RESUMO
N-methyl-D-aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, D-serine, in clinical trials has shown positive effects in patients. Therefore, inhibition of D-amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases D-serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications.
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Antipsicóticos , Esquizofrenia , Animais , Oxirredutases , Roedores , Esquizofrenia/tratamento farmacológico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Cognição , Serina/farmacologia , Aminoácidos , Receptores de N-Metil-D-AspartatoRESUMO
BACKGROUND: Despite an increasing body of research highlighting their efficacy to treat a broad range of medical conditions, psychedelic drugs remain a controversial issue among the public and politicians, tainted by previous stigmatisation and perceptions of risk and danger. OBJECTIVE: This narrative review examines the evidence for potential harms of the classic psychedelics by separating anecdotes and misinformation from systematic research. METHODS: Taking a high-level perspective, we address both psychological and psychiatric risks, such as abuse liability and potential for dependence, as well as medical harms, including toxicity and overdose. We explore the evidence base for these adverse effects to elucidate which of these harms are based largely on anecdotes versus those that stand up to current scientific scrutiny. RESULTS: Our review shows that medical risks are often minimal, and that many - albeit not all - of the persistent negative perceptions of psychological risks are unsupported by the currently available scientific evidence, with the majority of reported adverse effects not being observed in a regulated and/or medical context. CONCLUSIONS: This highlights the importance for clinicians and therapists to keep to the highest safety and ethical standards. It is imperative not to be overzealous and to ensure balanced media reporting to avoid future controversies, so that much needed research can continue.
Assuntos
Overdose de Drogas , Alucinógenos , Comunicação , Alucinógenos/farmacologia , Humanos , Dietilamida do Ácido Lisérgico/uso terapêutico , Psilocibina/uso terapêuticoRESUMO
Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients.
Assuntos
Antipsicóticos/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Piperazinas/farmacologia , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Comportamento Social , Animais , Cognição/efeitos dos fármacos , Transtornos Cognitivos/fisiopatologia , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Comportamento Exploratório/efeitos dos fármacos , Feminino , Atividade Motora/efeitos dos fármacos , Nootrópicos/farmacologia , Fenciclidina , Ratos , Reconhecimento Psicológico/efeitos dos fármacos , Risperidona/farmacologia , Esquizofrenia/fisiopatologiaRESUMO
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, these remain an unmet clinical need. In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4ß2 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 6h inter-trial interval (ITI). In all treatment groups, there was no preference for the left or right identical objects in the acquisition trial. Risperidone failed to enhance recognition memory in this paradigm whereas donepezil was effective such that rats discriminated between the novel and familiar object in the retention trial following a 6h ITI. Although a narrow dose range of PNU-282987 and RJR-2403 was tested, only one dose of each increased recognition memory, the highest dose of PNU-282987 (10mg/kg) and the lowest dose of RJR-2403 (0.1mg/kg), indicative of enhanced cognitive performance. Interestingly, these compounds were also 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.
Assuntos
Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Rememoração Mental/efeitos dos fármacos , Nicotina/análogos & derivados , Agonistas Nicotínicos/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Análise de Variância , Animais , Antipsicóticos/farmacologia , Inibidores da Colinesterase/farmacologia , Donepezila , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Feminino , Indanos/farmacologia , Locomoção/efeitos dos fármacos , Nicotina/farmacologia , Piperidinas/farmacologia , Ratos , Retenção Psicológica/efeitos dos fármacos , Risperidona/farmacologiaRESUMO
Neurocognitive impairment predicts disability in schizophrenia, making intervention theoretically attractive as a means to minimise chronic disability. Many trials confirm that cognitive remediation (CR) produces meaningful, durable improvements in cognition and functioning but fewer focus on the early stages. We systematically reviewed CR trials in early schizophrenia to determine its efficacy on global cognition, functioning and symptoms. Two reviewers independently searched electronic databases to identify randomised controlled trials investigating CR following a first episode of psychosis. Eleven trials with 615 participants were identified. Random effect models revealed a non-significant effect of CR on global cognition (effect size=0.13, 95% CI -0.04, 0.31; p0.14), p<0.05 in sensitivity analysis (effect size 0.19; CI 0.00, 0.38). One of seven neurocognitive domains showed a significant positive effect (verbal learning and memory) and five others showed borderline significant benefits. There was a significant effect on functioning (0.18; CI 0.01, 0.36; p<0.05) and symptoms (0.19; CI 0.02, 0.36; p<0.05). CR's effect on functioning and symptoms was larger in trials with adjunctive psychiatric rehabilitation and small group interventions. CR's effect sizes in early illness were smaller than those in chronic schizophrenia, perhaps because of participants' reduced scope for improvement, though trials' small number and size produces uncertain estimates of effect. However, significant benefits were seen in functioning and symptoms and moderator analyses indicate factors that may increase CR's effect. Findings here, theoretical considerations and trials in chronic schizophrenia suggest that targeting social cognition might also enhance its efficacy.
Assuntos
Cognição , Psicologia do Esquizofrênico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , EsquizofreniaRESUMO
OBJECTIVES: Variation in plasma hormone levels influences the neurobiology of brain regions involved in cognition and emotion processing. Fluctuations in hormone levels across the menstrual cycle could therefore alter cognitive performance and wellbeing; reports have provided conflicting results, however. The aim of this study was to assess whether objective assessment of cognitive performance and self-reported wellbeing during the follicular and luteal phases of the menstrual cycle is feasible and investigate the possible reasons for variation in effects previously reported. METHODS: The Cambridge Neuropsychological Test Automated Battery and Edinburgh Postnatal Depression Scale were used to assess the cognitive performance and wellbeing of 12 women. Data were analysed by self-reported and hormone-estimated phases of the menstrual cycle. RESULTS: Recruitment to the study and assessment of cognition and wellbeing was without issue. Plasma hormone and peptide estimation showed substantial individual variation and suggests inaccuracy in self-reported menstrual phase estimation. CONCLUSION: Objective assessment of cognitive performance and self-assessed wellbeing across the menstrual cycle is feasible. Grouping data by hormonal profile rather by self-reported phase estimation may influence phase-mediated results. Future studies should use plasma hormone and peptide profiles to estimate cycle phase and group data for analyses.
RESUMO
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.
Assuntos
Atenção , Encéfalo/patologia , Esquizofrenia/patologia , Psicologia do Esquizofrênico , Percepção Visual , Animais , Percepção Auditiva , Modelos Animais de Doenças , Substância Cinzenta/patologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Fenciclidina , Inibição Pré-Pulso , Ratos , Reflexo de SobressaltoRESUMO
Significant changes in endogenous plasma hormone levels are required to sustain pregnancy which provides a unique opportunity to study their effect on cognitive function. Four carefully selected tests from the Cambridge Neuropsychological Automated Test Battery (CANTAB) were administered to assess the cognitive function of a group of 23 women during each trimester of pregnancy and at three months following birth. Test scores were compared with a control group of 24 non-pregnant women. The Edinburgh Postnatal Depression Scale was administered to assess anxiety and risk of depression. The National Adult Reading Test (NART) was used as a measure of verbal intelligence. Plasma hormone levels were measured at each time-point. The pregnant group scored significantly lower than the control group on the Spatial Recognition Memory (SRM) test at the second trimester and postpartum assessments (p⩽0.004). A significant pregnant group-time interaction (p=0.005) for SRM performance was demonstrated. Compared to their first trimester assessment, the pregnant group scored on average 11.7% less on each subsequent SRM test. The pregnant group reported more symptoms of anxiety and depression compared to the control group (EPDS-4 point increase in mean score at each assessment, p=0.002). There were no plasma hormone levels and test score associations identified. These data suggest SRM performance is adversely affected by pregnancy. Other aspects of executive function seem to be unaffected. Although the pregnant group reported more symptoms of anxiety and depression compared to the control group, analysis indicates that this confounder is not responsible for the SRM differences.
Assuntos
Cognição/fisiologia , Função Executiva/fisiologia , Hormônios/sangue , Gravidez/psicologia , Adulto , Desidroepiandrosterona/sangue , Estradiol/sangue , Feminino , Humanos , Hidrocortisona/sangue , Estudos Longitudinais , Testes Neuropsicológicos , Gravidez/sangue , Progesterona/sangue , Prolactina/sangue , Reconhecimento Psicológico/fisiologia , Globulina de Ligação a Hormônio Sexual/análiseRESUMO
BACKGROUND: Cognitive deficits are a core symptom of schizophrenia, severely debilitating and untreated by current medication. However, to date there is limited research focusing on the precise nature of the cognitive disturbances at first episode in ethnic populations. Improved understanding of this will allow improved approaches to therapy. The aim of this study was to investigate cognitive function with a first episode of psychosis South Asian patients. METHODS: Twenty South Asian first episode psychosis patients and 15 healthy South Asian matched controls were recruited. All were second generation South Asian people living in the UK. Subjects who took part in the study completed the Positive and Negative Syndrome Scale (patient group), the Wechsler Test of Adult Reading and a battery of neuropsychological assessments to assess specific domains of cognition of relevance to Measurement and Treatment Research to Improve Cognition in Schizophrenia using the Cambridge Neuropsychological Test Automated Battery (CANTAB) (all groups). RESULTS: Results show that first episode patients performed significantly worse than controls across all cognitive domains tested using CANTAB. Significant impairments were found in tests of visual and spatial memory, executive function, working memory, spatial planning and attention. Importantly, a number of cognitive performance indices (visual memory, spatial memory, executive function) were positively correlated with the severity of negative symptoms. CONCLUSION: We demonstrate that first episode South Asian patients display significant and specific cognitive deficits with evidence to support an association between negative symptoms and certain cognitive domains at first episode in this patient population.
Assuntos
Transtornos Cognitivos/etiologia , Transtornos Psicóticos/fisiopatologia , Adulto , Ásia/etnologia , Atenção , Transtornos Cognitivos/etnologia , Transtornos Cognitivos/fisiopatologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Função Executiva , Feminino , Humanos , Masculino , Memória de Curto Prazo , Reconhecimento Visual de Modelos , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/etnologia , Transtornos Psicóticos/psicologia , Índice de Gravidade de Doença , Análise e Desempenho de Tarefas , Reino Unido , Adulto JovemRESUMO
INTRODUCTION: Asenapine is a novel antipsychotic drug approved for the treatment of acute schizophrenia, manic, or mixed episodes associated with bipolar I disorder, as a maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. AREAS COVERED: This review focuses on the preclinical profile of asenapine. It analyzes the pharmacological, neurochemical, behavioral, and molecular mechanisms of asenapine and their contribution to the beneficial therapeutic advantages of the drug as reported in published preclinical and clinical studies, product labels, and poster presentations. EXPERT OPINION: Asenapine exhibits a broad pharmacological profile that targets a wide range of neurotransmitter receptors with variable affinities. The drug preferentially increases dopamine, norepinephrine, and acetylcholine levels in cortical and limbic brain areas. It also potentiates cortical glutamatergic neurotransmission, and is active in behavioral animal models predictive of antipsychotic, antidepressant, and pro-cognitive activities. Chronic administration of asenapine alters the abundance of dopamine, serotonin, glutamate, adrenergic, and cholinergic receptor subtypes in different brain regions. These action mechanisms of asenapine might contribute to its unique psychopharmacological properties in the improved treatment of schizophrenia and other psychotic disorders.
Assuntos
Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Esquizofrenia/tratamento farmacológico , Animais , Antipsicóticos/metabolismo , Transtorno Bipolar/metabolismo , Dibenzocicloeptenos , Avaliação Pré-Clínica de Medicamentos/métodos , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Neurotransmissores/metabolismo , Esquizofrenia/metabolismoRESUMO
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.
Assuntos
Atenção/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Fenciclidina/administração & dosagem , Fenciclidina/toxicidade , Desempenho Psicomotor/efeitos dos fármacos , Animais , Feminino , Distribuição Aleatória , Ratos , Fatores de TempoRESUMO
RATIONALE: Impaired attention/vigilance is putatively core to schizophrenia. The dopaminergic D(1) receptor system has been reported as one of the most promising targets for improving cognition in patients with schizophrenia, with some evidence suggesting D(1) activation may improve sustained attention. OBJECTIVES: The purpose of this study was twofold: firstly assessing the applicability of using rats in the 5-Choice Continuous Performance Test (5 C-CPT), recently validated in mice. Secondly, the effect of systemic administration of a D(1) partial agonist, SKF 38393, on task performance during baseline, and a challenge session consisting of a reduced event-rate was investigated. METHODS: Animals were trained to perform the 5 C-CPT with performance assessed following systemic SKF 38393 (2, 4 and 6 mg/kg) vs. vehicle administration. RESULTS: Rats could discriminate between target (requiring a response) and non-target (requiring the inhibition of response) trials within the 5 C-CPT. Moreover, SKF 38393 treatment impaired performance during the baseline session reducing target detection, yet improved performance during the reduced event-rate challenge session, increasing target detection and improving signal discrimination indicating an SKF 38393-induced enhancement of vigilance. Thus, these data suggest that activation of the D(1) system affected 5 C-CPT performance in a baseline dependent manner. CONCLUSION: Rats can be trained to perform the 5 C-CPT, appropriately withholding from responding to non-target trials. Systemic administration of SKF 38393 impaired performance during baseline conditions. Following a task-related challenge, which reduced the event rate, activation of the dopamine (DA) D(1) system improved performance by heightening the animals' vigilance levels, quantified using signal detection theory.
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Cognição/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D1/agonistas , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , Animais , Atenção/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Modelos Animais , Ratos , Receptores de Dopamina D1/metabolismoRESUMO
The α7 nicotinic acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Adult female hooded Lister rats received sub-chronic phencyclidine (PCP) (2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days' washout. PCP-treated rats then received PNU-120596 (10 mg/kg; s.c.) or saline and were tested in the attentional set-shifting task. Sub-chronic PCP produced a significant cognitive deficit in the extra-dimensional shift (EDS) phase of the task (p < 0.001, compared with vehicle). PNU-120596 significantly improved performance of PCP-treated rats in the EDS phase of the attentional set-shifting task (p < 0.001). In conclusion, these data demonstrate that PNU-120596 improves cognitive dysfunction in our animal model of cognitive dysfunction in schizophrenia, most likely via modulation of α7 nACh receptors.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Isoxazóis/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Agonistas Nicotínicos/uso terapêutico , Fenciclidina/toxicidade , Compostos de Fenilureia/uso terapêutico , Receptores Nicotínicos/química , Regulação Alostérica , Animais , Atenção/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/fisiopatologia , Aprendizagem por Discriminação/efeitos dos fármacos , Modelos Animais de Doenças , Interações Medicamentosas , Feminino , Meia-Vida , Alucinógenos/administração & dosagem , Alucinógenos/toxicidade , Isoxazóis/metabolismo , Isoxazóis/farmacocinética , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacocinética , Síndromes Neurotóxicas/fisiopatologia , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacocinética , Fenciclidina/administração & dosagem , Compostos de Fenilureia/metabolismo , Compostos de Fenilureia/farmacocinética , Ratos , Ratos Endogâmicos , Distribuição Tecidual , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Sodium channel inhibition is a well precedented mechanism used to treat epilepsy and other hyperexcitability disorders. The established sodium channel blocker and broad-spectrum anticonvulsant lamotrigine is also effective in the treatment of bipolar disorder and has been evaluated in patients with schizophrenia. Double-blind placebo-controlled clinical trials found that the drug has potential to reduce cognitive symptoms of the disorder. However, because of compound-related side-effects and the need for dose titration, a conclusive evaluation of the drug's efficacy in patients with schizophrenia has not been possible. (5R)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-l-prolinamide (GSK2) and (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (GSK3) are two new structurally diverse sodium channel blockers with potent anticonvulsant activity. In this series of studies in the rat, we compared the efficacy of the two new molecules to prevent a cognitive deficit induced by the N-methyl-d-aspartic acid receptor antagonist phencyclidine (PCP) in the reversal-learning paradigm in the rat. We also explored the effects of the drugs to prevent brain activation and neurochemical effects of PCP. We found that, like lamotrigine, both GSK2 and GSK3 were able to prevent the deficit in reversal learning produced by PCP, thus confirming their potential in the treatment of cognitive symptoms of schizophrenia. However, higher doses than those required for anticonvulsant efficacy of the drugs were needed for activity in the reversal-learning model, suggesting a lower therapeutic window relative to mechanism-dependent central side effects for this indication.
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Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/prevenção & controle , Fenciclidina/toxicidade , Esquizofrenia/induzido quimicamente , Esquizofrenia/prevenção & controle , Bloqueadores dos Canais de Sódio/uso terapêutico , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Reversão de Aprendizagem/efeitos dos fármacos , Reversão de Aprendizagem/fisiologia , Bloqueadores dos Canais de Sódio/farmacologia , Resultado do TratamentoRESUMO
RATIONALE: Schizophrenia is a complex psychiatric disorder comprised of three main classes of symptoms: positive, negative and cognitive symptoms. Currently, no approved treatment exists for the cognitive symptoms. There is thus a great need for research aiming at identifying novel targets for treatment of this indication. Several neurotransmitter systems are affected in schizophrenia patients, including the γ-amino butyric acid (GABAergic) system, demonstrated by reduced parvalbumin-containing interneurons, glutamate decarboxylase (GAD) and the GABA transporter GAT-1. Furthermore, gene expression of several GABA(A) receptor sub-units, such as α1, α4 and δ is reduced in the dorsolateral prefrontal cortex of schizophrenia patients. OBJECTIVES: The psychotomimetic NMDA receptor antagonist phencyclidine (PCP) is frequently employed to model schizophrenia in animal disease models. Sub-chronic PCP treatment of female hooded Lister rats has repeatedly been shown to induce impairments in object recognition memory, and this model was therefore chosen for the examination of the potential of positive modulation of extrasynaptic GABA(A) receptors in alleviating the PCP-induced deficit. RESULTS: Rats treated sub-chronically with PCP showed significant impairments in recognition memory. This deficit was reversed by positive modulation of extrasynaptic GABA(A) receptors. CONCLUSION: The present study shows that extrasynaptic GABA(A) receptors may present a novel target for the development of therapeutics aimed at improving cognitive deficits in schizophrenia.
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Comportamento Animal/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Isoxazóis/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Análise de Variância , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ciclo Estral , Comportamento Exploratório/efeitos dos fármacos , Feminino , Atividade Motora/efeitos dos fármacos , Fenciclidina , Ratos , Receptores de GABA-A/metabolismo , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo , Fatores de TempoRESUMO
RATIONALE: Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. AIM: To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987. METHODS: Adult female hooded-Lister rats received sub-chronic PCP (2mg/kg) or vehicle i.p. twice daily for 7days, followed by 7 days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20mg/kg; s.c.) or vehicle and were tested in the reversal-learning task. In cohort 2, PCP-treated rats received PNU-282987 (10mg/kg; s.c.) or saline for 15days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance. RESULTS: Sub-chronic PCP produced significant deficits in both cognitive tasks (P<0.01-0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10mg/kg (P<0.01) and 20mg/kg (P<0.001), and in novel object recognition at 10mg/kg on day 1 (P<0.01) and on day 15 (P<0.001). CONCLUSIONS: These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15-day once daily dosing of PNU-282987 (10mg/kg s.c.) does not cause tolerance in the rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.
Assuntos
Benzamidas/uso terapêutico , Compostos Bicíclicos com Pontes/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/toxicidade , Agonistas Nicotínicos/uso terapêutico , Fenciclidina/toxicidade , Receptores Nicotínicos/metabolismo , Esquizofrenia/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzamidas/administração & dosagem , Benzamidas/sangue , Benzamidas/farmacocinética , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/sangue , Compostos Bicíclicos com Pontes/farmacocinética , Cognição/efeitos dos fármacos , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/etiologia , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Feminino , Meia-Vida , Aprendizagem/efeitos dos fármacos , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/sangue , Agonistas Nicotínicos/farmacocinética , Distribuição Aleatória , Ratos , Reversão de Aprendizagem/efeitos dos fármacos , Taquifilaxia , Receptor Nicotínico de Acetilcolina alfa7RESUMO
RATIONALE: Cognitive deficits are common in schizophrenia. Asenapine is an atypical antipsychotic approved by the US Food and Drug Administration in adults for treatment of schizophrenia or acute treatment, as monotherapy or adjunct therapy to lithium or valproate, of manic or mixed episodes of bipolar I disorder. OBJECTIVES: Based on the receptor pharmacology of asenapine, the current study assessed the efficacy and mechanism of action of asenapine to improve a subchronic phencyclidine (PCP)-induced deficit in visual recognition memory using the novel object recognition (NOR) paradigm in the rat, a paradigm of relevance to cognition in schizophrenia. METHODS: Female-hooded Lister rats received vehicle or PCP (2 mg/kg, i.p.) for 7 days, followed by a 7-day washout. On the test day, rats were given asenapine (0.001-0.1 mg/kg, s.c.) alone or in combination with the D(1) receptor antagonist SCH-23390 (0.05 mg/kg, i.p.) or 5-HT(1A) receptor antagonist WAY100635 (1 mg/kg, i.p.). Time spent exploring two identical objects during a 3-min acquisition trial (followed by a 1-min intertrial interval) and then a familiar and a novel object for another 3 min (retention trial) were recorded onto videotape and scored blind. RESULTS: In the retention trial, vehicle- but not PCP-treated animals explored the novel object significantly more than the familiar object (p < 0.001). Asenapine (0.01-0.075 mg/kg) reversed PCP-induced deficits in NOR (p < 0.01-0.001) in a dose-related manner. This effect was antagonised by SCH-23390 but not by WAY100635. CONCLUSIONS: These results demonstrate a role for D(1) but not 5-HT(1A) receptor mechanisms in mediating the cognitive effects of asenapine in this rodent model.
Assuntos
Antipsicóticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Fenciclidina/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Dibenzocicloeptenos , Relação Dose-Resposta a Droga , Feminino , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Endogâmicos , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Fatores de TempoRESUMO
BACKGROUND: Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and alpha(2)-adrenergic than dopaminergic D(2) receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats. METHODS: After operant training, rats were treated acutely with d-amphetamine (0.75 mg/kg intraperitoneally [i.p.]) or phencyclidine (PCP; 1.5mg/kg i.p.) or subchronically with PCP (2mg/kg i.p. for 7 days). We assessed the effects of acute coadministration of asenapine, risperidone, or olanzapine on acute d-amphetamine- and PCP-induced deficits and the effects of long-term coadministration of these agents (for 28 additional days) on the deficits induced by subchronic PCP. RESULTS: Deficits in reversal learning induced by acute d-amphetamine were attenuated by risperidone (0.2mg/kg i.p.). Acute PCP-induced impairment of reversal learning was attenuated by acute asenapine (0.025 mg/kg subcutaneously [s.c.]), risperidone (0.2mg/kg i.p.), and olanzapine (1.0mg/kg i.p.). Subchronic PCP administration induced an enduring deficit that was attenuated by acute asenapine (0.075 mg/kg s.c.) and by olanzapine (1.5mg/kg i.p.). Asenapine (0.075 mg/kg s.c.), risperidone (0.2mg/kg i.p.), and olanzapine (1.0mg/kg i.p.) all showed sustained efficacy with chronic (29 days) treatment to improve subchronic PCP-induced impairments. CONCLUSION: These data suggest that asenapine may have beneficial effects in the treatment of cognitive symptoms in schizophrenia. However, this remains to be validated by further clinical evaluation.