHENCYCLIDINE, PREFRONTAL CORTEX, OBJECT Keywords: RECOGNITION, RAT, ANIMAL MODEL, ASSOCIATIVE LEARNING, GLUTAMATE, LEARNING AND MEMORY, DISCRIMINATION Page 1 of 37 Psychopharmacology 1 2 3 Comparing the Effects of Subchronic Phencyclidine and Medial 4 5 Prefrontal Cortex Dysfunction on Cognitive Tests Relevant to 6 Schizophrenia 7 8 ab ab ab a,b a,b 9 McAllister KAL , Mar AC , Theobald DE , Saksida LM , Bussey TJ 10 11 a 12 University of Cambridge Department of Psychology, Downing Street, 13 Cambridge, CB2 3EB, UK 14 15 b MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, 16 University of Cambridge, Cambridge CB2 3EB, UK 17 18 19 Acknowledgements: KAL McAllister received funding from the Cambridge 20 Commonwealth Trusts and University of Cambridge Overseas Studentship 21 22 Programme. LM Saksida and TJ Bussey also received funding from the 23 Innovative Medicine Initiative Joint Undertaking under grant agreement no 24 115008 of which resources are composed of EFPIA in-kind contribution and 25 financial contribution from the European Union’s Seventh Framework 26 Programme (FP7/2007-2013). 27 28 29 Disclosures: LMS and TJB consult for Campden Instruments Ltd. 30 31 32 Communicating author: 33 34 KAL McAllister 35 36 20 Manchester Sq. 37 London, UK, W1U 3PZ 38 39 [email protected] 40 +44 (0)7898 989 195 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 Psychopharmacology Page 2 of 37 1 2 3 Abstract 4 5 Rationale 6 It is becoming increasingly clear that the development of treatments for 7 cognitive symptoms of schizophrenia requires urgent attention, and that valid 8 animal models of relevant impairments are required. With subchronic PCP 9 10 (scPCP) a putative model of such impairment, the extent to which changes 11 following scPCP do or do not resemble those following dysfunction of the 12 prefrontal cortex is of importance. 13 Objectives 14 15 The present study carried out a comparison of the most common scPCP 16 dosing regimen with excitotoxin-induced medial prefrontal cortex (mPFC) 17 dysfunction in the rat, across several cognitive tests relevant to schizophrenia. 18 19 Methods 20 ScPCP subjects were dosed i.p. with 5mg/kg PCP or vehicle twice daily for 21 one week followed by 1 week washout prior to behavioural testing. mPFC 22 23 dysfunction was induced via fibre-sparing excitotoxin infused into the 24 prelimbic and infralimbic cortex. Subjects were tested on spontaneous novel 25 object recognition, touchscreen object-location paired-associates learning, 26 and touchscreen reversal learning. 27 28 Results 29 A double-dissociation was observed between object-location paired- 30 associates learning and object recognition: mPFC dysfunction impaired 31 acquisition of the object-location task, but not spontaneous novel object 32 recognition, while scPCP impaired spontaneous novel object recognition, but 33 34 not object-location associative learning. Both scPCP and mPFC dysfunction 35 resulted in a similar facilitation of reversal learning. 36 Conclusions 37 38 The pattern of impairment following scPCP raises questions around its 39 efficacy as a model of cognitive impairment in schizophrenia, particularly if 40 importance is placed on faithfully replicating the effects of mPFC dysfunction. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 Page 3 of 37 Psychopharmacology 1 2 3 Introduction 4 5 6 It is becoming increasingly clear that the development of treatments for 7 the cognitive symptoms of schizophrenia requires urgent attention 8 (Minzenberg and Carter 2012; Schaefer et al. 2013; Vingerhoets et al. 2013). 9 10 To achieve this aim we need valid animal models of the cognitive impairments 11 in schizophrenia (Nestler and Hyman 2010). The psychotomimetic agent 12 phencyclidine (PCP) has been widely used to model schizophrenia in rodents 13 (Castner et al. 2004; Neill et al. 2010). In humans, PCP and other N-methyl- 14 D-aspartate receptor (NMDAR) antagonists can induce the symptoms of 15 schizophrenia and cause relapse for schizophrenics stabilized on anti- 16 psychotic medication (Itil et al. 1967; Javitt and Zukin 1991; Krystal et al. 17 1994; Lahti et al. 1995 & 2001; Malhotra et al. 1996 & 1997; Snyder 1980; 18 Tamminga 1998). These observations are consistent with the ‘glutamate 19 20 hypothesis of schizophrenia’, which posits that NMDAR function is disrupted 21 in schizophrenia (Javitt et al. 2012; Poels et al. 2014; Singh and Singh 2011). 22 Subchronic PCP (scPCP) in particular has many prima facie 23 advantages. For example, cognitive impairments relevant to schizophrenia 24 have been observed following scPCP (Arnt et al. 2010; Barnes et al. 2012; 25 26 Beninger et al. 2010; Howes et al. 2015; Laurent and Podhorna 2004; 27 McKibben et al. 2010; Meltzer et al. 2013) and the model, like other 28 subchronic treatments, allows assessment of the effects of the treatment 29 when the drug is no longer ‘on board’, thus minimizing motoric and/or 30 motivational changes which can seriously confound cognitive testing and 31 subsequent interpretation of the results. 32 33 Another attraction of the scPCP model is the assumption that it induces 34 dysfunction of the prefrontal cortex (Amitai et al. 2012; Young et al. 2015), a 35 major feature of the schizophrenic brain often cited as a major contributor to 36 cognitive deficits (Glahn et al. 2005; Hill et al. 2004; Ingvar and Franzen 37 1974). Therefore the extent to which changes following scPCP do or do not 38 resemble those found following dysfunction of the prefrontal cortex is of some 39 importance to researchers in this area. Therefore in the present study we 40 41 carried out a head-to-head comparison of the effects of the most common 42 scPCP dosing regimen (5mg/kg twice daily for seven days followed by 7 days 43 washout), with the effects of fibre-sparing excitotoxin-induced medial 44 prefrontal cortex (mPFC) dysfunction in the rat, across several cognitive tests 45 relevant to schizophrenia: object-location paired-associates learning, 46 spontaneous novel object recognition, and reversal learning. 47 48 Object-location learning (Experiment 1):Object-location learning, for 49 example as studied using the CANTAB PAL test (Sahakian et al. 1988), can 50 be used to investigate the MATRICS domain of visual learning and memory 51 and the CNTRICS domain of long term memory. Impairments in object- 52 location paired-associates learning (PAL) have been found in chronic 53 schizophrenia (Aubin et al. 2009; Donohoe et al. 2008; Haring et al. 2014; 54 Wood et al. 2002) and can also be present at first onset of the disorder and 55 may predict following clinical severity (Barnett et al. 2005). Additionally, 56 57 impairments on CANTAB PAL have been observed during the prodromal 58 phase and may be present in relatives at risk of developing schizophrenia 59 60 3 Psychopharmacology Page 4 of 37 1 2 3 (Bartok et al. 2005). Normal performance of CANTAB PAL depends on the 4 medial temporal lobe (Wood et al. 2002) and prefrontal cortex (Owen et al. 5 1995). 6 7 The rodent object-location paired-associates learning task (PAL) was 8 inspired by the CANTAB PAL task (Talpos et al. 2009) and has been 9 recommended by CNTRICS for studying long-term memory in animal models 10 of schizophrenia (Bussey et al. 2013). 11 12 Object Recognition (Experiment 2) . Spontaneous Object Recognition 13 (SOR) has been used to examine non-spatial memory impairments linked to 14 schizophrenia (Dere et al. 2007; Lyon et al. 2012). In studies of SOR and 15 scPCP immediately post-washout, significant impairments were observed 16 following various retention periods (Arnt et al. 2010; Horiguchi et al. 2011; 17 McKibben et al. 2010; Snigdha et al. 2010). Additionally, object recognition 18 impairments following scPCP are attenuated by clozapine and risperidone, 19 20 but not haloperidol (Grayson et al. 2007). 21 Reversal Learning (Experiment 3) : Reversal learning assesses the 22 subject’s ability to acquire a simple ‘rule’ and then adopt a new strategy when 23 the rule no longer holds. Reversal learning is impaired in schizophrenia 24 (Leeson et al. 2009; McKirdy et al. 2009; Murray et al. 2008; Waltz and Gold 25 26 2007) and has been recommended by CNTRICS for studying executive 27 function in animal models of schizophrenia (Gilmour et al. 2013). First, rats 28 learn to discriminate between an S+ and S- by perceptually discriminating 29 between S+ and S- and learning the reward contingency. Once the subject 30 has acquired the discrimination, the reward contingency is reversed (S+ 31 becomes the S-). The reversal stage requires the subject to inhibit 32 responding to the previously rewarded stimulus, and switch to the new reward 33 contingencies. 34 35 Reversal learning ability is dependent on the orbitofronal cortex 36 (Bissonette et al.
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