Subchronic Phencyclidine Administration Research Articles

A Kpna1-deficient psychotropic drug-induced schizophrenia model mouse for studying gene–environment interactions

KPNA1 is a mediator of nucleocytoplasmic transport that is abundantly expressed in the mammalian brain and regulates neuronal differentiation and synaptic function. De novo mutations in Kpna1 have been identified using genome-wide association studies in humans with schizophrenia; however, it remains unclear how KPNA1 contributes to schizophrenia pathogenesis. Recent studies have suggested a complex combination of genetic and environmental factors that are closely related to psychiatric disorders. Here, we found that subchronic administration of phencyclidine, a psychotropic drug, induced vulnerability and behavioral abnormalities consistent with the symptoms of schizophrenia in Kpna1-deficient mice. Microarray assessment revealed that the expression levels of dopamine d1/d2 receptors, an RNA editing enzyme, and a cytoplasmic dynein component were significantly altered in the nucleus accumbens brain region in a gene-environment (G × E) interaction-dependent manner. Our findings demonstrate that Kpna1-deficient mice may be useful as a G × E interaction mouse model for psychiatric disorders and for further investigation into the pathogenesis of such diseases and disorders.

Pharmacological characterization of SAGE-718, a novel positive allosteric modulator of N-methyl-d-aspartate receptors.

Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC), which is an N-methyl-d-aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction. Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE-718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile. SAGE-718 potentiated GluN1/GluN2A-D NMDA receptors with equipotency and increased NMDA receptor excitatory postsynaptic potential (EPSP) amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE-718 increased the rate of unblock of the NMDA receptor open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine-evoked increase in gamma frequency band power, as measured with electroencephalogram (EEG), suggesting that PAM activity is driven by increased channel open probability. SAGE-718 ameliorated deficits due to NMDA receptor hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioural and electrophysiological deficits from cholesterol and 24(S)-HC depletion caused by 7-dehydrocholesterol reductase inhibition. Finally, SAGE-718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing. These findings provide strong evidence that SAGE-718 is a neuroactive steroid NMDA receptor PAM with a mechanism that is well suited as a treatment for conditions associated with NMDA receptor hypofunction.

Optimization and pharmacological validation of a set-shifting procedure for assessing executive function in rats

BackgroundSet-shifting tests represent a reliable paradigm to assess executive functions in humans and animals. In the rat, set-shifting in a cross-maze is a recognized method. In this test, rats must learn an egocentric rule to locate food reinforcement. Once acquired, a second rule, based on visual-cue strategy, allows the location of the food. Ability of rats to shift from the first to the second rule is considered to reflect cognitive flexibility. New methodThis study aimed at optimizing the most currently used set-shifting protocol in a cross-maze for standardized drug testing by modulating the parameters related to caloric restriction, reward preference, and by redefining the notion of turn bias and classification of errors sub-types, i.e. perseverative vs. regressive. The new protocol has then been used to assess rats treated by sub-chronic phencyclidine administration and investigate the potential reversal effect of tolcapone, a brain penetrant catechol-O-methyl transferase inhibitor. ResultsThe new procedure resulted in a decreased total duration and a re-definition of turn bias and error subtypes. Despite preferences for sweet rewards, caloric restriction had to be maintained to motivate animals. Overall, sub-chronic PCP-treated rats made mostly perseverative errors compared to controls and required more trials to shift between the two rules. Tolcapone partly reversed impairments observed in PCP-treated rats. ConclusionThe new protocol has improved the reliability of key parameters and has contributed to the decrease of the test duration. PCP-treated rats submitted to this protocol have been shown to have significant deficits that could be reversed by tolcapone.

Re-evaluating the PCP challenge as a pre-clinical model of impaired cognitive flexibility in schizophrenia

NMDA-R antagonists are a popular translational pharmacological challenge to induce cognitive deficits associated with schizophrenia. Amongst their many cognitive and non-cognitive effects is an ability to impair cognitive flexibility in general, and reversal learning in particular. Here, we test the hypothesis that the NMDA-R antagonist phencyclidine when given acutely selectively effects reversal learning by simultaneously measuring reversal learning and baseline responding, or acquisition and baseline responding, under identical conditions. Animals were trained to simultaneously perform two different visual discriminations in a touch-screen equipped operant box. Accordingly the reward contingencies associated with one pair could be altered, while the second pair acted as an experimental control. As such, the effect of a manipulation on reversal learning, stimuli acquisition, or baseline responding can be more accurately evaluated through the use of a double visual discrimination. A similar approach was also used to investigate the influence of sub-chronic phencyclidine administration on cognitive flexibility. Phencyclidine (1mg/kg) given before testing caused a slowing in acquisition and reversal learning, while having a minimal effect on secondary measures. Sub-chronic phencyclidine administration had no significant effect on any of the measures used within this study. While acute phencyclidine impairs reversal learning, it is clear from these results that other aspects of cognition (learning/relearning) are also impaired, potentially questioning the specificity of acute phencyclidine in conjunction with reversal learning paradigms as a model of impaired cognitive flexibility.

Analysis of sociability and preference for social novelty in the acute and subchronic phencyclidine rat.

Both acute and sub-chronic phencyclidine administration produce behavioural and pathophysiological changes that resemble some features of schizophrenia. The present study aimed to determine if acute and sub-chronic phencyclidine treatment in male rats produces deficits in sociability and social novelty preference, which may reflect aspects of the negative symptomatology observed in schizophrenia. Rats were treated with phencyclidine acutely (2 or 5 mg/kg) or subchronically (2 or 5 mg/kg bi-daily for one week followed by a one week wash-out period) or vehicle. Social affiliative behaviour was assessed using the sociability and preference for social novelty paradigm where social interaction time was measured in (a) a chamber containing an unfamiliar conspecific vs an empty chamber (sociability), or (b) a chamber containing an unfamiliar conspecific vs a chamber containing a familiar conspecific (preference for social novelty). Results showed that acute administration of phencyclidine produced a reduction in measures of sociability but had no effect on preference for social novelty while sub-chronic administration of phencyclidine had no effect on sociability or social novelty. This study provides further evidence for the usefulness of phencyclidine models in modelling the symptomatology of schizophrenia.

EPA-0117 – The use of bacosides a and b to prevent a cognitive deficit in schizophrenia rat models resulting in increased vesicular glutamate transporter 2 (VGLUT2) in the cingulate gyrus

Cognitive impairment is a debilitating symptom of schizophrenic patients causing functional disability. Neither typical nor atypical antipsychotic drugs are able to control it. There is a strong potential that Bacosides A and B from the plant Bacopa monnieri (Brahmi) could be a novel neuroprotective compound for the prevention of cognnitive deficits in schizophrenia. To study neuroprotective effects of Brahmi on novel object recognition tasks and the cerebral VGLUT2 density in rat models that are schizophrenia induced through sub-chronic phencyclidine (PCP) administration. Rats were divided into 3 groups; Group-A: Control; Group-B: PCP and Group-C: Bacosides A and B + PCP. Discrimination ratio (DR) representing cognitive ability was obtained from novel object recognition test. VGLUT2 density was measured in prefrontal cortex, striatum, cornu ammonis fields 1 (CA1) 2/3 (CA2/3) of hippocampus using immunohistochemistry. DR in the PCP-group was significantly decreased compared with the control group. This occurred alongside reduced VGLUT2 in the cingulate gyrus. Bacosides A and B + PCP group showed a significant increase in DR score compared with PCP alone. This occurred alongside a significant increase in VGLUT2 in the cingulate gyrus. Cognitive deficit observed in rats receiving PCP administration was mediated by VGLUT2 reduction in the cingulate gyrus. Administration of Bacosides A and B before PCP administration can restore this cognitive deficit by increasing VGLUT2 density in this brain area to normal level. Conclusively, Bacosides A and B could be a novel neuroprotective compound for prevention of cognitive deficits in schizophrenia.

Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia

Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia-like psychosis in humans. Subchronic phencyclidine (PCP) administration is a well-established model for schizophrenia-like symptoms in rodents. The aim of the present study was to investigate whether subchronic PCP administration changes expression, binding, or functionality of cortical 5-HT2A Rs. As a measure of 5-HT2A R functionality, we used the 5-HT2A R agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch response (HTR) and mRNA expression of the immediate-early genes (IEGs) activity-related cytoskeletal associated-protein (Arc), c-fos, and early growth response protein 2 (egr-2) in the frontal cortex. Mice were treated with PCP (10 mg/kg) or saline for 10 days, followed by a 5-day washout period. The PCP pretreatment increased the overall induction of HTR and frontal cortex IEG mRNA expression following a single challenge with DOI. These functional changes were not associated with changes in 5-HT2A R binding. Also, binding of the 5-HT1A R and the 5-HT transporter was unaffected. Finally, basal mRNA level of Arc was increased in the prefrontal cortex after subchronic PCP administration as revealed with in situ hybridization. Together these findings indicate that PCP administration produces changes in the brain that result in an increase in the absolute effect of DOI. Therefore, neurotransmission involving the 5-HT2A R could contribute to the behavioral deficits observed after PCP treatment. © 2013 Wiley Periodicals, Inc.

Effects of novel, high affinity glycine transport inhibitors on frontostriatal dopamine release in a rodent model of schizophrenia

Dopaminergic hyperactivity within frontostriatal brain systems is a key feature of schizophrenia, and an objective neural correlate of positive schizophrenia symptoms. N-methyl-d-aspartate (NMDA) receptors are known to play a prominent role in regulation of frontostriatal dopamine release. Furthermore, disturbances in glutamatergic function are increasingly being linked to pathophysiology of both positive and negative symptoms of schizophrenia. Prior studies have demonstrated that subchronic continuous administration of the NMDA antagonist phencyclidine (PCP) induces schizophrenia-like hyper-reactivity of frontostriatal dopamine release to amphetamine (AMPH) in rodents, and that effects were reversed by glycine and the prototypic glycine transport inhibitor (GTI) NFPS. The present study investigates effectiveness of the novel, high affinity and well tolerated GTIs, R231857, R231860 and Org29335, to reverse schizophrenia-like enhancement of AMPH-induced DA release, along with effects of the partial glycine-site agonist d-cycloserine. As previously, PCP had no significant effect on basal DA levels, but significantly enhanced AMPH-induced DA release in prefrontal cortex. All GTIs tested, as well as d-cycloserine, significantly reduced PCP-induced enhancement of DA release in prefrontal cortex. Neither PCP nor GTIs significantly affected striatal DA release. Overall, these findings suggest that treatments which target the glycine modulatory site of the NMDA receptor may significantly reverse NMDA receptor antagonist-induced dysregulation of frontal DA systems, consistent with potential beneficial effects on positive-, in addition to negative-, symptoms of schizophrenia.

P-1288 - Neuroprotective and cognitive enhancement effects of bacopa monnieri on novel object recognition in schizophrenic rat model

Cognitive impairment is a common characteristic of schizophrenia. Bacopa monnieri (Brahmi), a traditional Indian medicine, was shown to improve cognition. This study aimed to investigate cognitive-enhancement and neuroprotective effects of Brahmi in a schizophrenic rat model, induced by sub-chronic phencyclidine (PCP) administration. The novel object recognition (NOR) was used to evaluate the cognitive function. 72 Male Wistar rats, weighting 200–220 g, were divided into four groups: Group-1 received PCP (2 mg/kg, i.p., twice daily, for 7 days); Group-2 received 0.9% NaCl i.p. for 7 days; Group-3 orally received Brahmi extract (40 mg/kg/day, for 14 days) followed by PCP injection for 7 days; Group-4 orally received vehicle for 14 days then 0.9% NaCl injection for 7 days. NOR was compared between Group-1 and Group-2, and between Group-3 and Group-4 using t-test. Group-1 rats were then divided into two groups: orally received Brahmi (Group-1A) and vehicle (Group-1B) for 14 days. Mean NOR was compared between the two groups. Mean NOR of Group-1 is less than Group-2 (p = 0.002). Mean NOR of Group-3 is significantly higher than Group-4 (p = 0.007), indicating a neuroprotection from Brahmi. When divided Group-1 rats into two sub-groups, mean NOR of the schizophrenic rats receiving Brahmi (Group-1A) is higher than those receiving vehicle (Group-1B) (p = 0.02). Conclusively, cognitive deficit occurs in the PCP-administered rats; however, it could be recovery after Brahmi administration. Moreover, Brahmi was shown to prevent the cognitive deficit. Overall, our data indicate that Brahmi has both neuroprotective and cognitive enhancement effects in schizophrenic rat model.

The Novel Antipsychotic Drug Lurasidone Enhances N-Methyl-d-aspartate Receptor-Mediated Synaptic Responses

N-Methyl-D-aspartate (NMDA) receptor (NMDAR) hypofunction has been postulated to contribute to the cognitive deficit of schizophrenia. In this study, we examined the effect of lurasidone (Latuda; Dainippon Sumitomo Pharma Co. Ltd., Tokyo, Japan), a newly approved atypical antipsychotic drug (APD), on NMDAR synaptic function in rat frontal cortical pyramidal neurons. In vivo administration of lurasidone produced a significant and selective enhancement of NMDAR-mediated synaptic responses and surface expression of NR2A and NR2B subunits. Lurasidone has high affinity for serotonin 5-HT(1A), 5-HT(2A), and 5-HT(7) receptors and dopamine D(2) receptors. In vivo administration of the 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2 -(2-(4-methyl-1-piperidinyl)ethyl)pyrrolidine (SB-269970) mimicked the enhancing effect of lurasidone on NMDAR responses, whereas the D(2) receptor antagonist haloperidol failed to do so. Previous studies have found that short-term administration of lurasidone reverses the cognitive impairment induced by subchronic administration of phencyclidine (PCP), an NMDAR noncompetitive antagonist. In this study, we found that lurasidone, as well as the prototypical atypical APD clozapine, restored NMDAR-mediated synaptic responses to normal levels in the PCP model of schizophrenia. These results suggest that NMDAR is the potential key molecular target of lurasidone, possibility via antagonizing 5-HT(7) receptors, which is consistent with evidence that 5-HT(7) receptor antagonism contributes to cognitive enhancement by atypical APDs in patients with schizophrenia.

Asenapine effects on cognitive and monoamine dysfunction elicited by subchronic phencyclidine administration

PurposeRepeated, intermittent administration of the psychotropic NMDA antagonist phencyclidine (PCP) to laboratory animals causes impairment in cognitive and executive functions, modeling important sequelae of schizophrenia; these effects are thought to be due to a dysregulation of neurotransmission within the prefrontal cortex. Atypical antipsychotic drugs have been reported to have measurable, if incomplete, effects on cognitive dysfunction in this model, and these effects may be due to their ability to normalize a subset of the physiological deficits occurring within the prefrontal cortex. Asenapine is an atypical antipsychotic approved in the US for the treatment of schizophrenia and for the treatment, as monotherapy or adjunctive therapy to lithium or valproate, of acute manic or mixed episodes associated bipolar I disorder. To understand its cognitive and neurochemical actions more fully, we explored the effects of short- and long-term dosing with asenapine on measures of cognitive and motor function in normal monkeys and in those previously exposed for 2 weeks to PCP; we further studied the impact of treatment with asenapine on dopamine and serotonin turnover in discrete brain regions from the same cohort. MethodsMonkeys were trained to perform reversal learning and object retrieval procedures before twice daily administration of PCP (0.3 mg/kg intra-muscular) or saline for 14 days. Tests confirmed cognitive deficits in PCP-exposed animals before beginning twice daily administration of saline (control) or asenapine (50, 100, or 150 μg/kg, intra-muscular). Dopamine and serotonin turnover were assessed in 15 specific brain regions by high-pressure liquid chromatography measures of the ratio of parent amine to its major metabolite. ResultsOn average, PCP-treated monkeys made twice as many errors in the reversal task as did control monkeys. Asenapine facilitated reversal learning performance in PCP-exposed monkeys, with improvements at trend level after 1 week of administration and reaching significance after 2–4 weeks of dosing. In week 4, the improvement with asenapine 150 μg/kg (p = 0.01) rendered the performance of PCP-exposed monkeys indistinguishable from that of normal monkeys without compromising fine motor function. Asenapine administration (150 μg/kg twice daily) produced an increase in dopamine and serotonin turnover in most brain regions of control monkeys and asenapine (50–150 μg/kg) increased dopamine and serotonin turnover in several brain regions of subchronic PCP-treated monkeys. No significant changes in the steady-state levels of dopamine or serotonin were observed in any brain region except for the central amygdala, in which a significant depletion of dopamine was observed in PCP-treated control monkeys; asenapine treatment reversed this dopamine depletion. A significant decrease in serotonin utilization was observed in the orbitofrontal cortex and nucleus accumbens in PCP monkeys, which may underlie poor reversal learning. In the same brain regions, dopamine utilization was not affected. Asenapine ameliorated this serotonin deficit in a dose-related manner that matched its efficacy for reversing the cognitive deficit. ConclusionsIn this model of cognitive dysfunction, asenapine produced substantial gains in executive functions that were maintained with long-term administration. The cognition-enhancing effects of asenapine and the neurochemical changes in serotonin and dopamine turnover seen in this study are hypothesized to be primarily related to its potent serotonergic and noradrenergic receptor binding properties, and support the potential for asenapine to reduce cognitive dysfunction in patients with schizophrenia and bipolar disorder.This article is part of a Special Issue entitled ‘Schizophrenia’.

Environmental enrichment ameliorates phencyclidine-induced cognitive deficits

Recent work has suggested that environmental enrichment during development can enhance aspects of learning and memory, however its effects on executive function and cognitive flexibility have not been well studied. The goal of this research was to evaluate whether environmental enrichment (EE) that included wheel running would improve cognitive performance in young male Long Evans rats that received subchronic administration of either phencyclidine (PCP) or saline. We used a sensitive extradimensional/intradimensional (ED/ID) test of cognitive flexibility similar to that used in humans and nonhuman primates for assessing executive function. PCP-treated rats demonstrated a selective impairment on ED shift (EDS) performance without significant impairment on other discrimination problems when compared to saline treated control animals. A separate group of animals that received PCP + EE demonstrated significantly improved performance on EDS and reversal learning problems, whereas the saline + EE group demonstrated a non-selective improvement in overall performance when compared to non-enriched saline controls. The saline + EE group demonstrated greater activity levels as measured by wheel running when compared to the PCP + EE group, but no significant associations were found between wheel running and cognitive performance. Together, these data suggest that EE that features wheel running may have promoted a general cognitive enhancement while also selectively acting upon neurobiological mechanisms that subserve executive function and cognitive flexibility in impaired animals. Development of novel treatment methodologies that target mechanisms underlying the ameliorative effects of EE in this model of cognitive impairment may be a useful tool in the development of new therapeutic strategies for disorders that feature cognitive dysfunction as a key symptom.

Erythropoietin reverses the attentional set-shifting impairment in a rodent schizophrenia disease-like model

Executive function impairment, as classically assessed using the Wisconsin Card Sort Test or intradimensional/extradimensional tests, is a key feature of schizophrenia but remains inadequately treated by existing therapies. Recently, however, erythropoietin has been shown to improve attentional set-shifting performance in schizophrenic patients. The present study utilized the rat intradimensional/extradimensional task to investigate the potential of erythropoietin to reverse a phencyclidine-induced extradimensional shift impairment when given alone or in combination with subchronic haloperidol treatment. Rats were subjected to a subchronic systemic administration (7 days, b.i.d) of either saline vehicle or phencyclidine (5 mg/kg) followed by a 7-day washout period during which haloperidol was given. Subsequently, rats were trained to dig in baited bowls for a food reward and to discriminate on the basis of digging media or bowl odor. In experiment 1, rats performed a series of discriminations following acute administration of vehicle, erythropoietin, or modafinil. In a second experiment, rats receiving either haloperidol in the drinking water or just normal drinking water were run in the attentional set-shifting task after acute administration of erythropoietin (1,000 or 10,000 IU/ml i.p., selected from experiment 1). The subchronic phencyclidine-induced extradimensional deficit was ameliorated by both erythropoietin and modafinil. When combined with subchronic haloperidol, the higher dose of erythropoietin tested was able to reverse the extradimensional shift impairment. Overall, these findings further support the use of erythropoietin as an adjunct to antipsychotic therapy in order to address, at least part of, the cognitive dysfunction associated with schizophrenia.

Analysis of licking microstructure provides no evidence for a reduction in reward value following acute or sub-chronic phencyclidine administration

The N-methyl D-aspartate antagonist phencyclidine (PCP) is purported to mimic the negative, cognitive and positive symptoms of schizophrenia. Thus, acute and sub-chronic PCP treatment in rodents might produce anhedonia, a decrease in the pleasure produced by rewards. Experiment 1 investigated whether acute PCP treatment changes the value of sucrose. A comparison was made to (+)MK-801, a drug often used interchangeably with PCP in preclinical studies. Experiment 2 assessed the effects of withdrawal from sub-chronic PCP treatment on the value of sucrose. Experiment 1 examined the dose-response effects of PCP and (+)MK-801 on licking microstructure during sucrose consumption. Experiment 2 assessed the effects of withdrawal from sub-chronic PCP treatment (5 mg/kg twice daily for 7 days), on licking microstructure during sucrose consumption. Locomotor activity testing was carried out in experiment 2 to confirm the sensitisation effect of the PCP regimen on amphetamine-induced hyperlocomotion. Low to moderate acute doses of PCP and (+)MK-801 increased the amount of sucrose consumed. Higher doses decreased consumption and the number of licks per cluster (cluster size) but also increased the average inter-lick interval, which may indicate motor impairment. There was no evidence that withdrawal from sub-chronic PCP treatment produced decreases in consumption or lick cluster size. Following acute PCP treatment, we found no evidence of reduced reward value without the presence of confounding motor deficits. Sub-chronic PCP withdrawal also produced no decrease in reward value. Therefore, the current results indicate that neither acute PCP treatment nor sub-chronic PCP withdrawal produce consummatory anhedonia.

Effect of subchronic phencyclidine administration on sucrose preference and hippocampal parvalbumin immunoreactivity in the rat

Persistent blockade of NMDA receptor function by repeated phencyclidine dosing produces pathophysiological changes that model deficits observed in schizophrenia. The present study investigates the effects of subchronic phencyclidine administration (PCP; 2 or 5 mg/kg bi-daily for 7 days followed by a drug-free period) on sucrose choice, a measure of anhedonia. Sucrose preference in a two-bottle sucrose–water choice test was assessed 1 and 2 weeks after PCP. Results showed no differences in sucrose intake between PCP rats and controls, nor a difference in water intake or total volume of liquid consumed at either time-point. Six weeks post-PCP, analysis of brains showed a reduction in expression of parvalbumin immunoreactive neurons in the hippocampus with significant reductions localised to the CA1 and CA2/3 regions. These results demonstrate that while subchronic PCP may not be a valid model for the negative symptom of anhedonia observed in schizophrenia, it induces pathology in the brain in hippocampal subregions that are reminiscent of changes observed in schizophrenia.

Effect of pretreatment with risperidone on phencyclidine-induced disruptions in object recognition memory and prefrontal cortex parvalbumin immunoreactivity in the rat

Sub-chronic administration of phencyclidine to the rat induces enduring cognitive and pathophysiological changes that resemble some features of schizophrenia. The present study aimed to determine if concurrent administration of the atypical antipsychotic, risperidone, could attenuate the effect of phencyclidine on object recognition memory and parvalbumin-containing neurons in the prefrontal cortex. Rats were administered phencyclidine at a dose of 2mg/kg i.p. bi-daily for 1 week, or vehicle. Half of the phencyclidine group was concurrently treated with risperidone (0.5mg/kg i.p.) twice daily for 10 days, beginning 3 days before the start of phencyclidine administration. Novel object recognition memory and subsequent brain analysis were assessed 6 weeks post-phencyclidine treatment. Phencyclidine produced a deficit in object recognition memory as measured by the discrimination ratio. In addition, 6 weeks post-phencyclidine, analysis of brains showed a reduction in expression of parvalbumin-immunoreactive neurons in the prefrontal cortex, with specific deficits observed in the prelimbic region, but not infralimbic or cingulate cortices. Concurrent administration of risperidone showed no protective effects against these deficits. These results show the importance of the sub-chronic phencyclidine rat in modelling cognitive and prefrontal pathophysiology observed in schizophrenia, but suggest that concurrent risperidone is not neuroprotective in this model.

Inhibition of fatty-acid amide hydrolase and CB1 receptor antagonism differentially affect behavioural responses in normal and PCP-treated rats

The 'cannabinoid hypothesis' of schizophrenia tulates that over-activity of the endocannabinoid system might contribute to the aetiology of schizophrenia. In keeping with this hypothesis, increased expression of CB1 receptors, elevation of the endocannabinoid anandamide (AEA) and cannabinoid-induced cognitive changes have been reported in animal models of schizophrenia and psychotic patients. In this study we measured brain endocannabinoid levels and [35S]GTPgammaS binding stimulated by the CB receptor agonist CP55,940 in rats undergoing withdrawal from subchronic administration of phencyclidine (PCP), a well-established pharmacological model of schizophrenia. We also investigated whether systemic application of the fatty-acid amide hydrolase (FAAH) inhibitor URB597 or CB1 receptor blockade by AM251 affected the following PCP-induced behavioural deficits reminiscent of schizophrenia-like symptoms: (1) working-memory impairment (cognitive deficit), (2) social withdrawal (negative symptom), and (3) hyperactivity in response to d-amphetamine challenge (positive symptoms). PCP-treated rats showed increased endocannabinoid levels in the nucleus accumbens and ventral tegmental area, whereas CB1 receptor expression and CP55,940-stimulated [35S]GTPgammaS binding were unaltered. URB597 reversed the PCP-induced social withdrawal but caused social withdrawal and working-memory deficits in saline-treated rats that were comparable to those observed after PCP treatment. Administration of AM251 ameliorated the working-memory deficit in PCP-treated rats, but impaired working memory in saline-injected controls. Taken together, these results suggest that FAAH inhibition may improve negative symptoms in PCP-treated rats but produce deleterious effects in untreated animals, possibly by disturbing endocannabinoid tone. A similar pattern (beneficial for schizophrenia-related cognitive deficits, but detrimental under normal conditions) accompanies CB1 receptor blockade.

Models of Aspects of Schizophrenia: Behavioral Sensitization Induced by Subchronic Phencyclidine Administration

Presented in this unit is a protocol using subchronically administered phencyclidine (PCP) for establishing a behavioral sensitization model of aspects of schizophrenia. This model is validated using haloperidol and risperidone. The end-point of the assay is locomotor hyperactivity, which is induced by PCP challenge following subchronic treatment with this NMDA receptor antagonist. The antipsychotics haloperidol, risperidone, and quetiapine all reduce hyperactivity in a dose-dependent and selective manner. While the effects of other antipsychotics such as clozapine, olanzapine, and ziprasidone are similar to haloperidol, the interpretation of responses to them is often confounded by nonspecific effects during habituation.

CS10-04 Are animal models of cognitive deficit relevant for man? Translational problems in schizophrenia

Since long working memory deficit has been considered as one of the major cognitive dysfunction encountered in schizophrenia. Working memory is critical for human reasoning, judgment and decision and depends upon the integrity of prefrontal and cingulate circuitry. As a consequence coupling pharmacological (amphetamine sensitization, subchronic phencyclidine administration, neurodevelopmental insult) and behavioral approaches of prefrontal functions in animals seems to be a cue totally appropriate for elucidating the mechanisms of this dysfunction in man (Castner,2004).In rodent models aberrant dopaminergic and glutamatergic signaling in medial prefrontal cortex has undoubtedly an impact on memory and learning, But the analogy between these deficits and a true working memory deficit in man is not obvious. Due to the higher degree of homology between human and non-human primates behavioral tests in apes seem to be more relevant but once again they can not be considered as reflecting strictly the consequences of working memory dysfunction in schizophrenia. Another approach is to extend the insights gained from the study of normal brain organization in animal models to better understand the neural basis on which working memory functions are based (Tanaka, 2006). Dissecting the cellular and circuit basis of prefrontal and cingulate cortices can give an idea how direct and indirect intercellular mechanisms are modulating working memory Nevertheless the behavioral part of this type of study remains non conclusive. It seems in fact that working memory itself is probably not a good candidate and that contextual-binding tasks (which explore encoding and retrieval) are more appropriate (Boyer,2007).