Subchronic PCP Treatment Research Articles

Sustained NMDA receptor hypofunction impairs brain-derived neurotropic factor signalling in the PFC, but not in the hippocampus, and disturbs PFC-dependent cognition in mice.

Cognitive deficits profoundly impact on the quality of life of patients with schizophrenia. Alterations in brain derived neurotrophic factor (BDNF) signalling, which regulates synaptic function through the activation of full-length tropomyosin-related kinase B receptors (TrkB-FL), are implicated in the aetiology of schizophrenia, as is N-methyl-D-aspartate receptor (NMDA-R) hypofunction. However, whether NMDA-R hypofunction contributes to the disrupted BDNF signalling seen in patients remains unknown. The purpose of this study was to characterise BDNF signalling and function in a preclinical rodent model relevant to schizophrenia induced by prolonged NMDA-R hypofunction. Using the subchronic phencyclidine (PCP) model, we performed electrophysiology approaches, molecular characterisation and behavioural analysis. The data showed that prolonged NMDA-R antagonism, induced by subchronic PCP treatment, impairs long-term potentiation (LTP) and the facilitatory effect of BDNF upon LTP in the medial prefrontal cortex (PFC) of adult mice. Additionally, TrkB-FL receptor expression is decreased in the PFC of these animals. By contrast, these changes were not present in the hippocampus of PCP-treated mice. Moreover, BDNF levels were not altered in the hippocampus or PFC of PCP-treated mice. Interestingly, these observations are paralleled by impaired performance in PFC-dependent cognitive tests in mice treated with PCP. Overall, these data suggest that NMDA-R hypofunction induces dysfunctional BDNF signalling in the PFC, but not in the hippocampus, which may contribute to the PFC-dependent cognitive deficits seen in the subchronic PCP model. Additionally, these data suggest that targeting BDNF signalling may be a mechanism to improve PFC-dependent cognitive dysfunction in schizophrenia.

P2X7 Receptor-Dependent Layer-Specific Changes in Neuron-Microglia Reactivity in the Prefrontal Cortex of a Phencyclidine Induced Mouse Model of Schizophrenia.

Background: It has been consistently reported that the deficiency of the adenosine triphosphate (ATP) sensitive purinergic receptor P2X7 (P2X7R) ameliorates symptoms in animal models of brain diseases.Objective: This study aimed to investigate the role of P2X7R in rodent models of acute and subchronic schizophrenia based on phencyclidine (PCP) delivery in animals lacking or overexpressing P2X7R, and to identify the underlying mechanisms involved.Methods: The psychotomimetic effects of acute i.p. PCP administration in C57Bl/6J wild-type, P2X7R knockout (P2rx7−/−) and overexpressing (P2X7-EGFP) young adult mice were quantified. The medial prefrontal cortex (mPFC) of P2rx7−/− and heterozygous P2X7-EGFP acutely treated animals was characterized through immunohistochemical staining. The prefrontal cortices of young adult P2rx7−/− and P2rx7tg/+ mice were examined with tritiated dopamine release experiments and the functional properties of the mPFC pyramidal neurons in layer V from P2rx7−/− mice were assessed by patch-clamp recordings. P2rx7−/− animals were subjected to a 7 days subchronic systemic PCP treatment. The animals working memory performance and PFC cytokine levels were assessed.Results: Our data strengthen the hypothesis that P2X7R modulates schizophrenia-like positive and cognitive symptoms in NMDA receptor antagonist models in a receptor expression level-dependent manner. P2X7R expression leads to higher medial PFC susceptibility to PCP-induced circuit hyperactivity. The mPFC of P2X7R knockout animals displayed distinct alterations in the neuronal activation pattern, microglial organization, specifically around hyperactive neurons, and were associated with lower intrinsic excitability of mPFC neurons.Conclusions: P2X7R expression exacerbated PCP-related effects in C57Bl/6J mice. Our findings suggest a pleiotropic role of P2X7R in the mPFC, consistent with the observed behavioral phenotype, regulating basal dopamine concentration, layer-specific neuronal activation, intrinsic excitability of neurons in the mPFC, and the interaction of microglia with hyperactive neurons. Direct measurements of P2X7R activity concerning microglial ramifications and dynamics could help to further elucidate the molecular mechanisms involved.

S187. Subchronic PCP Treatment in Mice Recapitulates Synaptic Proteomic Changes in Schizophrenia Cortex via Effects on CAMK2 and Microtubules and Rescue by Atypical Antipsychotic, Lurasidone

S187. Subchronic PCP Treatment in Mice Recapitulates Synaptic Proteomic Changes in Schizophrenia Cortex via Effects on CAMK2 and Microtubules and Rescue by Atypical Antipsychotic, Lurasidone

F38. WINTER-LIKE PHOTOPERIOD GESTATION DELETERIOUSLY AFFECT EXPERIENTIAL- BUT NOT EXPRESSIVE-RELATED BEHAVIORS, WHILE ADULT PHENCYCLIDINE TREATMENT INCREASES EXPERIENTIAL BEHAVIORS: RELEVANCE TO SCHIZOPHRENIA

BackgroundPatients with schizophrenia exhibit negative symptoms that predict functional outcome. Understanding the mechanisms underlying these symptoms are important for developing novel therapeutic treatments. These negative symptoms can be grouped into experiential- (motivational) or expressive- (social) based behaviors testable in rodents. Increased incidences of schizophrenia have been reported with winter gestation, while antagonizing NMDA receptor function in adulthood has been used to model other symptoms of schizophrenia. These two approaches were used to determine mechanisms that may contribute to negative symptoms in schizophrenia and test potential therapeutics.MethodsNormal dam mice were housed in custom photoperiod chambers for one week under normal photoperiod conditions (12 hour light:12 hour dark) to allow for initial acclimation. Half of the photoperiod chambers were then shifted to a short active (SA) condition (19 hours light: 5 hours dark) with mating triads formed. After a two-week pairing, pregnant dams were single-housed. The resulting pups were reared under these photoperiod conditions until P28, at which time they were weaned by sex into tetrads and moved into a standard vivarium room under normal active (NA) photoperiod. Mice were trained to perform nose-poke responses in a five-choice operant chamber. Adult Long Evans rats were also trained in separate 5-choice chambers and repeatedly treated with phencyclidine (PCP). Motivational behavior was tested on a progressive ratio breakpoint (PRB). Social behavior of mice were also assessed using a 3-chocie social recognition paradigm.ResultsIn PRB, breakpoint was decreased in WT mice reared in SA vs. NA photoperiod (F(1,66)=4.4, p<0.05). In contrast however, no deficits in social interaction was observed (F<1, ns). Unlike the SA gestation-induced reduction in breakpoint, subchronic PCP increased breakpoint 1 [t(21)=5.3, p<0.0001], 7 [t(21)=2.2, p<0.0001] and 14 days after treatment to rats.DiscussionWinter-like photoperiod births in mice induced psychiatry-relevant amotivation as measured by breakpoint, though did not affect social interaction or recognition. In contrast, subchronic PCP treatment increased breakpoint in rats tested 1 and 7 days after treatment. Hence, neurodevelopmental mechanisms underlying the winter-like gestation likely contribute to experiential- but not expressive-related behaviors, while altered NMDA receptor function are unlikely to contribute to such experiential-related abnormalities. Ongoing work will characterize epigenetic, synaptic, and/or system-level adaptations underlying developmental differences between NA and SA photoperiod born mice as well as defining critical periods throughout gestation and rearing that are driving these effects.

Male rats treated with subchronic PCP show intact olfaction and enhanced interest for a social odour in the olfactory habituation/dishabituation test

The olfactory system participates in many sensory processes, and olfactory endophenotypes appear in a variety of neurological disorders such as Alzheimer’s and Parkinson’s disease, depression and schizophrenia. Social withdrawal is a core negative symptom of schizophrenia and animal models have proven to be invaluable for studying the neurobiological mechanisms and cognitive processes behind the formation of social relationships. The subchronic phencyclidine (PCP) rat model is a validated model for negative symptoms of schizophrenia, such as impaired sociability. However, the complete range of social behaviour and deficits in the model are still not fully understood. Intact rodent olfaction is essential for a wide range of social behaviour and disrupted olfactory function could have severe effects on social communication and recognition. In order to examine the olfactory ability of male rats treated with subchronic PCP, we conducted an olfactory habituation/dishabituation test including both non-social and social odours. The subchronic PCP-treated rats successfully recognized and discriminated among the odours, indicative of intact olfaction. Interestingly, the subchronic PCP-treated rats showed greater interest for a novel social odour compared to the saline-treated rats and the rationale remains to be elucidated. Our data indicate that subchronic PCP treatment does not disrupt olfactory function in male rats. By ruling out impaired olfaction as cause for the poor social interaction performance in subchronic PCP-treated rats, our data supports the use of NMDA receptor antagonists to model the negative symptoms of schizophrenia.

Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices

The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release. We showed that the orthosteric mGluR2 agonist LY379268 (0.1 µM, 1 µM and 10 µM) and mGluR5 positive allosteric modulator CDPPB (1 µM and 10 µM) both attenuated potassium-evoked dopamine release, underscoring their role in modulating dopamine neurotransmission in the nucleus accumbens. Sub-chronic PCP treatment, which caused cognitive deficits measured by performance in the novel object recognition task, modelling aspects of behavioral deficits seen in schizophrenia, induced neurobiological changes that enhanced dopamine release in the nucleus accumbens, but had no effect on mGluR2 or mGluR5 mediated changes in dopamine release. Therefore it is unlikely that schizophrenia-related behavioural changes seen after sub-chronic phencyclidine pre-treatment are mediated through mGluR modulation of dopamine release.

Effects of 2-bromoterguride, a dopamine D2 receptor partial agonist, on cognitive dysfunction and social aversion in rats

Rationale2-Bromoterguride, a dopamine D2 receptor partial agonist with antagonist properties at serotonin 5-HT2A receptors and α2C-adrenoceptors, meets the prerequisites of a putative atypical antipsychotic drug (APD). We recently showed that 2-bromoterguride is effective in tests of positive symptoms of schizophrenia in rats without inducing extrapyramidal side effects or metabolic changes.ObjectiveIn continuation of our recent work, we now investigated the effect of 2-bromoterguride on apomorphine and phencyclidine (PCP)-induced disruptions of prepulse inhibition (PPI) of the acoustic startle response, a measure of sensory gating. In addition, we used subchronic PCP treatment to produce cognitive deficits and social aversion, and assessed the effect of 2-bromoterguride on the performance in the novel object recognition (NOR) task (model for studying cognitive deficit symptoms of schizophrenia) and the social interaction test (model for studying negative symptoms of schizophrenia). Finally, we extended the side effect profile of 2-bromoterguride by measuring the prolactin response to systemic administration of the drug in rats.ResultsTreatment with 2-bromoterguride (0.1 and 0.3 mg/kg) reversed PPI deficits induced by apomorphine and PCP, respectively. Subchronic PCP induced impairments in object memory and social interaction behavior which were ameliorated by 2-bromoterguride but not by clozapine and aripiprazole, respectively. Prolactin concentration in blood serum was not elevated at 1, 2, or 4 h post-2-bromoterguride treatment, which further supports the safe and effective use of this drug.ConclusionsOur data support 2-bromoterguride as a promising APD candidate due to its beneficial effect on cognitive impairments and negative symptoms of schizophrenia.

Prolonged reversal of the phencyclidine-induced impairment in novel object recognition by a serotonin (5-HT)1A-dependent mechanism

Many acute treatments transiently reverse the deficit in novel object recognition (NOR) produced by subchronic treatment with the N-methyl-d-aspartate receptor non-competitive antagonist, phencyclidine (PCP), in rodents. Treatments which restore NOR for prolonged periods after subchronic PCP treatment may have greater relevance for treating the cognitive impairment in schizophrenia than those which restore NOR transiently. We examined the ability of post-PCP subchronic lurasidone, an atypical APD with potent serotonin (5-HT)1A partial agonism and subchronic tandospirone, a selective 5-HT1A partial agonist, to enable prolonged reversal of the subchronic PCP-induced NOR deficit. Rats treated with subchronic PCP (2mg/kg, twice daily for 7 days) or vehicle, followed by a 7day washout period were subsequently administered lurasidone or tandospirone twice daily for 7 days (day 15–21), and tested for NOR weekly for up to two additional weeks. Subchronic lurasidone (1, but not 0.1mg/kg) or tandospirone (5, but not 0.6mg/kg) significantly reversed the PCP-induced NOR deficit at 24h and 7days after the last injection, respectively. The effect of lurasidone persisted for one more week (day 36, 14 days after the last lurasidone dose), while tandospirone-treated rats were able to perform NOR at 7, but not 14, days after the last tandospirone dose. Co-administration of WAY100635 (0.6mg/kg), a 5-HT1A antagonist, with lurasidone, blocked the ability of lurasidone to restore NOR, suggesting that 5-HT1A receptor stimulation is necessary for lurasidone to reverse the effects of PCP. The role of dopamine, GABA and the MAPK/ERK signalling pathway in the persistent, but not indefinite, restoration of NOR is discussed.

Investigating the long-term effect of subchronic phencyclidine-treatment on novel object recognition and the association between the gut microbiota and behavior in the animal model of schizophrenia

Subchronic phencyclidine (subPCP) treatment induces schizophrenic-like behavior in rodents, including cognitive deficits and increased locomotor sensitivity towards acute administration of PCP. Evidence is accumulating that the gut microbiota (GM) influences behavior through modulation of the microbiota–gut–brain axis, and hence, part of the variation within this animal model may derive from variation in the GM. The aims of this study was to investigate first, the duration of subPCP-induced cognitive impairment in the novel object recognition test, and second, the possible effect of subchronic PCP-treatment on the GM, and the association between the GM and the behavioral parameters. The association was further investigated by antibiotic reduction of the GM. Male Lister Hooded rats were dosed twice daily i.p. with either 5mg/kg PCP or sterile isotonic saline for seven days followed by a seven-day washout period. Rats were tested in the novel object recognition and the locomotor activity assays immediately after, three weeks after, or six weeks after washout, and the fecal GM was analyzed by high throughput sequencing. Antibiotic- and control-treated rats were tested in the same manner following washout. In conclusion, subPCP-treatment impaired novel object recognition up to three weeks after washout, whereas locomotor sensitivity was increased for at least six weeks after washout. Differences in the core gut microbiome immediately after washout suggested subPCP treatment to alter the GM. GM profiles correlated to memory performance. Administration of ampicillin abolished the subPCP-induced memory deficit. It thus seems reasonable to speculate that the GM influences memory performance, contributing to variation within the model.

Disruption of medial prefrontal synchrony in the subchronic phencyclidine model of schizophrenia in rats

Subchronic treatment with the N-methyl-d-aspartate (NMDA) antagonist phencyclidine (PCP) produces behavioral abnormalities in rodents which are considered a reliable pharmacological model of neurocognitive deficits in schizophrenia. Alterations in prefrontal neuronal firing after acute PCP administration have been observed, however enduring changes in prefrontal activity after subchronic PCP treatment have not been studied. To address this we have recorded cortical oscillations and unit responses in putative cortical pyramidal cells in subchronic PCP-treated rats (2mg/kg twice daily for 7days) under urethane anesthesia. We found that this regimen reduced theta oscillations in the medial prefrontal cortex. It further produced abnormal cortical synchronization in putative cortical pyramidal cells. These alterations in prefrontal cortex functioning may contribute to cognitive deficits seen in subchronic NMDA antagonist pre-treated animals in prefrontal-dependent tasks.

Impaired limbic cortico-striatal structure and sustained visual attention in a rodent model of schizophrenia.

Background:N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology of schizophrenia. Accordingly, NMDAR antagonists such as phencyclidine (PCP) are used widely in experimental animals to model cognitive impairment associated with this disorder. However, it is unclear whether PCP disrupts the structural integrity of brain areas relevant to the profile of cognitive impairment in schizophrenia.Methods:Here we used high-resolution magnetic resonance imaging and voxel-based morphometry to investigate structural alterations associated with sub-chronic PCP treatment in rats.Results:Sub-chronic exposure of rats to PCP (5mg/kg twice daily for 7 days) impaired sustained visual attention on a 5-choice serial reaction time task, notably when the attentional load was increased. In contrast, sub-chronic PCP had no significant effect on the attentional filtering of a pre-pulse auditory stimulus in an acoustic startle paradigm. Voxel-based morphometry revealed significantly reduced grey matter density bilaterally in the hippocampus, anterior cingulate cortex, ventral striatum, and amygdala. PCP-treated rats also exhibited reduced cortical thickness in the insular cortex.Conclusions:These findings demonstrate that sub-chronic NMDA receptor antagonism is sufficient to produce highly-localized morphological abnormalities in brain areas implicated in the pathogenesis of schizophrenia. Furthermore, PCP exposure resulted in dissociable impairments in attentional function.

PCP-induced deficits in murine nest building activity: Employment of an ethological rodent behavior to mimic negative-like symptoms of schizophrenia

Schizophrenia is a severe psychiatric disorder characterized by three symptom domains, positive (hallucinations, obsession), negative (social withdrawal, apathy, self-neglect) and cognitive (impairment in attention, memory and executive function). Whereas current medication ameliorates positive symptomatology, negative symptoms as well as cognitive dysfunctions remain untreated. The development of improved therapies for negative symptoms has proven particularly difficult, in part due to the inability of mimicking these in rodents. Here, we address the predictive validity of combining an ethologically well preserved behavior in rodents, namely nest building activity, with an established animal model of schizophrenia, the sub-chronic PCP model, for negative symptoms. Decline in rodent nesting activity has been suggested to mirror domains of negative symptoms of schizophrenia, including social withdrawal, anhedonia and self-neglect, whereas repeated treatment with the NMDAR antagonist PCP induces and exacerbates schizophrenia-like symptoms in rodents and human subjects. Using a back-translational approach of pharmacological validation, we tested the effects of two agents targeting the nicotinic α7 receptor (EVP-6124 and TC-5619) that were reported to exert some beneficial effect on negative symptoms in schizophrenic patients. Sub-chronic PCP treatment resulted in a significant nest building deficit in mice and treatment with EVP-6124 and TC-5619 reversed this PCP-induced deficit. In contrast, the atypical antipsychotic drug risperidone remained ineffective in this assay. In addition, EVP-6124, TC-5619 and risperidone were tested in the Social Interaction Test (SIT), an assay suggested to address negative-like symptoms. Results obtained in SIT were comparable to results in the nest building test (NEST). Based on these findings, we propose nest building in combination with the sub-chronic PCP model as a novel approach to assess negative-like symptoms of schizophrenia in rodents.

The involvement of distraction in memory deficits induced by NMDAR antagonism: Relevance to cognitive deficits in schizophrenia

Recognition memory, impaired in neuropsychiatric conditions and currently untreated, may be assessed by the novel object recognition (NOR) task with robust impairments induced by sub-chronic treatment with the N-methyl-d-aspartate receptor antagonist phencyclidine (PCP). The aim of the present study was to investigate how sub-chronic PCP produces its effects in this task. Forty adult female rats received vehicle or PCP (2mg/kg i.p. twice daily for 7 days followed by 7 days washout). Rats completed a 3-min acquisition trial followed by differential inter-trial-interval (ITI) conditions (1 min in the home cage, 10s in the home cage, 1 min in the NOR test box in the presence of an unfamiliar object or 1 min in the NOR test box completely undisturbed) followed by a 3-min retention trial. Control rats spent significantly more time exploring the novel compared with the familiar object in retention. This effect was abolished in the sub-chronic PCP treated animals following all ITI conditions except in rats left completely undisturbed in the NOR test box for a 1 min ITI. The combined influence of sub-chronic PCP treatment and the effect of distraction provides further support for the validity of the NOR test in mimicking cognitive deficits of relevance to schizophrenia.

Differential effects of subchronic Phencyclidine on anxiety in the light-enhanced startle-, light/dark exploration- and open field tests

Subchronic treatment with the N-methyl-d-aspartate receptor antagonist phencyclidine (PCP) is a valuable approach to model the symptomatology of schizophrenia, a multi-facetted psychiatric disorder, in rodents.We addressed the question whether subchronic PCP (scPCP) treatment (5mg/kg bidaily for 7 days) would affect anxiety in rats, since contradictory findings have been reported so far. Anxiety-like behaviour was assessed using the light-enhanced startle paradigm (LES), a method which measures the effect of the natural aversion to light on the startle reflex and does not depend on motivated behaviour or exploratory drive. For comparison, anxiety-like behaviour was measured in the light–dark exploration test (LDT) and in an open field environment (OFT).The scPCP-treatment did not affect baseline startle reactivity or light-enhanced startle, suggesting normal anxiety levels in treated animals. Further, normal anxiety-like behaviour was also found in the OFT. In the LDT, scPCP treated rats displayed shorter latencies to enter the lit compartment and shuttled more between the dark and lit compartments, behaviours indicative of decreased anxiety and/or increased exploratory activity.Our findings therefore suggest that the effects of scPCP-treatment on anxiety-like behaviour are task-dependent and recommend the additional use of tests independent from exploratory drive or other motivated behaviours, such as the LES paradigm.

Sustained NMDA Receptor Hypofunction Induces Compromised Neural Systems Integration and Schizophrenia-Like Alterations in Functional Brain Networks

Compromised functional integration between cerebral subsystems and dysfunctional brain network organization may underlie the neurocognitive deficits seen in psychiatric disorders. Applying topological measures from network science to brain imaging data allows the quantification of complex brain network connectivity. While this approach has recently been used to further elucidate the nature of brain dysfunction in schizophrenia, the value of applying this approach in preclinical models of psychiatric disease has not been recognized. For the first time, we apply both established and recently derived algorithms from network science (graph theory) to functional brain imaging data from rats treated subchronically with the N-methyl-D-aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). We show that subchronic PCP treatment induces alterations in the global properties of functional brain networks akin to those reported in schizophrenia. Furthermore, we show that subchronic PCP treatment induces compromised functional integration between distributed neural systems, including between the prefrontal cortex and hippocampus, that have established roles in cognition through, in part, the promotion of thalamic dysconnectivity. We also show that subchronic PCP treatment promotes the functional disintegration of discrete cerebral subsystems and also alters the connectivity of neurotransmitter systems strongly implicated in schizophrenia. Therefore, we propose that sustained NMDA receptor hypofunction contributes to the pathophysiology of dysfunctional brain network organization in schizophrenia.

Possible involvement of BDNF dysfunction in the synaptic loss caused by phencyclidine

Subchronic treatment with the N-methyl-d-aspartate (NMDA) antagonist phencyclidine (PCP) produces behavioral abnormalities in rodents which are considered a reliable pharmacological model of neurocognitive deficits in schizophrenia. Alterations in prefrontal neuronal firing after acute PCP administration have been observed, however enduring changes in prefrontal activity after subchronic PCP treatment have not been studied. To address this we have recorded cortical oscillations and unit responses in putative cortical pyramidal cells in subchronic PCP-treated rats (2 mg/kg twice daily for 7 days) under urethane anesthesia. We found that this regimen reduced theta oscillations in the medial prefrontal cortex. It further produced abnormal cortical synchronization in putative cortical pyramidal cells. These alterations in prefrontal cortex functioning may contribute to cognitive deficits seen in subchronic NMDA antagonist pre-treated animals in prefrontal-dependent tasks.

Levels of Ionotropic Glutamate and Muscarinic Receptors in Three Animal Models of Schizophrenia

There are well validated rodent paradigms of schizophrenia which are based on environmental manipulation (e.g. altered rearing conditions) or drug challenges. These manipulations induce behavioural changes in rodents that are thought to involve neuronal circuitry similar to the ones that are affected by the pathophysiology of the disorder. This study has investigated whether three such rodent paradigms (isolation rearing, neonatal PCP treatment or sub-chronic PCP treatment) are associated with changes in muscarinic receptors (CHRMs) or ionotropic glutamate receptors, some of which have been reported to be altered in the CNS of subjects with schizophrenia. ( 3 H)pirenzepine (CHRM1), ( 3 H)4DAMP (CHRM1/CHRM3), ( 3 H)MK801 (NMDA receptors) and ( 3 H)kainate (kainate receptors; KAR) binding were measured using in situ radioligand binding and autoradiography. Isolation rearing caused widespread decreases in ( 3 H)4DAMP (p = 0.01) and ( 3 H)kainate binding (p = 0.03). Neonatal PCP caused widespread increases in ( 3 H)4DAMP binding (p <0.0001), whereas sub-chronic PCP treatment caused widespread decreases in the binding of that radioligand (p < 0.002) and widespread increases in (3H)MK801 binding (p < 0.0001). There were no changes in ( 3 H)pirenzepine binding to CHRM1 receptors in any paradigm or no significant within region changes in the binding of any radioligand. In conclusion, in the absence of any changes in CHRM1 receptors, our ( 3 H)4DAMP and the binding of (3H)MK801 data would suggest that different rodent paradigms cause variable changes in levels of CHRM3 and KAR in the rat CNS. Our data raises the possibility that such changes may, in part, modulate the behavioural differences that have been observed after isolation rearing, neonatal PCP treatment or sub-chronic PCP treatment.

Loss of asymmetric spine synapses in dorsolateral prefrontal cortex of cognitively impaired phencyclidine-treated monkeys

Schizophrenia patients, long-term abusers of phencyclidine (PCP), and monkeys treated with PCP all exhibit enduring cognitive deficits. Evidence indicates that loss of prefrontal cortex spine synapses results in cognitive dysfunction, suggesting the presence of synaptic pathology in the monkey PCP model; however, there is no direct evidence of such changes. In this study we use the monkey PCP model of schizophrenia to investigate at the ultrastructural level whether remodelling of dorsolateral prefrontal cortex (DLPFC) asymmetric spine synapses occurs following PCP. Subchronic PCP treatment resulted in a decrease in the number of asymmetric spine synapses, which was greater in layer II/III than layer V of DLPFC, compared to vehicle-treated controls. This decrease may contribute to PCP-induced cognitive dysfunction in the non-human primate model and perhaps in schizophrenia. Thus, the synapse loss in the PCP model provides a novel target for the development of potential treatments of cognitive dysfunction in this model and in schizophrenia.

Rats tested after a washout period from sub-chronic PCP administration exhibited impaired performance in the 5-Choice Continuous Performance Test (5C-CPT) when the attentional load was increased

It is well documented that schizophrenia patients exhibit dysfunction in various cognitive domains, including attention/vigilance, as demonstrated by impaired performance in the myriad of Continuous Performance Tests (CPTs). NMDA receptor antagonists provide a pharmacological model in animals of the cognitive disruption presented in the disorder. We therefore examined the effects of a sub-chronic PCP treatment regimen (5.0mg/kg 7-days bi-daily) in the recently developed rodent test of vigilance, the 5-Choice Continuous Performance Test (5C-CPT). We assessed the effects of this regimen after at least a 7-day washout period on both baseline performance and when the attentional load was increased. Sub-chronic PCP treatment impaired 5C-CPT performance in a manner consistent with impaired vigilance in patients with schizophrenia, with reduced hit rate and impaired signal sensitivity. These effects were only evident when performance was challenged following parameter manipulations. These data demonstrate that attention/vigilance is sensitive to disruption following sub-chronic PCP treatment in a pre-clinical task that may demonstrate increased analogy to human vigilance tasks. Although the PCP-induced attentional deficits are not as large as those deficits observed in other domains, these data provide evidence that this pharmacological model can affect multiple cognitive domains and may be useful for assessing putative pro-cognitive therapeutics for schizophrenia.This article is part of a Special Issue entitled ‘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.