Research reportAtypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat
Introduction
Schizophrenic patients suffer from enduring and persistent psychotic symptoms including a chronic deficiency in their cognitive ability [7], [55]. Current pharmacotherapies relieve positive symptoms but are still lacking in their ability to improve cognitive symptoms such as executive function, verbal, visual and working memory deficits [10] which seriously reduce quality of life [19]. Indeed, the recent collaboration between the National Institute of Mental Health, the University of California, Los Angeles, and the United States Food and Drug Administration termed Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) is an initiative dedicated to encouraging the development of cognition-enhancing drugs for schizophrenia [39]. It is of considerable importance to develop better pre-clinical models to improve our understanding of the neuro- and psychopathology of cognitive deficits in schizophrenia and so improve therapy.
PCP is a non-competitive NMDA receptor antagonist which can induce a psychotic state that has some similarities to schizophrenia. PCP or ketamine given acutely to healthy human subjects induces hyperactivity, paranoia, hallucinations, formal thought disorder and cognitive impairments [24], [25], [35]. Both ketamine and PCP exacerbate the symptoms of patients with schizophrenia [38]. A single dose of PCP has been shown to intensify the symptoms of schizophrenia in patients, to produce hallucinations and reduce cognitive function [28], [34], [55]. The ability of PCP to mimic the varying aspects of schizophrenia has undoubtedly provided new insight into the pathology of schizophrenia. Thus, the influence of PCP on many neurotransmitter systems including glutamate and GABA is increasingly being studied in an attempt to provide an improved understanding of the pathology of psychosis (for review see [5]). Olney et al. [47] have proposed that hypofunctional NMDA receptors, affecting glutamate and GABA neurotransmission, may provide a generalised dysfunction accounting for both the symptoms and chronic course of schizophrenia.
PCP is increasingly being used as a research tool to model psychosis in pre-clinical tests. Unlike amphetamine, which primarily produces positive symptoms [13], acute PCP produces deficits in pre-pulse inhibition (PPI) of the startle response [4] reviewed in note by [15] increases locomotor activity [41], [49], [59] and has been shown by us and others to produce cognitive deficits of particular relevance to schizophrenia [1], [12], [17], [22] reviewed in note by [28], [53]. However, sub-chronic PCP treatment in animals has been shown to produce more persistent effects on stereotypy and locomotor activity [9], [56], and to produce more enduring cognitive deficits of particular relevance to schizophrenia [2], [3], [21], [23], [25], [26], [50]. More specifically, sub-chronic PCP and other NMDA receptor antagonists impair performance on tasks that depend on hippocampal function, such as acquisition of a spatial continuous recognition memory task [33], as well as attentional set-shifting that may be sub-served by frontal cortical function [50]. We have demonstrated that sub-chronic PCP produces a lasting cognitive deficit in rats in an operant reversal learning paradigm attenuated by atypical but not classical antipsychotics [2] demonstrating a good level of predictive validity. Furthermore, our PCP dosing regime induces neurobiological changes of particular relevance to the pathology of schizophrenia, including reduced parvalbumin containing GABAergic neurons in the hippocampus [3] and BDNF mRNA levels in several brain regions (Snigdha et al., unpublished findings) indicating some level of construct validity.
As early as 1950, Berlyne found that rats spent significantly more time exploring a novel object than two familiar objects [6]. Subsequently the novel object recognition (NOR) task was developed, based on the natural propensity of rats to explore novel objects [14]. It is a non-rewarded, ethologically relevant, relatively simple test [48]. Such tests are increasingly being used to study and screen potential novel antipsychotic drugs. Indeed, NOR has been listed under the TURNS initiative as relevant for studying visual learning and memory deficits in schizophrenia (TURNS.ucla.edu).
The aim of the present study was to further assess the ability of PCP to induce a memory deficit in female rats using the novel object recognition (NOR) paradigm and to determine the validity of this model for studying cognitive deficit symptoms of schizophrenia by comparing the ability of two atypical and one classical antipsychotic agent to attenuate the cognitive impairment produced.
Section snippets
Animals
Forty-two adult female hooded-Lister rats (Harlan, UK) with a mean weight of 195 g were used for experiments 1 and 2 and 50 adult female hooded-Lister rats (Harlan, UK) with a mean weight of approximately 208 g were used for experiment 3. Rats were housed in groups of four to five on a 12 h light/dark cycle (lights on at 07.00), with all experiments being conducted during the light phase. Food (Special Diet Services, Essex, UK) and water was available ad libitum in the home cage. Room temperature
Acquisition trial
All groups of rats spent equivalent time exploring the identical objects (left and right) in the acquisition phase (Fig. 1a). Statistical analysis showed no significant difference in time spent exploring the identical objects in the acquisition phase in any group.
Retention trial
Rats treated sub-chronically with vehicle spent significantly (p < 0.05) longer exploring the novel object compared with the familiar object (Fig. 1b). The ability to discriminate familiar and novel objects was abolished following
Discussion
In the present study, we assessed the cognitive deficit induced by a sub-chronic PCP dosing regimen in the NOR paradigm and the ability of antipsychotics to reverse this deficit. Female rats were used as we have found them to perform better in NOR than males and have demonstrated no effect of oestrus cycle on performance in the NOR task [57]. Furthermore, in previous studies, female rats have been shown to be more sensitive to the behavioural effects of acute PCP compared to males [42], [43],
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