The cognitive deficits of schizophrenia have been identified as an unmet clinical need. They are ... more The cognitive deficits of schizophrenia have been identified as an unmet clinical need. They are predictive of functional outcome [Green et al., 2000] and quality of life [Fujii et al., 2004], yet there are no treatments able to normalise cognition in schizophrenia. There is increasing evidence that exercise is helpful for these symptoms [Geyer et al., 2012], but the systems involved remain enigmatic. Animal models can be used to scrutinise both the behavioural and biological effects of exercise. The sub-chronic phencyclidine (PCP) rat model for schizophrenia is a well-established and widely utilised model that is used to investigate schizophrenia-like cognitive deficits [Neill et al., 201]. This two-part study investigates whether voluntary wheel running is able to reverse cognitive impairment in the sub-chronic PCP rat model for schizophrenia, and how long the effect of exercise lasts. Methods: Female Lister Hooded rats (n=80) were pseudo-randomised into four groups: vehicle-control; vehicle-exercise; PCP-control and PCP-exercise (n=20 per group). Rats were treated either with saline (vehicle) or PCP (2mg/kg, i.p. bi-daily, followed by a seven-day washout period). Vehicle and PCP exercise groups had access to a wheel for 1 hour a day, 5 days a week, for 6 weeks. The vehicle and PCP control groups were treated in the same way, but the wheels were locked. Rats were tested in the novel object recognition (NOR) memory paradigm pre-exercise (time point 1, T1) post-exercise (time point 2, T2), after two weeks rest (time point 3, T3) and four weeks rest (time point 4, T4). Half of the animals from each group (n=10 per group) were sacrificed post exercise (T2), and the remaining animals were sacrificed after 4 weeks rest. For each animal, 1 brain hemisphere was collected for protein analysis and 1 hemisphere was fixed for immunohistochemistry. Behavioural data were analysed using two-way ANOVA and post-hoc t-tests. Results: Pre-exercise (T1), in the retention phase both vehicle groups were spent more time exploring the novel over the familiar object, an effect that was not seen in the PCP groups. Post-exercise (T2 & T3), in the retention phase both vehicle groups and the PCP exercise group spent more time exploring the novel over the familiar object, an effect that was not seen in the PCP-control group. Post-exercise (T4) in the retention phase both vehicle groups were spent more time exploring the novel over the familiar object, an effect that was not seen in the PCP groups. Discussion: Exercise is able to rescue the NOR cognitive deficit seen in the sub-chronic rat model for schizophrenia. This corresponds with human studies reporting positive effects of exercise in patients with schizophrenia and provides a potential tool to thoroughly investigate the pro-cognitive effects of exercise The benefits of the exercise intervention were observed 2 weeks post-exercise with the deficits returning in the PCP treated animals when they were tested 4 weeks post-exercise. Post-mortem analysis is underway to determine the potential mechanisms by which exercise improves cognitive impairment.
Rationale: Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cogni... more Rationale: Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Methods: Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for seven days, followed by seven days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Results: Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial (P<0.01). scPCP produced a significant deficit in NOR (P<0.05 vs. control) and no PFC dopamine increase was observed. Conclusions: These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology.
Negative and cognitive deficit symptoms in schizophrenia remain an unmet clinical need. Improved ... more Negative and cognitive deficit symptoms in schizophrenia remain an unmet clinical need. Improved understanding of the neuro-and psychopathology of cognitive dysfunction in the illness is urgently required to enhance the development of new improved therapeutic strategies. Careful validation of animal models that mimic the behaviour and pathology of complex psychiatric disorders is an essential step towards this goal. Non-competitive NMDAR (N-Methyl-D-aspartate receptor) antagonists e.g. phencyclidine (PCP), ketamine and dizocilpine (MK-801) can effectively replicate certain aspects of negative and cognitive deficits associated with schizophrenia in animals. In 2010 we reviewed the effects of NMDAR antagonism in tests for domains of cognition affected in schizophrenia, social behaviour and neuropathology, and in 2014, in tests for negative symptoms. In this update, we evaluate the most recent pharmacological strategies for restoring cognition in schizophrenia using NMDAR antagonist models, published since our original review in 2010 (cited over 225 times, excluding self-citations). Tests reviewed are, novel object recognition for visual recognition memory, attentional set shifting for executive function, and operant tests incorporating recent touchscreen technology for a range of domains including working memory, problem solving and attention, all impaired in schizophrenia. Moreover, we include an update on parvalbumin (PV)expressing GABAergic interneurons and review, for the first time, the effects of NMDAR antagonists on gamma oscillations, circuitry integral for effective cognition. Data summarized in this review strongly confirm the reliability and usefulness of NMDAR antagonist animal models for evaluating novel therapeutic candidates, and for improving our understanding of the pathophysiology of cognitive deficits in schizophrenia.
Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developi... more Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developing schizophrenia and other neurodevelopmental disorders. To understand the biological mechanisms underlying the link between MIA and increased risk, preclinical animal models have focussed on specific signalling pathways in the brain that mediate symptoms associated with neurodevelopmental disorders such as cognitive dysfunction. Reelin signalling in multiple brain regions is involved in neuronal migration, synaptic plasticity and long-term potentiation, and has been implicated in cognitive deficits. However, how regulation of Reelin expression is affected by MIA across cortical development and associated cognitive functions remains largely unclear. Using a MIA rat model, here we demonstrate cognitive deficits in adolescent object-location memory in MIA offspring and reductions in Reln expression prenatally and in the adult prefrontal cortex. Further, developmental disturbances in gene/protein expression and DNA methylation of downstream signalling components occurred subsequent to MIA-induced Reelin dysregulation and prior to cognitive deficits. We propose that MIA-induced dysregulation of Reelin signalling contributes to the emergence of prefrontal cortex-mediated cognitive deficits through altered NMDA receptor function, resulting in inefficient long-term potentiation. Our data suggest a developmental window during which attenuation of Reelin signalling may provide a possible therapeutic target.
In schizophrenia, mGlu5 receptor hypofunction has been linked with neuropathology and cognitive d... more In schizophrenia, mGlu5 receptor hypofunction has been linked with neuropathology and cognitive deficits, making it an attractive therapeutic target. The cognitive impairment associated with schizophrenia remains an unmet clinical need, with existing antipsychotics primarily targeting positive symptoms, with weaker and more variable effects on cognitive deficits. Using the sub-chronic phencyclidine rat model, widely shown to mimic the cognitive impairment and neuropathology of schizophrenia, we have investigated two mGlu5 receptor positive allosteric modulators (PAMs), VU0409551 and VU0360172. We compared the efficacy of these compounds in restoring cognitive deficits and, since these two PAMs have reportedly distinct signalling mechanisms, changes in mGlu5 receptor signalling molecules AKT and MAPK in the PFC. Although not effective at 0.05 and 1 mg/kg, cognitive deficits were significantly alleviated by both PAMs at 10 and 20 mg/kg. The compounds appeared to have differential effects on the scPCP-induced increases in AKT and MAPK phosphorylation: VU0409551 induced a significant decrease in expression of p-AKT, whereas VU0360172 had this effect on p-MAPK levels. Thus, the beneficial effects of PAMs on scPCP-induced cognitive impairment are accompanied by at least partial reversal of scPCP-induced elevated levels of p-MAPK and p-AKT, whose dysfunction is strongly implicated in schizophrenia pathology. These promising data imply an important role for mGlu5 receptor signalling pathways in improving cognition in the scPCP model and provide support for mGlu5 receptor PAMs as a possible therapeutic intervention for schizophrenia.
Background: Sub-chronic phencyclidine treatment (scPCP) provides a translational rat model for co... more Background: Sub-chronic phencyclidine treatment (scPCP) provides a translational rat model for cognitive impairments associated with schizophrenia (CIAS). CIAS genetic risk factors may be more easily studied in mice; however, CIAS associated biomarker changes are relatively unstudied in the scPCP mouse. Aim: To characterize deficits in object recognition memory and synaptic markers in frontal cortex and hippocampus of the scPCP mouse. Methods: Female c57/bl6 mice received 10 daily injections of PCP (scPCP; 10 mg/kg, s.c.) or vehicle ( n = 8/group). Mice were tested for novel object recognition memory after either remaining in the arena (‘no distraction’) or being removed to a holding cage (‘distraction’) during the inter-trial interval. Expression changes for parvalbumin (PV), glutamic acid decarboxylase (GAD67), synaptosomal-associated protein 25 (SNAP-25) and postsynaptic density 95 (PDS95) were measured in frontal cortex, dorsal and ventral hippocampus. Results: scPCP mice showed...
With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic ben... more With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synapt...
Journal of psychopharmacology (Oxford, England), 2017
Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfun... more Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for 7 days, followed by 7 days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial ( p < 0.01). scPCP produced a significant deficit in NOR ( p < 0.05 vs. control) and no PFC dopamine increase w...
Aim: A deficit in parvalbumin neurons is found in schizophrenia and several animal models of the ... more Aim: A deficit in parvalbumin neurons is found in schizophrenia and several animal models of the disease. In this preliminary study, we determined whether one such model, phencyclidine (PCP) administration, results in changes in DNA methylation in the rat Pvalb promoter. Materials & methods: DNA from hippocampus and prefrontal cortex from rats, which 6 weeks previously received either 2 mg/kg PCP or vehicle for 7 days, underwent bisulphite pyrosequencing to determine methylation. Results: PCP administration induced significantly greater methylation at one of two Pvalb CpG sites in both prefrontal cortex and hippocampus, while no significant difference was found in long interspersed nucleotide element-1, a global measure of DNA methylation. Conclusion: Subchronic PCP administration results in a specific hypermethylation in the Pvalb promoter which may contribute to parvalbumin deficits in this animal model of psychosis.
Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's diseas... more Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's disease and has also been postulated to contribute to cognitive dysfunction observed in various psychiatric disorders, including schizophrenia. Deficits are found across a number of cognitive domains and in spite of several attempts to develop new therapies, remain an unmet clinical need. In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4β2 receptor agonists to reverse a delay-induced deficit in recognition memory. Adult female hooded-Lister rats received drug treatments and were tested in the novel object recognition (NOR) task following a 6 hour inter-trial interval (ITI). In all treatment groups there was no preference for the left or right identical objects in the acquisition trial. In the retention trial vehicle, risperidone (0.16mg/kg), PNU-282987, an α7 agonist (5mg/kg) and RJR-2403, an α4β2 agonist (1mg/kg) treated rats were unable to discriminate between the novel and familiar objects following a 6 hour ITI. In contrast, donepezil (1.0mg/kg), PNU-282987 (10mg/kg) and RJR-2403 (0.1mg/kg) treated rats spent significantly more time exploring the novel compared to the familiar object following the 6 hour ITI, indicative of enhanced cognitive performance (P<0.05-P<0.01). Interestingly, these compounds were efficacious when administered either before the acquisition or the retention trial of the task, suggesting an important role for nicotinic receptor subtypes in the formation and retrieval of recognition memory.
whose Dex/CRH-Cortisol was less than 1 μg/dl. The remaining individuals were considered to be 'mo... more whose Dex/CRH-Cortisol was less than 1 μg/dl. The remaining individuals were considered to be 'moderate-suppressors'. SPQ scores were compared between these three groups, using the analysis of covariance (ANCOVA) controlling for age and gender. Results: The ANCOVA showed a significant main effect of the suppression status on the "ideas of reference" and "suspiciousness" subscales and cognitive-perceptual factor (all p < 0.01). Post-hoc analyses with Bonferroni correction revealed that the enhancedsuppressors scored significantly higher in the "ideas of reference" and "suspiciousness" subscales and cognitive-perceptual factor, compared to the other two groups or to the moderate-suppressors alone. No significant differences were seen between incompleteand moderate-suppressors. Discussion: Our results indicate that schizotypal traits, particularly positive schizotypy, in a healthy adult sample would be associated with dampened HPA axis reactivity (or enhanced suppression), a pattern which has been observed in schizophrenia patients in previous studies. This supports the notion that schizotypy can be viewed as a dimensional trait ranging from non-clinical people to schizophrenic spectrum patients.
Varying levels of attention and impulsivity deficits are core features of the three subtypes of a... more Varying levels of attention and impulsivity deficits are core features of the three subtypes of adult attention deficit-hyperactivity disorder (ADHD). To date, little is known about the neurobiological correlates of these subtypes. Development of a translational animal model is essential to improve our understanding and improve therapeutic strategies. The 5-choice continuous performance task (5C-CPT) in rats can be used to examine different forms of attention and impulsivity. Adult rats were trained to pre-set 5C-CPT criterion and subsequently separated into subgroups according to baseline levels of sustained attention, vigilance, premature responding and response disinhibition in the 5C-CPT. The behavioural subgroups were selected to represent the different subtypes of adult ADHD. Consequently, effects of the clinically used pharmacotherapies (methylphenidate and atomoxetine) were assessed in the different subgroups. Four subgroups were identified: low-attentive (LA), high-attentive (HA), high-impulsive (HI) and low-impulsive (LI). Methylphenidate and atomoxetine produced differential effects in the subgroups. Methylphenidate increased sustained attention and vigilance in LA animals, and reduced premature responding in HI animals. Atomoxetine also improved sustained attention and vigilance in LA animals, and reduced response disinhibition and premature responding in HI animals. This is the first study using adult rats to demonstrate the translational value of the 5C-CPT to select subgroups of rats, which may be used to model the subtypes observed in adult ADHD. Our findings suggest that this as an important paradigm to increase our understanding of the neurobiological underpinnings of adult ADHD-subtypes and their response to pharmacotherapy.
Recognition memory, impaired in neuropsychiatric conditions and currently untreated, may be asses... more 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.
• NOR deficits are demonstrated in animal models of human disorders and conditions. • The NOR tes... more • NOR deficits are demonstrated in animal models of human disorders and conditions. • The NOR test is cost and time effective, non-rewarded and ethologically relevant. • The NOR test is invaluable in identifying the neural basis of cognitive deficits. • The NOR test is useful in evaluating the efficacy of novel therapeutic targets.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 31, 2014
N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology... more 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. Here we used high-resolution magnetic resonance imaging and voxel-based morphometry to investigate structural alterations associated with sub-chronic PCP treatment in rats. 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...
RO4583298. Discussion: In the current study, we observed a good correlation between in vivo activ... more RO4583298. Discussion: In the current study, we observed a good correlation between in vivo activity of RO4583298 in gerbil and mouse and its mode of antagonism. The pseudo-irreversible mode of antagonism at gNK1, likely contributed to RO4583298's robust and prolonged in vivo activity in the gerbil NK1 agonist-induced foot tapping model (ID50=0.4 mg/kg, po), while RO4583298's competitive mode of antagonism at mNK3, was demonstrated as a 14-fold higher dose was required to produce in vivo activity in the mouse senktide-induced tail whip model (ID50=5.6 mg/kg, po). In conclusion, RO4583298 is a high affinity, dual antagonist with an apparent non-competitive mode of antagonism and in vivo activity at both NK1 and NK3. Thus, RO4583298 could prove useful when investigating the role of NK1 and NK3 receptors in pathophysiological processes of psychiatric disorders such as anxiety, depression and schizophrenia.
SAS score and the first-degree family history of psychiatric disorders. In the Tunisian patients,... more SAS score and the first-degree family history of psychiatric disorders. In the Tunisian patients, the NSS total score was associated with the CGI-severity of illness, the low educational level and the PANSS negative sub-score. Discussion: These studies provide a confirmation in two distinct samples of the high prevalence of NSS in patients with schizophrenia, despite differences between the two samples concerning ethnic (Caucasian in the French sample vs. Arab or Berber in the Tunisian sample), socioeconomic level, clinical and therapeutic features. The difference observed between the two studies in the multiple regression analysis could reflect differences in the relative importance of genetic and environmental factors and the possible influence of other variables such as ethnicity, socioeconomic origin and medication effects. These findings highlight the need to take into account the ethnic and socioeconomic status in clinical researches in schizophrenia.
The cognitive deficits of schizophrenia have been identified as an unmet clinical need. They are ... more The cognitive deficits of schizophrenia have been identified as an unmet clinical need. They are predictive of functional outcome [Green et al., 2000] and quality of life [Fujii et al., 2004], yet there are no treatments able to normalise cognition in schizophrenia. There is increasing evidence that exercise is helpful for these symptoms [Geyer et al., 2012], but the systems involved remain enigmatic. Animal models can be used to scrutinise both the behavioural and biological effects of exercise. The sub-chronic phencyclidine (PCP) rat model for schizophrenia is a well-established and widely utilised model that is used to investigate schizophrenia-like cognitive deficits [Neill et al., 201]. This two-part study investigates whether voluntary wheel running is able to reverse cognitive impairment in the sub-chronic PCP rat model for schizophrenia, and how long the effect of exercise lasts. Methods: Female Lister Hooded rats (n=80) were pseudo-randomised into four groups: vehicle-control; vehicle-exercise; PCP-control and PCP-exercise (n=20 per group). Rats were treated either with saline (vehicle) or PCP (2mg/kg, i.p. bi-daily, followed by a seven-day washout period). Vehicle and PCP exercise groups had access to a wheel for 1 hour a day, 5 days a week, for 6 weeks. The vehicle and PCP control groups were treated in the same way, but the wheels were locked. Rats were tested in the novel object recognition (NOR) memory paradigm pre-exercise (time point 1, T1) post-exercise (time point 2, T2), after two weeks rest (time point 3, T3) and four weeks rest (time point 4, T4). Half of the animals from each group (n=10 per group) were sacrificed post exercise (T2), and the remaining animals were sacrificed after 4 weeks rest. For each animal, 1 brain hemisphere was collected for protein analysis and 1 hemisphere was fixed for immunohistochemistry. Behavioural data were analysed using two-way ANOVA and post-hoc t-tests. Results: Pre-exercise (T1), in the retention phase both vehicle groups were spent more time exploring the novel over the familiar object, an effect that was not seen in the PCP groups. Post-exercise (T2 & T3), in the retention phase both vehicle groups and the PCP exercise group spent more time exploring the novel over the familiar object, an effect that was not seen in the PCP-control group. Post-exercise (T4) in the retention phase both vehicle groups were spent more time exploring the novel over the familiar object, an effect that was not seen in the PCP groups. Discussion: Exercise is able to rescue the NOR cognitive deficit seen in the sub-chronic rat model for schizophrenia. This corresponds with human studies reporting positive effects of exercise in patients with schizophrenia and provides a potential tool to thoroughly investigate the pro-cognitive effects of exercise The benefits of the exercise intervention were observed 2 weeks post-exercise with the deficits returning in the PCP treated animals when they were tested 4 weeks post-exercise. Post-mortem analysis is underway to determine the potential mechanisms by which exercise improves cognitive impairment.
Rationale: Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cogni... more Rationale: Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Methods: Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for seven days, followed by seven days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Results: Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial (P<0.01). scPCP produced a significant deficit in NOR (P<0.05 vs. control) and no PFC dopamine increase was observed. Conclusions: These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology.
Negative and cognitive deficit symptoms in schizophrenia remain an unmet clinical need. Improved ... more Negative and cognitive deficit symptoms in schizophrenia remain an unmet clinical need. Improved understanding of the neuro-and psychopathology of cognitive dysfunction in the illness is urgently required to enhance the development of new improved therapeutic strategies. Careful validation of animal models that mimic the behaviour and pathology of complex psychiatric disorders is an essential step towards this goal. Non-competitive NMDAR (N-Methyl-D-aspartate receptor) antagonists e.g. phencyclidine (PCP), ketamine and dizocilpine (MK-801) can effectively replicate certain aspects of negative and cognitive deficits associated with schizophrenia in animals. In 2010 we reviewed the effects of NMDAR antagonism in tests for domains of cognition affected in schizophrenia, social behaviour and neuropathology, and in 2014, in tests for negative symptoms. In this update, we evaluate the most recent pharmacological strategies for restoring cognition in schizophrenia using NMDAR antagonist models, published since our original review in 2010 (cited over 225 times, excluding self-citations). Tests reviewed are, novel object recognition for visual recognition memory, attentional set shifting for executive function, and operant tests incorporating recent touchscreen technology for a range of domains including working memory, problem solving and attention, all impaired in schizophrenia. Moreover, we include an update on parvalbumin (PV)expressing GABAergic interneurons and review, for the first time, the effects of NMDAR antagonists on gamma oscillations, circuitry integral for effective cognition. Data summarized in this review strongly confirm the reliability and usefulness of NMDAR antagonist animal models for evaluating novel therapeutic candidates, and for improving our understanding of the pathophysiology of cognitive deficits in schizophrenia.
Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developi... more Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developing schizophrenia and other neurodevelopmental disorders. To understand the biological mechanisms underlying the link between MIA and increased risk, preclinical animal models have focussed on specific signalling pathways in the brain that mediate symptoms associated with neurodevelopmental disorders such as cognitive dysfunction. Reelin signalling in multiple brain regions is involved in neuronal migration, synaptic plasticity and long-term potentiation, and has been implicated in cognitive deficits. However, how regulation of Reelin expression is affected by MIA across cortical development and associated cognitive functions remains largely unclear. Using a MIA rat model, here we demonstrate cognitive deficits in adolescent object-location memory in MIA offspring and reductions in Reln expression prenatally and in the adult prefrontal cortex. Further, developmental disturbances in gene/protein expression and DNA methylation of downstream signalling components occurred subsequent to MIA-induced Reelin dysregulation and prior to cognitive deficits. We propose that MIA-induced dysregulation of Reelin signalling contributes to the emergence of prefrontal cortex-mediated cognitive deficits through altered NMDA receptor function, resulting in inefficient long-term potentiation. Our data suggest a developmental window during which attenuation of Reelin signalling may provide a possible therapeutic target.
In schizophrenia, mGlu5 receptor hypofunction has been linked with neuropathology and cognitive d... more In schizophrenia, mGlu5 receptor hypofunction has been linked with neuropathology and cognitive deficits, making it an attractive therapeutic target. The cognitive impairment associated with schizophrenia remains an unmet clinical need, with existing antipsychotics primarily targeting positive symptoms, with weaker and more variable effects on cognitive deficits. Using the sub-chronic phencyclidine rat model, widely shown to mimic the cognitive impairment and neuropathology of schizophrenia, we have investigated two mGlu5 receptor positive allosteric modulators (PAMs), VU0409551 and VU0360172. We compared the efficacy of these compounds in restoring cognitive deficits and, since these two PAMs have reportedly distinct signalling mechanisms, changes in mGlu5 receptor signalling molecules AKT and MAPK in the PFC. Although not effective at 0.05 and 1 mg/kg, cognitive deficits were significantly alleviated by both PAMs at 10 and 20 mg/kg. The compounds appeared to have differential effects on the scPCP-induced increases in AKT and MAPK phosphorylation: VU0409551 induced a significant decrease in expression of p-AKT, whereas VU0360172 had this effect on p-MAPK levels. Thus, the beneficial effects of PAMs on scPCP-induced cognitive impairment are accompanied by at least partial reversal of scPCP-induced elevated levels of p-MAPK and p-AKT, whose dysfunction is strongly implicated in schizophrenia pathology. These promising data imply an important role for mGlu5 receptor signalling pathways in improving cognition in the scPCP model and provide support for mGlu5 receptor PAMs as a possible therapeutic intervention for schizophrenia.
Background: Sub-chronic phencyclidine treatment (scPCP) provides a translational rat model for co... more Background: Sub-chronic phencyclidine treatment (scPCP) provides a translational rat model for cognitive impairments associated with schizophrenia (CIAS). CIAS genetic risk factors may be more easily studied in mice; however, CIAS associated biomarker changes are relatively unstudied in the scPCP mouse. Aim: To characterize deficits in object recognition memory and synaptic markers in frontal cortex and hippocampus of the scPCP mouse. Methods: Female c57/bl6 mice received 10 daily injections of PCP (scPCP; 10 mg/kg, s.c.) or vehicle ( n = 8/group). Mice were tested for novel object recognition memory after either remaining in the arena (‘no distraction’) or being removed to a holding cage (‘distraction’) during the inter-trial interval. Expression changes for parvalbumin (PV), glutamic acid decarboxylase (GAD67), synaptosomal-associated protein 25 (SNAP-25) and postsynaptic density 95 (PDS95) were measured in frontal cortex, dorsal and ventral hippocampus. Results: scPCP mice showed...
With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic ben... more With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synapt...
Journal of psychopharmacology (Oxford, England), 2017
Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfun... more Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for 7 days, followed by 7 days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial ( p < 0.01). scPCP produced a significant deficit in NOR ( p < 0.05 vs. control) and no PFC dopamine increase w...
Aim: A deficit in parvalbumin neurons is found in schizophrenia and several animal models of the ... more Aim: A deficit in parvalbumin neurons is found in schizophrenia and several animal models of the disease. In this preliminary study, we determined whether one such model, phencyclidine (PCP) administration, results in changes in DNA methylation in the rat Pvalb promoter. Materials & methods: DNA from hippocampus and prefrontal cortex from rats, which 6 weeks previously received either 2 mg/kg PCP or vehicle for 7 days, underwent bisulphite pyrosequencing to determine methylation. Results: PCP administration induced significantly greater methylation at one of two Pvalb CpG sites in both prefrontal cortex and hippocampus, while no significant difference was found in long interspersed nucleotide element-1, a global measure of DNA methylation. Conclusion: Subchronic PCP administration results in a specific hypermethylation in the Pvalb promoter which may contribute to parvalbumin deficits in this animal model of psychosis.
Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's diseas... more Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's disease and has also been postulated to contribute to cognitive dysfunction observed in various psychiatric disorders, including schizophrenia. Deficits are found across a number of cognitive domains and in spite of several attempts to develop new therapies, remain an unmet clinical need. In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4β2 receptor agonists to reverse a delay-induced deficit in recognition memory. Adult female hooded-Lister rats received drug treatments and were tested in the novel object recognition (NOR) task following a 6 hour inter-trial interval (ITI). In all treatment groups there was no preference for the left or right identical objects in the acquisition trial. In the retention trial vehicle, risperidone (0.16mg/kg), PNU-282987, an α7 agonist (5mg/kg) and RJR-2403, an α4β2 agonist (1mg/kg) treated rats were unable to discriminate between the novel and familiar objects following a 6 hour ITI. In contrast, donepezil (1.0mg/kg), PNU-282987 (10mg/kg) and RJR-2403 (0.1mg/kg) treated rats spent significantly more time exploring the novel compared to the familiar object following the 6 hour ITI, indicative of enhanced cognitive performance (P<0.05-P<0.01). Interestingly, these compounds were efficacious when administered either before the acquisition or the retention trial of the task, suggesting an important role for nicotinic receptor subtypes in the formation and retrieval of recognition memory.
whose Dex/CRH-Cortisol was less than 1 μg/dl. The remaining individuals were considered to be 'mo... more whose Dex/CRH-Cortisol was less than 1 μg/dl. The remaining individuals were considered to be 'moderate-suppressors'. SPQ scores were compared between these three groups, using the analysis of covariance (ANCOVA) controlling for age and gender. Results: The ANCOVA showed a significant main effect of the suppression status on the "ideas of reference" and "suspiciousness" subscales and cognitive-perceptual factor (all p < 0.01). Post-hoc analyses with Bonferroni correction revealed that the enhancedsuppressors scored significantly higher in the "ideas of reference" and "suspiciousness" subscales and cognitive-perceptual factor, compared to the other two groups or to the moderate-suppressors alone. No significant differences were seen between incompleteand moderate-suppressors. Discussion: Our results indicate that schizotypal traits, particularly positive schizotypy, in a healthy adult sample would be associated with dampened HPA axis reactivity (or enhanced suppression), a pattern which has been observed in schizophrenia patients in previous studies. This supports the notion that schizotypy can be viewed as a dimensional trait ranging from non-clinical people to schizophrenic spectrum patients.
Varying levels of attention and impulsivity deficits are core features of the three subtypes of a... more Varying levels of attention and impulsivity deficits are core features of the three subtypes of adult attention deficit-hyperactivity disorder (ADHD). To date, little is known about the neurobiological correlates of these subtypes. Development of a translational animal model is essential to improve our understanding and improve therapeutic strategies. The 5-choice continuous performance task (5C-CPT) in rats can be used to examine different forms of attention and impulsivity. Adult rats were trained to pre-set 5C-CPT criterion and subsequently separated into subgroups according to baseline levels of sustained attention, vigilance, premature responding and response disinhibition in the 5C-CPT. The behavioural subgroups were selected to represent the different subtypes of adult ADHD. Consequently, effects of the clinically used pharmacotherapies (methylphenidate and atomoxetine) were assessed in the different subgroups. Four subgroups were identified: low-attentive (LA), high-attentive (HA), high-impulsive (HI) and low-impulsive (LI). Methylphenidate and atomoxetine produced differential effects in the subgroups. Methylphenidate increased sustained attention and vigilance in LA animals, and reduced premature responding in HI animals. Atomoxetine also improved sustained attention and vigilance in LA animals, and reduced response disinhibition and premature responding in HI animals. This is the first study using adult rats to demonstrate the translational value of the 5C-CPT to select subgroups of rats, which may be used to model the subtypes observed in adult ADHD. Our findings suggest that this as an important paradigm to increase our understanding of the neurobiological underpinnings of adult ADHD-subtypes and their response to pharmacotherapy.
Recognition memory, impaired in neuropsychiatric conditions and currently untreated, may be asses... more 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.
• NOR deficits are demonstrated in animal models of human disorders and conditions. • The NOR tes... more • NOR deficits are demonstrated in animal models of human disorders and conditions. • The NOR test is cost and time effective, non-rewarded and ethologically relevant. • The NOR test is invaluable in identifying the neural basis of cognitive deficits. • The NOR test is useful in evaluating the efficacy of novel therapeutic targets.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 31, 2014
N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology... more 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. Here we used high-resolution magnetic resonance imaging and voxel-based morphometry to investigate structural alterations associated with sub-chronic PCP treatment in rats. 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...
RO4583298. Discussion: In the current study, we observed a good correlation between in vivo activ... more RO4583298. Discussion: In the current study, we observed a good correlation between in vivo activity of RO4583298 in gerbil and mouse and its mode of antagonism. The pseudo-irreversible mode of antagonism at gNK1, likely contributed to RO4583298's robust and prolonged in vivo activity in the gerbil NK1 agonist-induced foot tapping model (ID50=0.4 mg/kg, po), while RO4583298's competitive mode of antagonism at mNK3, was demonstrated as a 14-fold higher dose was required to produce in vivo activity in the mouse senktide-induced tail whip model (ID50=5.6 mg/kg, po). In conclusion, RO4583298 is a high affinity, dual antagonist with an apparent non-competitive mode of antagonism and in vivo activity at both NK1 and NK3. Thus, RO4583298 could prove useful when investigating the role of NK1 and NK3 receptors in pathophysiological processes of psychiatric disorders such as anxiety, depression and schizophrenia.
SAS score and the first-degree family history of psychiatric disorders. In the Tunisian patients,... more SAS score and the first-degree family history of psychiatric disorders. In the Tunisian patients, the NSS total score was associated with the CGI-severity of illness, the low educational level and the PANSS negative sub-score. Discussion: These studies provide a confirmation in two distinct samples of the high prevalence of NSS in patients with schizophrenia, despite differences between the two samples concerning ethnic (Caucasian in the French sample vs. Arab or Berber in the Tunisian sample), socioeconomic level, clinical and therapeutic features. The difference observed between the two studies in the multiple regression analysis could reflect differences in the relative importance of genetic and environmental factors and the possible influence of other variables such as ethnicity, socioeconomic origin and medication effects. These findings highlight the need to take into account the ethnic and socioeconomic status in clinical researches in schizophrenia.
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Papers by Michael Harte