Dopamine dysregulation in the prefrontal cortex relates to cognitive deficits in the sub-chronic PCP-model for schizophrenia: A preliminary investigation.

Samantha L Mclean,Andrew Mj Young,Michael K Harte,Joanna C Neill

doi:10.1177/0269881117704988

Abstract

Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for 7 days, followed by 7 days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial ( p < 0.01). scPCP produced a significant deficit in NOR ( p < 0.05 vs. control) and no PFC dopamine increase was observed. These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology.

Highlights

The novel object recognition (NOR) task was developed by Ennaceur and Delacour and is based on the natural propensity of rats to explore novel objects (Ennaceur and Delacour, 1988)
Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the prefrontal cortex (PFC) during the retention trial (P
Much of the evidence indicates a critical role for the perirhinal cortex in object recognition memory following short inter-trial interval (ITI) (Gaffan and Murray, 1992; Meunier et al, 1993; Ennaceur et al, 1996; Brown and Aggleton, 2001; Hannesson et al, 2004), research suggests that the prefrontal cortex (PFC) may contribute to recognition memory

Summary

Introduction

The novel object recognition (NOR) task was developed by Ennaceur and Delacour and is based on the natural propensity of rats to explore novel objects (Ennaceur and Delacour, 1988) It is a non-rewarded, ethologically relevant test of visual object recognition memory (Puma et al, 1998). NOR has been listed by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative as relevant for studying visual learning and memory deficits in schizophrenia (Young et al, 2009) Such tests of visual recognition memory are increasingly being used to detect novel drugs for improvement of cognitive dysfunction in schizophrenia and other human disorders including Alzheimer’s disease, Parkinson’s disease, and Autism Spectrum Disorder (Grayson et al, 2015). There is conflicting evidence showing that cytotoxic lesions of the mPFC spared object recognition performance following a 10 min ITI (Yee, 2000); this further highlights the need to further investigate the role of the PFC in this behavioural task

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