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Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat
Behavioural Brain Research 184 (2007) 31–38
Research report
Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat B. Grayson, N.F. Idris, J.C. Neill ∗ Bradford School of Pharmacy, University of Bradford, West Yorkshire, Bradford BD7 1DP, United Kingdom Received 21 February 2007; received in revised form 12 June 2007; accepted 26 June 2007 Available online 29 June 2007
Abstract The novel object recognition (NOR) task is a paradigm employed to detect both disruption and improvement of non-spatial memory in rats. PCP (phencyclidine) may be used to model aspects of schizophrenia symptomology in rats, in particular cognitive deficits. The aim of this study was to investigate the ability of typical and atypical antipsychotics to improve a sub-chronic PCP-induced impairment in cognition using the NOR task. Female hooded-Lister rats (195 ± 12 g) received either vehicle (0.9% saline twice daily) or PCP (2 mg/kg, twice daily) for 7 days followed by 7-days drug free. Haloperidol (0.05 and 0.075 mg/kg), clozapine (1 and 5 mg/kg), risperidone (0.05, 0.1 and 0.2 mg/kg) or vehicle (veh, saline) was administered i.p. 30 min prior to testing. Rats completed an acquisition trial followed by an inter-trial interval of 1 min, then a retention trial. Following sub-chronic vehicle treatment, rats spent significantly (p < 0.05) more time exploring the novel compared to the familiar object, an effect that was abolished in the sub-chronic PCP treated animals. Clozapine (1.0 and 5.0 mg/kg) and risperidone (0.2 mg/kg) but not haloperidol significantly attenuated the PCP-induced impairment such that animals again spent significantly more time exploring the novel compared with familiar object (p < 0.05). These results support our earlier work showing that acute PCP induces a robust object recognition deficit in female rats. Clozapine and risperidone but not haloperidol showed efficacy to reverse the deficit induced by sub-chronic PCP suggesting that this test may have some validity for assessing efficacy for improvement of cognitive deficit symptoms of schizophrenia. © 2007 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Phencyclidine; Novel object recognition; Antipsychotics; Cognition; Rat
1. 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
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0166-4328/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2007.06.012
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
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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. 2. Materials and methods 2.1. 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 (21 ± 2 ◦ C) and humidity (45–55%) were kept constant throughout. The experiments were performed in accordance
with the Animals Scientific Procedures act (1986) and were approved by the University of Bradford ethical review process.
2.2. Drug administration 2.2.1. Sub-chronic PCP treatment A total of 92 rats were randomly assigned to receive either vehicle (n = 20; 0.9% saline twice a day, i.p.) or PCP (n = 72; 2 mg/kg twice a day, i.p.) in a volume of 1 ml/kg for 7 days as previously described [2,3,23]. Subsequently, animals were given a 7-day drug-free period prior to NOR testing. This was based on a previous study [27], which suggested that at least a 1-week period of withdrawal was necessary following the final drug administration to ensure that behaviour was not influenced by any residual drug effects. PCP HCl (Sigma, UK) was dissolved in 0.9% saline. In experiment 1, rats that had been treated sub-chronically with PCP were randomly assigned to receive an acute injection of haloperidol (0.05 or 0.075 mg/kg, i.p., n = 7–12 per group) or vehicle (0.9% saline, i.p., n = 10). Haloperidol (Serenace liquid, 2 mg/ml) was prepared in distilled water. Ten of the rats treated sub-chronically with vehicle, received vehicle acutely. The doses of haloperidol were chosen on the basis of our previous work showing that 0.05 mg/kg haloperidol significantly attenuated a d-amphetamine-induced reversal learning impairment in female hooded-Lister rats [22]. Furthermore this dose of haloperidol has been shown to occupy 50% of dopamine D2 receptors [31,32]. In experiment 2, following a 1-week washout period from experiment 1, the sub-chronically PCP treated rats were randomly assigned (however, unavoidably, some rats that received haloperidol in experiment 1 received clozapine in experiment 2 and some rats that received vehicle in experiment 2 received vehicle in experiment 1) to receive an acute injection of clozapine (1 and 5 mg/kg, i.p., n = 12) or vehicle (0.9% saline, i.p., n = 10), 30 min prior to behavioural testing. The other 10 sub-chronically treated vehicle rats received an acute vehicle injection. Clozapine (Sigma, UK) was dissolved in a minimum volume of acetic acid, made up to volume with distilled water and pH adjusted to 6 with 0.1 M NaOH. The doses of clozapine were chosen on the basis of our previous work showing that 5 mg/kg clozapine significantly attenuated a sub-chronic PCP-induced reversal learning impairment in female hooded-Lister rats [2]. In experiment 3, the second group of 40 sub-chronically PCP treated rats was used in the risperidone study. Ten sub-chronically vehicle treated rats received vehicle acutely. The sub-chronically PCP treated rats were randomly assigned to receive an acute injection of risperidone (0.05–0.2 mg/kg, i.p., n = 9–10 per group) or vehicle (0.9% saline, n = 9), 30 min prior to testing. Risperidone was dissolved in 0.9% saline. A dose range of 0.05–0.2 mg/kg of risperidone is slightly lower than the doses required for clinically comparable D2 receptor occupancy (0.5–1.0 mg/kg [30,32]). However, we have demonstrated in our operant studies, risperidone at 0.2 mg/kg was efficacious against a sub-chronic and acute PCP-induced cognitive deficit [44,45].
2.3. Apparatus The apparatus consisted of an open box made of Plexiglas (52 cm L; 52 cm W; 31 cm H) and was positioned 27 cm above the floor on a moveable trolley. The walls of the box were black and the objects to be discriminated (in triplicate) were made of Plexiglas, metal, glass or wood. The height of the objects was approximately the same (10 ± 2 cm) and they were heavy enough not to be displaced by the animals, to achieve this, some objects were filled with NaCl, e.g. bottles. Objects were positioned 6 cm away from the walls of the box, in opposite corners. After each trial, 10% alcohol was used to clean the objects in an attempt to remove any lingering olfactory cues on the objects and in the box. The familiar and novel objects were counterbalanced to the left and right position to prevent bias for a particular location. In an attempt to limit the number of animals used, we re-tested the rats (experiments 1 and 2). However, unseen sets of objects were used in these studies. 2.3.1. Habituation During the week prior to the first behavioural testing procedure, all rats were handled daily. For 3 days prior to behavioural testing, rats were given daily 1 h exploration periods in the NOR box to ensure habituation to the empty apparatus and test room environment.
B. Grayson et al. / Behavioural Brain Research 184 (2007) 31–38 2.3.2. Behavioural testing A further 3-min habituation session preceded the experimental trials on the day of testing. In the object recognition task, each rat was placed into the box and exposed to two identical objects (A1 and A2) for a period of 3 min. The rats were then returned to their home cage for a 1-min inter-trial interval, the entire box was cleaned, both objects removed and one replaced with an identical familiar copy and one with a novel object. Following the 1-min inter-trial interval, rats were returned to explore the familiar and novel object (B) in the test box for a 3-min retention trial. The location of the novel object in the retention trial was randomly assigned for each rat using a Gellerman schedule. All experiments were filmed and video recorded for subsequent behavioural analysis by an experimenter blind to the treatments. Object exploration was defined as the rats sniffing, licking or touching the objects with forepaws whilst sniffing but not by leaning against, turning around, standing or sitting on the objects [16]. The exploration time (s) of each object in each trial was recorded manually using two stopwatches and the following factors were calculated: E1 = the total exploration time of both objects in the acquisition trial (EA1 + EA2 ), E2 = the total exploration time of both objects in the retention trial (EA + EB ), and H = the habituation of exploratory activity (E1 − E2 ). The index of habituation to the familiar object measures differences between the average time spent in exploring the objects in the acquisition and the retention trials. DI = discrimination index (EB − EA )/(EB + EA ), the discrimination index represents the difference in exploration time expressed as a proportion of the total time spent exploring the two objects in the retention trial.
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Locomotor activity was recorded by counting the total number of sectors (i.e. lines) crossed by the rats during the acquisition and retention trials, there were nine square sectors in the box measuring 17.3 cm × 17.3 cm.
2.4. Statistical analysis The data are expressed as mean ± S.E.M. Student’s paired t-test was performed to compare the effect of treatment on the time spent exploring the familiar versus the novel object. LMA data are expressed as mean ± S.E.M. of the total number of lines crossed during the acquisition and retention trials. Analysis of the LMA and DI data was performed using a one-way ANOVA followed by post hoc Dunnett’s t-test.
3. Results 3.1. Experiment 1 3.1.1. Effect of acute haloperidol treatment in rats sub-chronically treated with PCP 3.1.1.1. Acquisition trial. All groups of rats spent equivalent time exploring the identical objects (left and right) in the
Fig. 1. (a) The effect of acute haloperidol (h; 0.05 and 0.075 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of identical objects in the 3-min acquisition trial of the NOR test. Data are expressed as the mean ± S.E.M. (n = 7–12 per group). (b) The effect of acute haloperidol (h; 0.05 and 0.075 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of a familiar object and a novel object in the 3-min retention trial. Data are expressed as the mean ± S.E.M. (n = 7–12 per group). *p < 0.05, significant difference in time spent exploring the novel compared with the familiar object. (c) The effect of haloperidol (h; 0.05–0.075 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on the discrimination index (DI). Data are expressed as the mean ± S.E.M. (n = 7–12 per group). *p < 0.05; significant reduction in DI. (d) The effect of acute haloperidol (h; 0.05 and 0.075 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on locomotor activity. Data are expressed as mean ± S.E.M. total number of line crossings in both acquisition and retention trial in the NOR task (n = 7–12 per group).
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acquisition phase (Fig. 1a). Statistical analysis showed no significant difference in time spent exploring the identical objects in the acquisition phase in any group.
of lines crossed for both the acquisition and the retention trial) [F(3, 37) = 1.80, p = 0.17] (Fig. 1d). 3.2. Experiment 2
3.1.1.2. 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 sub-chronic PCP treatment, whereby there was no significant difference in exploration of the novel and familiar object (Fig. 1b). Haloperidol at both doses (0.05 and 0.075 mg/kg) failed to improve the sub-chronic PCP-induced impairment. One-way ANOVA revealed a significant effect of treatment on the DI [F(3, 37) = 4.50, p = 0.01]. The DI was significantly (p < 0.05, compared with vehicle) reduced following sub-chronic PCP treatment, an effect that was also observed in haloperidol treated animals (Fig. 1c). 3.1.1.3. Locomotor activity. One-way ANOVA revealed no significant effect of any treatment on locomotor activity (number
3.2.1. Effect of acute clozapine treatment in rats sub-chronically treated with PCP 3.2.1.1. Acquisition trial. Statistical analysis revealed that rats spent similar times exploring the two identical objects in all treatment groups (Fig. 2a). 3.2.1.2. Retention trial. Rats spent significantly more time exploring the novel object compared with the familiar object following sub-chronic vehicle treatment (p < 0.05). In contrast there was no significant difference between the time spent exploring the novel and the familiar object in the sub-chronic PCP treated rats (Fig. 2b). Acute treatment with clozapine, at both doses (1.0 and 5.0 mg/kg), significantly attenuated the sub-chronic PCPinduced impairment such that a significant increase in time spent exploring the novel compared with the familiar object was again
Fig. 2. (a) The effect of acute clozapine (c; 1.0 and 5.0 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of identical objects in the 3-min acquisition trial. Data are expressed as the mean ± S.E.M. (n = 8–11 per group). (b) The effect of acute clozapine (c; 1.0 and 5.0 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of a familiar object and a novel object in the 3-min retention trial. Data are expressed as the mean ± S.E.M. (n = 8–11 per group) *p < 0.05, significant difference in time spent exploring the novel compared with the familiar object. (c) The effect of clozapine (c; 1.0–5.0 mg/kg, i.p.) on sub-chronic PCP treatment on the discrimination index (DI). Data are expressed as the mean ± S.E.M. (n = 8–11 per group). (d) The effect of acute clozapine (c; 1.0 and 5.0 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on locomotor activity. Data are expressed as mean ± S.E.M. total number of line crossings in both acquisition and retention trial in the NOR task (n = 8–11 per group).
B. Grayson et al. / Behavioural Brain Research 184 (2007) 31–38
observed (p < 0.05). One-way ANOVA revealed no significant effect of drug treatment on the DI [F(3, 39) = 0.28, p = 0.83] (Fig. 2c). 3.2.1.3. Locomotor activity. One-way ANOVA revealed no significant effect of any treatment on locomotor activity (number of lines crossed for both the acquisition and the retention trial) [F(3, 39) = 0.68, p = 0.57] (Fig. 2d). 3.3. Experiment 3 3.3.1. Effect of risperidone treatment in rats sub-chronically treated with PCP 3.3.1.1. Acquisition trial. Rats spent similar time exploring the two identical objects in the acquisition phase of the NOR task (Fig. 3a). Statistical analysis showed no significant difference in exploration of the identical objects in the acquisition phase in any treatment group.
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3.3.1.2. Retention trial. Statistical analysis revealed that rats spent significantly more time exploring the novel object compared with the familiar object following sub-chronic vehicle treatment (p < 0.05; Fig. 3b). The ability to discriminate the familiar and novel object was abolished following sub-chronic PCP treatment, whereby there was no significant difference in exploration of the novel and familiar object. Acute treatment with the highest dose of risperidone (0.2 mg/kg) attenuated the sub-chronic PCP-induced impairment such that a significant increase in time spent exploring the novel compared with familiar object was restored (p < 0.05, Fig. 3b). The lower doses (0.05 and 0.1 mg/kg) of risperidone failed to affect the PCP-induced deficit. A one-way ANOVA revealed a significant effect of treatment [F(4, 45) = 6.84, p = 0.001] on DI. The DI was significantly (p < 0.001; *p < 0.05) reduced following subchronic PCP treatment, and in sub-chronic PCP treated rats that received 0.05 mg/kg risperidone acutely. 0.2 mg/kg risperidone significantly (p < 0.01) reversed the sub-chronic PCP-induced reduction in DI (Fig. 3c).
Fig. 3. (a) The effect of acute risperidone treatment (r; 0.05–0.2, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of identical objects in the 3-min retention trial. Data are expressed as the mean ± S.E.M. (n = 9–11 per group). (b) The effect of acute risperidone treatment (r; 0.05–0.2 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of a familiar object and a novel object in the 3-min retention trial. Data are expressed as the mean ± S.E.M. (9–11 per group). *p < 0.05, significant difference in time spent exploring the novel compared with the familiar object. (c) The effect of risperidone (r; 0.05–0.2 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on the discrimination index (DI). Data are expressed as the mean ± S.E.M. (n = 9–11 per group). ***p < 0.001; *p < 0.05 significant decrease in DI. ≈p < 0.01; significant reversal of reduction in DI. (d) The effect of acute risperidone (r; 0.05–0.2 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on locomotor activity. Data are expressed as mean ± S.E.M. total number of line crossings in both the acquisition and retention trial in the NOR task (n = 9–11 per group).
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3.3.1.3. Locomotor activity. One-way ANOVA revealed no significant effect of any treatment on locomotor activity (number of lines crossed for both the acquisition and the retention trial) [F(4, 45) = 0.58, p = 0.67] (Fig. 3d). 4. 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 [42,43,58], possibly due to the differences in pharmacokinetics (Gartlon unpublished findings) Indeed, we have found male rats to be insensitive to effects of acute PCP in NOR [18]. One of the major findings of this study is that a sub-chronic (2.0 mg/kg bi-daily for 7 days) PCP dosing regimen produced a robust cognitive deficit in the NOR task in female rats. This result is supported by the findings of Abdul-Monim et al. [2,3] and Jentsch and Taylor [29] in the rat using reversal learning paradigms. Furthermore, another non-competitive NMDA receptor antagonist, MK801 impairs object recognition in rats [11]. Neuropathological changes in the CA2/3 sub-region of the hippocampus have been observed in the rat following the sub-chronic PCP dosing regimen used in this series of experiments [3]. Decreases in GABAergic interneurons are consistent with pathological changes observed in the hippocampus of post mortem studies in schizophrenia [60]. These corresponding neuropathological effects observed in sub-chronically PCP treated rats and schizophrenic patients provide further evidence to support the validity of sub-chronic PCP as a model of schizophrenia. There was no significant effect on exploration of the two identical objects in the acquisition trial in any treatment group, indicating that animals did not have a preference for either object following PCP and/or antipsychotic treatment. As there were no significant differences in activity observed between vehicle and sub-chronic PCP treated groups or indeed, in any drug treated group, it may be assumed that the cognitive deficit observed and the reported drug effects on object exploration are independent of effects on locomotor activity. In contrast, existing literature [56] has shown that following treatment with a relatively high dose of 10 mg/kg PCP for 15 days, rats demonstrated a persistent (28 days) increase in locomotor activity. However, we have not observed any persistent effects on activity levels of the animals following our PCP treatment regimen in any of our previous studies [23,2,3]. Our study is not without its limitations. The time spent exploring the objects is typically less than 10% of the total time spent in the NOR apparatus. This could be due to our relatively large test apparatus which may perhaps reduce object interaction. Use of a narrow dose range of antipsychotics and re-use of animals is a limitation of the present study. Indeed re-use of animals may explain why the DI for experiment 2 was not significant, and why PCP had a less marked, although still significant, effect
on object exploration time. The nature of the deficit induced by PCP requires further exploration, however, PCP does not produce a deficit if the inter-trial interval is 0 min suggesting that PCP-treated animals can recognise and encode information about the objects and that the memory deficit is delay-dependent (Grayson, unpublished findings) However, in spite of these limitations, the NOR task assesses visual learning and memory, one of the domains of cognitive dysfunction in schizophrenia highlighted by the MATRICS initiative (TURNS.ucla.edu). NOR may therefore provide a relatively quick and simple means of evaluating novel therapies for aspects of cognition in schizophrenia. Furthermore, we have recently demonstrated efficacy of the ampakine, farampator, in this model against PCP, ampakines are a class of compounds with potential as cognitive enhancers [46]. The second major finding of this work is that the PCP-induced cognitive deficit was reversed by the atypical antipsychotics clozapine (1.0 and 5.0 mg/kg) and risperidone (0.2 mg/kg) but not the classical agent haloperidol. Previous studies in our laboratory using the reversal learning paradigm have shown that clozapine and risperidone but not haloperidol can reverse the cognitive deficits induced by sub-chronic PCP treatment [2,45]. In addition, we have recently shown [23] that clozapine (5 mg/kg) but not haloperidol (0.05 mg/kg), when administered in conjunction with the daily sub-chronic PCP treatment regimen, can prevent the PCP-induced cognitive deficit in the NOR paradigm. Our current findings are in agreement with a recent study by Hashimoto et al. [21] who showed, using a subchronic PCP dosing regimen of 10 mg/kg, s.c. once daily for 10 days, administered on days 1–5 and 8–12, that clozapine (5 mg/kg) but not haloperidol (0.1 mg/kg) when administered once daily for 2 weeks, attenuated the sub-chronic PCP-induced deficit in object recognition in mice. Furthermore, Schroeder et al. [53] showed improvement of a sub-chronic (5 mg/kg once daily for 5 days) PCP-induced deficit in holeboard learning by risperidone (0.1 mg/kg). Sams-Dodd [52] has described dose dependent amelioration of PCP-induced social withdrawal by risperidone (0.02–0.63 mg/kg). A study investigating the effect of risperidone in schizophrenic patients on working memory has revealed positive effects [40]. Rossi et al. [51] reported that risperidone improved performance on the Wisconsin Card Sort Test (WCST). Some clinical studies provide further support for our results, the atypical antipsychotic drug, clozapine has shown promise in treating neurocognitive deficits in humans, whereas the typical antipsychotic haloperidol failed to improve the various domains of cognitive function [20]. Therefore the efficacy of clozapine and risperidone, but not haloperidol in the present study demonstrates a good level of predictive validity. The ability of clozapine to reverse the cognitive deficit in the NOR task induced by sub-chronic PCP may be attributed to its high affinity for 5-HT2A receptors [8]. Whereas, the inability of haloperidol to reverse the deficit may be due to its high D2 receptor affinity and minimal 5-HT2A receptor affinity [54]. However, risperidone was highly effective and has both high 5-HT2A and D2 receptor affinity [36]. Risperidone is suggested to be the most effective atypical antipsychotic to improve working memory in the clinic [40].
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We believe the single dose of antipsychotics used in this study are a relevant approximation of the clinical situation since Kapur et al. [32] have shown that similar doses achieve 50% D2 receptor occupancy levels in human. However, the efficacy of clozapine and risperidone to ameliorate the sub-chronic PCP-induced cognitive deficit is unlikely to be due exclusively to the blockade of the D2 receptor. Antipsychotic agents have been shown to alter glutamatergic neurotransmission by modulating the release of glutamate through interaction with glutamate receptors or by altering the density or subunit composition of glutamate receptors [16]. Furthermore, it has been shown that the atypical antipsychotics can exert differential effects on the NMDA receptor compared with the classical agents [37] and chronic antipsychotic treatment has been shown to alter the expression of mRNA encoding NMDA receptor subunits. In conclusion, the present study demonstrates that subchronic PCP treatment in combination with the NOR test may be a useful model for detecting compounds with therapeutic potential in treating the symptomology of cognitive dysfunction associated with schizophrenia. Further studies are required to elucidate the mechanisms underlying the effect of PCP in this test and the ability of the atypical antipsychotics clozapine and risperidone to reverse the deficits induced by sub-chronic PCP administration. References [1] Abdul-Monim Z, Reynolds GP, Neill JC. The atypical antipsychotic ziprasidone, but not haloperidol, improves PCP-induced cognitive deficits in a reversal learning task. J Psychopharmacol 2003;17:57– 66. [2] Abdul-Monim Z, Reynolds GP, Neill JC. The effect of atypical and classical antipsychotics on sub-chronic PCP induced cognitive deficits in a reversallearning paradigm. Behav Brain Res 2006;169:263–73. [3] Abdul-Monim Z, Neill JC, Reynolds GP. Sub-chronic PCP induces a deficit in reversal learning and in parvalbumin-immunoreactive GABAergic neurons in the rat. J Psychopharmacol 2007;21:198–205. [4] Ballmaier M, Zoli M, Mazzoncini R, Gennarelli M, Spano F. Combined alpha 2-adrenergic/D2 dopamine receptor blockade fails to reproduce the ability of clozapine to reverse phencyclidine-induced deficits in prepulse inhibition of startle. Psychopharmacology 2001;159:105–10. [5] Benes FM, Berretta S. GABAergic interneurons. Implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001;25:1–27. [6] Berlyne DE. Novelty and curiosity as determinants of exploratory behavior. Br J Psychol 1950;41:68–80. [7] Braff DL, Saccuzzo DP, Geyer MA. Information processing dysfunction in schizophrenia: studies of visual backward masking, sensorimotor gating and habituation. In: Zubin J, Steinhauer S, Gruzelier JH, editors. Handbook of schizophrenia, volume 4. Neuropsychology, psychophysiology, and information processing. Iowa City, IA: Elsevier Publishers; 1991. p. 303–34. [8] Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996;14. [9] Castellani S, Adams PM. Acute and chronic phencyclidine effects on locomotor activity, stereotypy and ataxia in rats. Eur J Pharmacol 1981;73:143–54. [10] Conklin HM, Curtis CE, Calkins ME, Iacono WG. Working memory functioning in schizophrenia patients and their first degree relatives: cognitive functioning shedding light on etiology. Neuropsychologia 2005; 43:930–42.
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[11] De Lima MNM, Lasranja DC, Bromberg E, Roesler R, Schroeder N. Pre- or post-training administration of the NMDA receptor blocker MK-801 impairs object recognition memory in rats. Behav Brain Res 2005;156:139–43. [12] Egerton A, Reid L, McGregor S, Morris BJ, Pratt JA. Chronic phencyclidine administration produces attentional set shifting deficits in the rat, 2004; Program No. 796.13. Abstract Viewer/itinerary planner. Online. Washington, DC: Society for Neuroscience. [13] Ellison G, Eison MS. Continuous intoxication: an animal model of the acute psychotic episode. Psychol Med 1983;13:751–61. [14] Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. Behav Brain Res 1988;31:47–59. [15] Geyer MA, Krebs-Thomas K, Braff DL, Swerdlow NR. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology 2001;156:117–54. [16] Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiat 2001:1367–77. [17] Grayson B, Neill JC. The effect of PCP on novel object recognition in the rat. J Psychopharmacol 2004;18(3):A55. [18] Grayson B, Leviers N, Neill JC. Acute PCP does not affect novel object recognition in male hooded-Lister rats. J Psychopharmacol 2005;19:A13. [19] Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiat 1996;153:321–30. [20] Harvey PD, Keefe RSE. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiat 2001;158:176–84. [21] Hashimoto K, Fujita Y, Shimizu E, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent sub-chronic administration of clozapine, but not haloperidol. Eur J Pharmacol 2005;519:114–7. [22] Idris NF, Repeto P, Neill JC, Large CH. Investigation of the effects of lamotrigine and clozapine to improve reversal learning impairments induced by acute PCP and d-amphetamine in the rat. Psychopharmacology 2005;179:336–48. [23] Idris NF, Grayson B, Platford E, Neill JC. The ability of antipsychotics to prevent a sub-chronic pcp-induced cognitive deficit in the novel object recognition task in the rat. Soc. Neurosci. Abstr. 2005b;67.15. [24] Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiat 1991;148:1301–8. [25] Jentsch JD, Redmond DE, Elsworth JD, Taylor JR, Younren KD, Roth RH. Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science 1997;277:953–5. [26] Jentsch JD, Tran A, Le D, Youngren KD, Roth RH. Sub-chronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat. Neuropsychopharmacology 1997;17:92–9. [27] Jentsch JD, Dazzi L, Chhatwal JP, Verrico CD, Roth RH. Reduced prefrontal cortical dopamine, but not acetylcholine, release in vivo after repeated, intermittent phencyclidine administration to rats. Neurosci Lett 1998;258:175–8. [28] Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1999;20:201–25. [29] Jentsch JD, Taylor JR. Impaired inhibition of conditioned responses produced by subchronic administration of phencyclidine to rats. Neuropsychopharmacology 2001;24:66–74. [30] Kapur S, Remington G. Dopamine D2 receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiat 2001;50:873–83. [31] Kapur S, Seehuman P. Does fast dissociation from the dopamine D2 receptors explain atypical antipsychotic action—a new hypothesis. Am J Psychiat 2001;158:360–9. [32] Kapur S, Vanderspek SC, Brownlee BA, Nobrega JN. Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy. J Pharmacol Exp Ther 2003;305:625–31. [33] Kesner RP, Dakis M. Phencyclidine disrupts acquisition and retention performance within a spatial continuous recognition memory task. Pharmacol Biochem Behav 1993;44:419–24.
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[48] Puma C, Baudoin C, Bizot JC. Effects of intraseptal infusions of NMDA receptor ligands on memory in an object recognition task in rats. Neurosci Lett 1998;244:97–100. [49] Redmond AM, Harkin A, Kelly JP, Leonard BE. Effects of acute and chronic antidepressant administration on phencyclidine (PCP) induced locomotor hyperactivity. Eur Neuropsychopharmacol 1999;9:165– 70. [50] Rodefer JS, Murphy ER, Baxter MG. PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set shifting in rats. Eur J Neurosci 2005;21:1070–6. [51] Rossi A, Humancini F, Stratta P, et al. Risperidone, negative symptoms and cognitive deficit in schizophrenia: an open study. Acta Psychiat Scand 1997;95:40–3. [52] Sams-Dodd F. The effects of novel antipsychotic drugs on PCP-induced stereotyped behaviour and social isolation in the rat social interaction test. Behav Pharmacol 1997;8:196–215. [53] Schroeder U, Schroeder H, Schwegler H, Sabel BA. Neuroleptics ameliorate phencyclidine-induced impairments of short-term memory. Br J Pharmacol 2000;130:33–40. [54] Siegfried SL, Fleischacker W, Liberman JA. Pharmacological treatment of schizophrenia. In: Liebman JA, Murray RM, editors. Comprehensive care of schizophrenia: a textbook of clinical management. London: Martin Dunitz Ltd.; 2001. p. 59–107. [55] Steinpreis RE. The behavioural and neurochemical effects of phencyclidine in humans and animals: some implications for modelling psychosis. Behav Brain Res 1996;74:45–55. [56] Sturgeon RD, Fesslen R, London SF, Meltzer HY. Behavioral effects of chronic phencyclidine administration in rats. Psychopharmacology 1982;76:52–6. [57] Sutcliffe JS, Marshall K, Neill JC. Influence of gender on working and spatial memory in the novel object recognition task in the rat. Behav Brain Res 2007;177:117–25. [58] Wessinger WD. Sexual dimorphic effects of chronic phencyclidine in rats. Eur J Pharmacol 1995;277:107–12. [59] Yamaguchi K, Nabeshima T, Kameyama T. Role of dopaminergic and GABAergic mechanisms in discrete brain areas in phencyclidineinduced locomotor stimulation and turning behaviour. J Pharmacobiodyn 1986;12:975–86. [60] Zhang ZJ, Reynolds GP. A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizoph Res 2002;1:1–10.
Research report
Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat B. Grayson, N.F. Idris, J.C. Neill ∗ Bradford School of Pharmacy, University of Bradford, West Yorkshire, Bradford BD7 1DP, United Kingdom Received 21 February 2007; received in revised form 12 June 2007; accepted 26 June 2007 Available online 29 June 2007
Abstract The novel object recognition (NOR) task is a paradigm employed to detect both disruption and improvement of non-spatial memory in rats. PCP (phencyclidine) may be used to model aspects of schizophrenia symptomology in rats, in particular cognitive deficits. The aim of this study was to investigate the ability of typical and atypical antipsychotics to improve a sub-chronic PCP-induced impairment in cognition using the NOR task. Female hooded-Lister rats (195 ± 12 g) received either vehicle (0.9% saline twice daily) or PCP (2 mg/kg, twice daily) for 7 days followed by 7-days drug free. Haloperidol (0.05 and 0.075 mg/kg), clozapine (1 and 5 mg/kg), risperidone (0.05, 0.1 and 0.2 mg/kg) or vehicle (veh, saline) was administered i.p. 30 min prior to testing. Rats completed an acquisition trial followed by an inter-trial interval of 1 min, then a retention trial. Following sub-chronic vehicle treatment, rats spent significantly (p < 0.05) more time exploring the novel compared to the familiar object, an effect that was abolished in the sub-chronic PCP treated animals. Clozapine (1.0 and 5.0 mg/kg) and risperidone (0.2 mg/kg) but not haloperidol significantly attenuated the PCP-induced impairment such that animals again spent significantly more time exploring the novel compared with familiar object (p < 0.05). These results support our earlier work showing that acute PCP induces a robust object recognition deficit in female rats. Clozapine and risperidone but not haloperidol showed efficacy to reverse the deficit induced by sub-chronic PCP suggesting that this test may have some validity for assessing efficacy for improvement of cognitive deficit symptoms of schizophrenia. © 2007 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Phencyclidine; Novel object recognition; Antipsychotics; Cognition; Rat
1. 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
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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
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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. 2. Materials and methods 2.1. 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 (21 ± 2 ◦ C) and humidity (45–55%) were kept constant throughout. The experiments were performed in accordance
with the Animals Scientific Procedures act (1986) and were approved by the University of Bradford ethical review process.
2.2. Drug administration 2.2.1. Sub-chronic PCP treatment A total of 92 rats were randomly assigned to receive either vehicle (n = 20; 0.9% saline twice a day, i.p.) or PCP (n = 72; 2 mg/kg twice a day, i.p.) in a volume of 1 ml/kg for 7 days as previously described [2,3,23]. Subsequently, animals were given a 7-day drug-free period prior to NOR testing. This was based on a previous study [27], which suggested that at least a 1-week period of withdrawal was necessary following the final drug administration to ensure that behaviour was not influenced by any residual drug effects. PCP HCl (Sigma, UK) was dissolved in 0.9% saline. In experiment 1, rats that had been treated sub-chronically with PCP were randomly assigned to receive an acute injection of haloperidol (0.05 or 0.075 mg/kg, i.p., n = 7–12 per group) or vehicle (0.9% saline, i.p., n = 10). Haloperidol (Serenace liquid, 2 mg/ml) was prepared in distilled water. Ten of the rats treated sub-chronically with vehicle, received vehicle acutely. The doses of haloperidol were chosen on the basis of our previous work showing that 0.05 mg/kg haloperidol significantly attenuated a d-amphetamine-induced reversal learning impairment in female hooded-Lister rats [22]. Furthermore this dose of haloperidol has been shown to occupy 50% of dopamine D2 receptors [31,32]. In experiment 2, following a 1-week washout period from experiment 1, the sub-chronically PCP treated rats were randomly assigned (however, unavoidably, some rats that received haloperidol in experiment 1 received clozapine in experiment 2 and some rats that received vehicle in experiment 2 received vehicle in experiment 1) to receive an acute injection of clozapine (1 and 5 mg/kg, i.p., n = 12) or vehicle (0.9% saline, i.p., n = 10), 30 min prior to behavioural testing. The other 10 sub-chronically treated vehicle rats received an acute vehicle injection. Clozapine (Sigma, UK) was dissolved in a minimum volume of acetic acid, made up to volume with distilled water and pH adjusted to 6 with 0.1 M NaOH. The doses of clozapine were chosen on the basis of our previous work showing that 5 mg/kg clozapine significantly attenuated a sub-chronic PCP-induced reversal learning impairment in female hooded-Lister rats [2]. In experiment 3, the second group of 40 sub-chronically PCP treated rats was used in the risperidone study. Ten sub-chronically vehicle treated rats received vehicle acutely. The sub-chronically PCP treated rats were randomly assigned to receive an acute injection of risperidone (0.05–0.2 mg/kg, i.p., n = 9–10 per group) or vehicle (0.9% saline, n = 9), 30 min prior to testing. Risperidone was dissolved in 0.9% saline. A dose range of 0.05–0.2 mg/kg of risperidone is slightly lower than the doses required for clinically comparable D2 receptor occupancy (0.5–1.0 mg/kg [30,32]). However, we have demonstrated in our operant studies, risperidone at 0.2 mg/kg was efficacious against a sub-chronic and acute PCP-induced cognitive deficit [44,45].
2.3. Apparatus The apparatus consisted of an open box made of Plexiglas (52 cm L; 52 cm W; 31 cm H) and was positioned 27 cm above the floor on a moveable trolley. The walls of the box were black and the objects to be discriminated (in triplicate) were made of Plexiglas, metal, glass or wood. The height of the objects was approximately the same (10 ± 2 cm) and they were heavy enough not to be displaced by the animals, to achieve this, some objects were filled with NaCl, e.g. bottles. Objects were positioned 6 cm away from the walls of the box, in opposite corners. After each trial, 10% alcohol was used to clean the objects in an attempt to remove any lingering olfactory cues on the objects and in the box. The familiar and novel objects were counterbalanced to the left and right position to prevent bias for a particular location. In an attempt to limit the number of animals used, we re-tested the rats (experiments 1 and 2). However, unseen sets of objects were used in these studies. 2.3.1. Habituation During the week prior to the first behavioural testing procedure, all rats were handled daily. For 3 days prior to behavioural testing, rats were given daily 1 h exploration periods in the NOR box to ensure habituation to the empty apparatus and test room environment.
B. Grayson et al. / Behavioural Brain Research 184 (2007) 31–38 2.3.2. Behavioural testing A further 3-min habituation session preceded the experimental trials on the day of testing. In the object recognition task, each rat was placed into the box and exposed to two identical objects (A1 and A2) for a period of 3 min. The rats were then returned to their home cage for a 1-min inter-trial interval, the entire box was cleaned, both objects removed and one replaced with an identical familiar copy and one with a novel object. Following the 1-min inter-trial interval, rats were returned to explore the familiar and novel object (B) in the test box for a 3-min retention trial. The location of the novel object in the retention trial was randomly assigned for each rat using a Gellerman schedule. All experiments were filmed and video recorded for subsequent behavioural analysis by an experimenter blind to the treatments. Object exploration was defined as the rats sniffing, licking or touching the objects with forepaws whilst sniffing but not by leaning against, turning around, standing or sitting on the objects [16]. The exploration time (s) of each object in each trial was recorded manually using two stopwatches and the following factors were calculated: E1 = the total exploration time of both objects in the acquisition trial (EA1 + EA2 ), E2 = the total exploration time of both objects in the retention trial (EA + EB ), and H = the habituation of exploratory activity (E1 − E2 ). The index of habituation to the familiar object measures differences between the average time spent in exploring the objects in the acquisition and the retention trials. DI = discrimination index (EB − EA )/(EB + EA ), the discrimination index represents the difference in exploration time expressed as a proportion of the total time spent exploring the two objects in the retention trial.
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Locomotor activity was recorded by counting the total number of sectors (i.e. lines) crossed by the rats during the acquisition and retention trials, there were nine square sectors in the box measuring 17.3 cm × 17.3 cm.
2.4. Statistical analysis The data are expressed as mean ± S.E.M. Student’s paired t-test was performed to compare the effect of treatment on the time spent exploring the familiar versus the novel object. LMA data are expressed as mean ± S.E.M. of the total number of lines crossed during the acquisition and retention trials. Analysis of the LMA and DI data was performed using a one-way ANOVA followed by post hoc Dunnett’s t-test.
3. Results 3.1. Experiment 1 3.1.1. Effect of acute haloperidol treatment in rats sub-chronically treated with PCP 3.1.1.1. Acquisition trial. All groups of rats spent equivalent time exploring the identical objects (left and right) in the
Fig. 1. (a) The effect of acute haloperidol (h; 0.05 and 0.075 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of identical objects in the 3-min acquisition trial of the NOR test. Data are expressed as the mean ± S.E.M. (n = 7–12 per group). (b) The effect of acute haloperidol (h; 0.05 and 0.075 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of a familiar object and a novel object in the 3-min retention trial. Data are expressed as the mean ± S.E.M. (n = 7–12 per group). *p < 0.05, significant difference in time spent exploring the novel compared with the familiar object. (c) The effect of haloperidol (h; 0.05–0.075 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on the discrimination index (DI). Data are expressed as the mean ± S.E.M. (n = 7–12 per group). *p < 0.05; significant reduction in DI. (d) The effect of acute haloperidol (h; 0.05 and 0.075 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on locomotor activity. Data are expressed as mean ± S.E.M. total number of line crossings in both acquisition and retention trial in the NOR task (n = 7–12 per group).
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acquisition phase (Fig. 1a). Statistical analysis showed no significant difference in time spent exploring the identical objects in the acquisition phase in any group.
of lines crossed for both the acquisition and the retention trial) [F(3, 37) = 1.80, p = 0.17] (Fig. 1d). 3.2. Experiment 2
3.1.1.2. 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 sub-chronic PCP treatment, whereby there was no significant difference in exploration of the novel and familiar object (Fig. 1b). Haloperidol at both doses (0.05 and 0.075 mg/kg) failed to improve the sub-chronic PCP-induced impairment. One-way ANOVA revealed a significant effect of treatment on the DI [F(3, 37) = 4.50, p = 0.01]. The DI was significantly (p < 0.05, compared with vehicle) reduced following sub-chronic PCP treatment, an effect that was also observed in haloperidol treated animals (Fig. 1c). 3.1.1.3. Locomotor activity. One-way ANOVA revealed no significant effect of any treatment on locomotor activity (number
3.2.1. Effect of acute clozapine treatment in rats sub-chronically treated with PCP 3.2.1.1. Acquisition trial. Statistical analysis revealed that rats spent similar times exploring the two identical objects in all treatment groups (Fig. 2a). 3.2.1.2. Retention trial. Rats spent significantly more time exploring the novel object compared with the familiar object following sub-chronic vehicle treatment (p < 0.05). In contrast there was no significant difference between the time spent exploring the novel and the familiar object in the sub-chronic PCP treated rats (Fig. 2b). Acute treatment with clozapine, at both doses (1.0 and 5.0 mg/kg), significantly attenuated the sub-chronic PCPinduced impairment such that a significant increase in time spent exploring the novel compared with the familiar object was again
Fig. 2. (a) The effect of acute clozapine (c; 1.0 and 5.0 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of identical objects in the 3-min acquisition trial. Data are expressed as the mean ± S.E.M. (n = 8–11 per group). (b) The effect of acute clozapine (c; 1.0 and 5.0 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of a familiar object and a novel object in the 3-min retention trial. Data are expressed as the mean ± S.E.M. (n = 8–11 per group) *p < 0.05, significant difference in time spent exploring the novel compared with the familiar object. (c) The effect of clozapine (c; 1.0–5.0 mg/kg, i.p.) on sub-chronic PCP treatment on the discrimination index (DI). Data are expressed as the mean ± S.E.M. (n = 8–11 per group). (d) The effect of acute clozapine (c; 1.0 and 5.0 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on locomotor activity. Data are expressed as mean ± S.E.M. total number of line crossings in both acquisition and retention trial in the NOR task (n = 8–11 per group).
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observed (p < 0.05). One-way ANOVA revealed no significant effect of drug treatment on the DI [F(3, 39) = 0.28, p = 0.83] (Fig. 2c). 3.2.1.3. Locomotor activity. One-way ANOVA revealed no significant effect of any treatment on locomotor activity (number of lines crossed for both the acquisition and the retention trial) [F(3, 39) = 0.68, p = 0.57] (Fig. 2d). 3.3. Experiment 3 3.3.1. Effect of risperidone treatment in rats sub-chronically treated with PCP 3.3.1.1. Acquisition trial. Rats spent similar time exploring the two identical objects in the acquisition phase of the NOR task (Fig. 3a). Statistical analysis showed no significant difference in exploration of the identical objects in the acquisition phase in any treatment group.
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3.3.1.2. Retention trial. Statistical analysis revealed that rats spent significantly more time exploring the novel object compared with the familiar object following sub-chronic vehicle treatment (p < 0.05; Fig. 3b). The ability to discriminate the familiar and novel object was abolished following sub-chronic PCP treatment, whereby there was no significant difference in exploration of the novel and familiar object. Acute treatment with the highest dose of risperidone (0.2 mg/kg) attenuated the sub-chronic PCP-induced impairment such that a significant increase in time spent exploring the novel compared with familiar object was restored (p < 0.05, Fig. 3b). The lower doses (0.05 and 0.1 mg/kg) of risperidone failed to affect the PCP-induced deficit. A one-way ANOVA revealed a significant effect of treatment [F(4, 45) = 6.84, p = 0.001] on DI. The DI was significantly (p < 0.001; *p < 0.05) reduced following subchronic PCP treatment, and in sub-chronic PCP treated rats that received 0.05 mg/kg risperidone acutely. 0.2 mg/kg risperidone significantly (p < 0.01) reversed the sub-chronic PCP-induced reduction in DI (Fig. 3c).
Fig. 3. (a) The effect of acute risperidone treatment (r; 0.05–0.2, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of identical objects in the 3-min retention trial. Data are expressed as the mean ± S.E.M. (n = 9–11 per group). (b) The effect of acute risperidone treatment (r; 0.05–0.2 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on exploration time (s) of a familiar object and a novel object in the 3-min retention trial. Data are expressed as the mean ± S.E.M. (9–11 per group). *p < 0.05, significant difference in time spent exploring the novel compared with the familiar object. (c) The effect of risperidone (r; 0.05–0.2 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on the discrimination index (DI). Data are expressed as the mean ± S.E.M. (n = 9–11 per group). ***p < 0.001; *p < 0.05 significant decrease in DI. ≈p < 0.01; significant reversal of reduction in DI. (d) The effect of acute risperidone (r; 0.05–0.2 mg/kg, i.p.) and sub-chronic PCP (2.0 mg/kg, i.p., twice daily for 7 days) on locomotor activity. Data are expressed as mean ± S.E.M. total number of line crossings in both the acquisition and retention trial in the NOR task (n = 9–11 per group).
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3.3.1.3. Locomotor activity. One-way ANOVA revealed no significant effect of any treatment on locomotor activity (number of lines crossed for both the acquisition and the retention trial) [F(4, 45) = 0.58, p = 0.67] (Fig. 3d). 4. 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 [42,43,58], possibly due to the differences in pharmacokinetics (Gartlon unpublished findings) Indeed, we have found male rats to be insensitive to effects of acute PCP in NOR [18]. One of the major findings of this study is that a sub-chronic (2.0 mg/kg bi-daily for 7 days) PCP dosing regimen produced a robust cognitive deficit in the NOR task in female rats. This result is supported by the findings of Abdul-Monim et al. [2,3] and Jentsch and Taylor [29] in the rat using reversal learning paradigms. Furthermore, another non-competitive NMDA receptor antagonist, MK801 impairs object recognition in rats [11]. Neuropathological changes in the CA2/3 sub-region of the hippocampus have been observed in the rat following the sub-chronic PCP dosing regimen used in this series of experiments [3]. Decreases in GABAergic interneurons are consistent with pathological changes observed in the hippocampus of post mortem studies in schizophrenia [60]. These corresponding neuropathological effects observed in sub-chronically PCP treated rats and schizophrenic patients provide further evidence to support the validity of sub-chronic PCP as a model of schizophrenia. There was no significant effect on exploration of the two identical objects in the acquisition trial in any treatment group, indicating that animals did not have a preference for either object following PCP and/or antipsychotic treatment. As there were no significant differences in activity observed between vehicle and sub-chronic PCP treated groups or indeed, in any drug treated group, it may be assumed that the cognitive deficit observed and the reported drug effects on object exploration are independent of effects on locomotor activity. In contrast, existing literature [56] has shown that following treatment with a relatively high dose of 10 mg/kg PCP for 15 days, rats demonstrated a persistent (28 days) increase in locomotor activity. However, we have not observed any persistent effects on activity levels of the animals following our PCP treatment regimen in any of our previous studies [23,2,3]. Our study is not without its limitations. The time spent exploring the objects is typically less than 10% of the total time spent in the NOR apparatus. This could be due to our relatively large test apparatus which may perhaps reduce object interaction. Use of a narrow dose range of antipsychotics and re-use of animals is a limitation of the present study. Indeed re-use of animals may explain why the DI for experiment 2 was not significant, and why PCP had a less marked, although still significant, effect
on object exploration time. The nature of the deficit induced by PCP requires further exploration, however, PCP does not produce a deficit if the inter-trial interval is 0 min suggesting that PCP-treated animals can recognise and encode information about the objects and that the memory deficit is delay-dependent (Grayson, unpublished findings) However, in spite of these limitations, the NOR task assesses visual learning and memory, one of the domains of cognitive dysfunction in schizophrenia highlighted by the MATRICS initiative (TURNS.ucla.edu). NOR may therefore provide a relatively quick and simple means of evaluating novel therapies for aspects of cognition in schizophrenia. Furthermore, we have recently demonstrated efficacy of the ampakine, farampator, in this model against PCP, ampakines are a class of compounds with potential as cognitive enhancers [46]. The second major finding of this work is that the PCP-induced cognitive deficit was reversed by the atypical antipsychotics clozapine (1.0 and 5.0 mg/kg) and risperidone (0.2 mg/kg) but not the classical agent haloperidol. Previous studies in our laboratory using the reversal learning paradigm have shown that clozapine and risperidone but not haloperidol can reverse the cognitive deficits induced by sub-chronic PCP treatment [2,45]. In addition, we have recently shown [23] that clozapine (5 mg/kg) but not haloperidol (0.05 mg/kg), when administered in conjunction with the daily sub-chronic PCP treatment regimen, can prevent the PCP-induced cognitive deficit in the NOR paradigm. Our current findings are in agreement with a recent study by Hashimoto et al. [21] who showed, using a subchronic PCP dosing regimen of 10 mg/kg, s.c. once daily for 10 days, administered on days 1–5 and 8–12, that clozapine (5 mg/kg) but not haloperidol (0.1 mg/kg) when administered once daily for 2 weeks, attenuated the sub-chronic PCP-induced deficit in object recognition in mice. Furthermore, Schroeder et al. [53] showed improvement of a sub-chronic (5 mg/kg once daily for 5 days) PCP-induced deficit in holeboard learning by risperidone (0.1 mg/kg). Sams-Dodd [52] has described dose dependent amelioration of PCP-induced social withdrawal by risperidone (0.02–0.63 mg/kg). A study investigating the effect of risperidone in schizophrenic patients on working memory has revealed positive effects [40]. Rossi et al. [51] reported that risperidone improved performance on the Wisconsin Card Sort Test (WCST). Some clinical studies provide further support for our results, the atypical antipsychotic drug, clozapine has shown promise in treating neurocognitive deficits in humans, whereas the typical antipsychotic haloperidol failed to improve the various domains of cognitive function [20]. Therefore the efficacy of clozapine and risperidone, but not haloperidol in the present study demonstrates a good level of predictive validity. The ability of clozapine to reverse the cognitive deficit in the NOR task induced by sub-chronic PCP may be attributed to its high affinity for 5-HT2A receptors [8]. Whereas, the inability of haloperidol to reverse the deficit may be due to its high D2 receptor affinity and minimal 5-HT2A receptor affinity [54]. However, risperidone was highly effective and has both high 5-HT2A and D2 receptor affinity [36]. Risperidone is suggested to be the most effective atypical antipsychotic to improve working memory in the clinic [40].
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We believe the single dose of antipsychotics used in this study are a relevant approximation of the clinical situation since Kapur et al. [32] have shown that similar doses achieve 50% D2 receptor occupancy levels in human. However, the efficacy of clozapine and risperidone to ameliorate the sub-chronic PCP-induced cognitive deficit is unlikely to be due exclusively to the blockade of the D2 receptor. Antipsychotic agents have been shown to alter glutamatergic neurotransmission by modulating the release of glutamate through interaction with glutamate receptors or by altering the density or subunit composition of glutamate receptors [16]. Furthermore, it has been shown that the atypical antipsychotics can exert differential effects on the NMDA receptor compared with the classical agents [37] and chronic antipsychotic treatment has been shown to alter the expression of mRNA encoding NMDA receptor subunits. In conclusion, the present study demonstrates that subchronic PCP treatment in combination with the NOR test may be a useful model for detecting compounds with therapeutic potential in treating the symptomology of cognitive dysfunction associated with schizophrenia. Further studies are required to elucidate the mechanisms underlying the effect of PCP in this test and the ability of the atypical antipsychotics clozapine and risperidone to reverse the deficits induced by sub-chronic PCP administration. References [1] Abdul-Monim Z, Reynolds GP, Neill JC. The atypical antipsychotic ziprasidone, but not haloperidol, improves PCP-induced cognitive deficits in a reversal learning task. J Psychopharmacol 2003;17:57– 66. [2] Abdul-Monim Z, Reynolds GP, Neill JC. The effect of atypical and classical antipsychotics on sub-chronic PCP induced cognitive deficits in a reversallearning paradigm. Behav Brain Res 2006;169:263–73. [3] Abdul-Monim Z, Neill JC, Reynolds GP. Sub-chronic PCP induces a deficit in reversal learning and in parvalbumin-immunoreactive GABAergic neurons in the rat. J Psychopharmacol 2007;21:198–205. [4] Ballmaier M, Zoli M, Mazzoncini R, Gennarelli M, Spano F. Combined alpha 2-adrenergic/D2 dopamine receptor blockade fails to reproduce the ability of clozapine to reverse phencyclidine-induced deficits in prepulse inhibition of startle. Psychopharmacology 2001;159:105–10. [5] Benes FM, Berretta S. GABAergic interneurons. Implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001;25:1–27. [6] Berlyne DE. Novelty and curiosity as determinants of exploratory behavior. Br J Psychol 1950;41:68–80. [7] Braff DL, Saccuzzo DP, Geyer MA. Information processing dysfunction in schizophrenia: studies of visual backward masking, sensorimotor gating and habituation. In: Zubin J, Steinhauer S, Gruzelier JH, editors. Handbook of schizophrenia, volume 4. Neuropsychology, psychophysiology, and information processing. Iowa City, IA: Elsevier Publishers; 1991. p. 303–34. [8] Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996;14. [9] Castellani S, Adams PM. Acute and chronic phencyclidine effects on locomotor activity, stereotypy and ataxia in rats. Eur J Pharmacol 1981;73:143–54. [10] Conklin HM, Curtis CE, Calkins ME, Iacono WG. Working memory functioning in schizophrenia patients and their first degree relatives: cognitive functioning shedding light on etiology. Neuropsychologia 2005; 43:930–42.
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