The contextual fear conditioning deficit presented by spontaneously hypertensive rats (SHR) is not improved by mood stabilizers

Objectives: We have recently reported that spontaneously hypertensive rats (SHR) present a contextual fear conditioning (CFC) deficit. This deficit is improved by antipsychotic drugs, potentiated by proschizophrenia manipulations and not altered by acute administration of carbamazepine, lamotrigine and valproic acid. Nevertheless, the effects of lithium a classical mood stabilizer or repeated treatment with these drugs were not evaluated. the main aim of the present study was to extend our previous work by investigating a possible beneficial effect of acute and/or chronic treatments with lithium or lamotrigine on the acquisition deficit of CFC presented by SHR.Methods: Rats were submitted to CFC task after an acute treatment with lithium and/or a repeated treatment with lithium and lamotrigine.Results: Our data revealed that the CFC deficit presented by SHR is not improved by acute or repeated treatment with lithium. Repeated lamotrigine treatment potentiated the deficit presented by SHR and impaired CFC in control animals (Wistar Rats).Conclusions: These data reinforce the absence of beneficial effects of mood stabilizers on the emotional context processing impairment modeled by SHR. (C) 2011 Elsevier Inc. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo, Dept Psychiat, LiNC, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pharmacol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, LiNC, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pharmacol, BR-04039032 São Paulo, BrazilWeb of Scienc

Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain

Clinical and neurobiological findings suggest that the cannabinoids and the endocannabinoid system may be implicated in the pathophysiology and treatment of schizophrenia. We described that the spontaneously hypertensive rats (SHR) strain presents a schizophrenia behavioral phenotype that is specifically attenuated by antipsychotic drugs, and potentiated by proschizophrenia manipulations. Based on these findings, we have suggested this strain as an animal model of schizophrenia. the aim of this study was to evaluate the effects of cannabinoid drugs on the deficit of prepulse inhibition (PPI) of startle, the main paradigm used to study sensorimotor gating impairment related to schizophrenia, presented by the SHR strain. the following drugs were used: (1) WIN55212,2 (cannabinoid agonist), (2) rimonabant (CB1 antagonist), (3) AM404 (anandamide uptake inhibitor), and (4) cannabidiol (CBD; indirect CB1/CB2 receptor antagonist, among other effects). VVistar rats (VVRs) and SHRs were treated with vehicle (VEH) or different doses of WIN55212 (0.3, 1, or 3 mg/kg), rimonabant (0.75, 1.5, or 3 mg/kg), AM404 (1, 5, or 10 mg/kg), or CBD (15, 30, or 60 mg/kg). VEH-treated SHRs showed a decreased PPI when compared to VVRs. This PPI deficit was reversed by 1 mg/kg WIN and 30 mg/kg CBD. Conversely, 0.75 mg/kg rimonabant decreased PPI in SHR strain, whereas AM404 did not modify it. Our results reinforce the role of the endocannabinoid system in the sensorimotor gating impairment related to schizophrenia, and point to cannabinoid drugs as potential therapeutic strategies.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Pharmacol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Lab Interdisciplinar Neurociencias Clin, BR-04039032 São Paulo, BrazilUniv São Paulo, Dept Neurosci & Behav, BR-14049 Ribeirao Preto, BrazilNatl Council Sci & Technol Dev, Natl Inst Sci & Technol Translat Med, Ribeirao Preto, BrazilUniversidade Federal de São Paulo, Dept Pharmacol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Lab Interdisciplinar Neurociencias Clin, BR-04039032 São Paulo, BrazilFAPESP: FAPESP - 2010/07994-3Web of Scienc

Cannabidiol exhibits anxiolytic but not antipsychotic property evaluated in the social interaction test

Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that Spontaneously Hypertensive Rats (SHRs) present a deficit in social interaction that is ameliorated by atypical antipsychotics. in addition, SHRs present a hyperlocomotion that is reverted by typical and atypical antipsychotics, suggesting that this strain could be useful to study negative symptoms (modeled by a decrease in social interaction) and positive symptoms (modeled by hyperlocomotion) of schizophrenia as well as the effects of potential antipsychotics drugs. At the same time, an increase in social interaction in control animals similar to that induced by benzodiazepines is used to screen potential anxiolytic drugs. the aim of this study was to investigate the effects of CBD on social interaction presented by control animals (Wistar) and SHRs. the lowest dose of CBD (1 mg/kg) increased passive and total social interaction of Wistar rats. However, the hyperlocomotion and the deficit in social interaction displayed by SHRs were not altered by any dose of CBD. Our results do not support an antipsychotic property of cannabidiol on symptoms-like behaviors in SHRs but reinforce the anxiolytic profile of this compound in control rats. (C) 2012 Elsevier Inc. All rights reserved.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Farmacol, UNIFESP, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, Lab Interdisciplinar Neurociencias Clin, São Paulo, BrazilUniv São Paulo, Dept Neurociencias & Ciencias Comportamento, BR-14049 Ribeirao Preto, BrazilInst Nacl Ciencia & Tecnol Translac Med, INCT TM, CNPq, Ribeirao Preto, BrazilUniversidade Federal de São Paulo, Dept Farmacol, UNIFESP, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, Lab Interdisciplinar Neurociencias Clin, São Paulo, BrazilFAPESP: FAPESP - 2010/07994-3Web of Scienc

Adolescent mice are more vulnerable than adults to single injection-induced behavioral sensitization to amphetamine

Drug-induced behavioral sensitization in rodents has enhanced our understanding of why drugs acquire increasing motivational and incentive value. Compared to adults, human adolescents have accelerated dependence courses with shorter times from first exposure to dependence. We compared adolescent and adult mice in their ability to develop behavioral sensitization to amphetamine following a single injection. Adult (90-day-old) and adolescent (45-day-old) male Swiss mice received an acute intraperitoneal injection of saline or amphetamine (1.0. 2.0 or 4.0 mg/kg). Seven days later, half of the mice from the saline group received a second injection of saline. the remaining animals were challenged with 2.0 mg/kg amphetamine. Following all of the injections, mice were placed in activity chambers and locomotion was quantified for 45 min. the magnitude of both the acute and sensitized locomotor stimulatory effect of amphetamine was higher in the adolescent mice. Previous experience with the test environment inhibited the acute amphetamine stimulation in both adolescent and adult mice, but facilitated the detection of elevated spontaneous locomotion in adolescent animals. These results support the notion that the adolescent period is associated with an increased risk for development of drug abuse. Additionally, they indicate a complex interaction between the environmental novelty, adolescence and amphetamine. (C) 2011 Elsevier Inc. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundo de Apoio ao Docente e Aluno (FADA)Associacao Fundo de Pesquisa em Psicobiologia (AFIP)Universidade Federal de São Paulo, Dept Farmacol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pediat, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biosci, BR-11060001 Santos, SP, BrazilUniversidade Federal de São Paulo, Dept Farmacol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pediat, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biosci, BR-11060001 Santos, SP, BrazilWeb of Scienc

Neuroleptic drugs revert the contextual fear conditioning deficit present in Spontaneously Hypertensive Rats: a potencial animal model of emotional context processing in schizophrenia?

Transtornos psiquiátricos como a esquizofrenia, o transtorno de déficit de atenção e hiperatividade (TDAH) e o transtorno do humor bipolar apresentam anormalidades no processamento de emoções. Um estudo prévio mostrou que os ratos espontaneamente hipertensos (SHR), que têm sido sugeridos como um modelo de TDAH, apresentaram um déficit de resposta de medo condicionado. O objetivo deste estudo foi caracterizar o déficit de medo condicionado ao contexto apresentado pela linhagem SHR. Para isso, ratos adultos das linhagens Wistar e SHR foram submetidos à tarefa de medo condicionado ao contexto. A sensibilidade ao choque (avaliada pela vocalização) e a resposta condicionada foram inicialmente quantificadas. Em seqüência, manipulações que facilitariam o aprendizado da tarefa foram investigadas. Para a caracterização farmacológica, diferentes drogas foram administradas na aquisição do medo condicionado ao contexto: pentilenotetrazol (ansiogênico) e clordiazepóxido (ansiolítico); metilfenidato e anfetamina (usados para o tratamento do TDAH); lamotrigina, carbamazepina, ácido valpróico e lítio (estabilizadores do humor); haloperidol, clozapina, ziprasidona, risperidona, amisulprida e quetiapina (usados para o tratamento da esquizofrenia); metoclopramida e SCH23390 (antagonistas dopaminérgicos sem atividade antipsicótica) e a quetamina (psicotomimético). Os efeitos da privação de sono paradoxal (que desencadeia surtos psicóticos em portadores de esquizofrenia) e a performance em um protocolo de inibição latente (cujo déficit é descrito na esquizofrenia e em modelos dessa patologia) da tarefa de medo condicionado ao contexto foram investigados. Nenhuma diferença na...(au).BV UNIFESP: Teses e dissertaçõe

Study of an animal model of attention-deficit/hyperactivity disorder(ADHD) and addiction: amphetamine-induced behavioral sensitization by spontaneously hypertensive rats

A desordem de deficit atencional / hiperatividade (ADHD) caracteriza-se por hiperatividade, dificuldades de aprendizagem / memoria e impulsividade, estando presente em 21 a 6 por cento das criancas em idade escolar. Alem disso, e de importancia para esta tese, a ADHD tem sido considerada um fator de risco para o abuso de drogas. Alteracoes na transmissao dopaminergica central tem sido implicadas no desenvolvimento dessa desordem, bem como na dependencia de drogas de abuso. Algumas dessas alteracoes dopaminergicas tambem estao presentes em ratos espontaneamente hipertensos (SHR), considerados um modelo animal de ADHD. A presente tese tem como objetivo verificar os efeitos da administracao repetida de anfetamina, droga de escolha para o tratamento da ADHD, sobre o desenvolvimento de sensibilizacao comportamental a hiperatividade locomotora, comportamento relacionado principalmente) com' estimulacao dopaminergica mesolimbica, e, ao comportamento estereotipado, relacionado com estimulacao dopaminergica nigroestriatal. Nesse sentido, a sensibilizacao comportamental tem sido extensivamente sugerido como um modelo para o estudo da dependencia a drogas de abuso. Nossos resultados mostraram que as linhagens Wistar UMA (normotensos) e SHR apresentam diferencas marcantes no desenvolvimento de sensibilizacao comportamental principalmente no que concerne a influencia do aprendizado I condicionamento nesse fenomeno. No primeiro experimento observamos que embora ambas as linhagens tenham desenvolvido a sensibilizacao ao comportamento estereotipado apos desafio com uma dose alta de anfetamina e com pareamento ao ambiente, o fenomeno apresentou menor magnitude nos ratos SHR. Na analise da atividade locomotora induzida por doses moderadas de anfetamina, verificamos que animais SHR naturalmente mostram-se mais impulsivos, exploradores e ativos. Nesse segundo experimento, a linhagem SHR exibiu uma hiperatividade locomotora sensibilizada apos administracao repetida e pareamento ambientala(au)BV UNIFESP: Teses e dissertaçõe

Spontaneously Hypertensive Rats (SHR) present deficits in prepulse inhibition of startle specifically reverted by clozapine

AbstractDeficits in an operational measure of sensorimotor gating – the prepulse inhibition of startle (PPI) – are presented in psychiatric disorders such as schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). Some previous studies showed that the spontaneously hypertensive rats (SHR) present PPI deficit. Although SHR is suggested as an animal model to study ADHD, we have suggested that the behavioral phenotype of this strain mimics some aspects of schizophrenia. The aim of this study was to characterize the PPI response in SHR. Pharmacological characterization consisted in the evaluation of the effects of the following drugs administered to adult Wistar rats (WR) and SHR previously to the PPI test: amphetamine (used for ADHD and also a psychotomimetic drug), haloperidol and clozapine (antipsychotic drugs), metoclopramide (dopamine antagonist without antipsychotic properties) and carbamazepine (mood stabilizer). Our results showed that SHR presented reduced PPI. This deficit was similar to that induced by amphetamine in WR. Only the atypical antipsychotic clozapine improved the PPI deficit observed in SHR. These findings reinforce the SHR strain as an animal model to study several aspects of schizophrenia, including the abnormalities in sensorimotor gating associated with this disease

Is adenosine associated with sudden death in schizophrenia?:A new framework linking the adenosine pathway to risk of sudden death

Schizophrenia is associated with an increased mortality from cardiovascular disease. Relatively few studies have assessed the putative association of schizophrenia pathophysiology with sudden death. Low adenosine levels have been associated with schizophrenia. In cardiology, increased mortality among patients with congestive heart failure has been associated with genetic polymorphisms that potentially lead to lower adenosine levels. Thus, we hypothesize that adenosine could link schizophrenia and cardiovascular mortality, with decreased adenosine levels leading to increased vulnerability to hyperexcitability following hypoxic insults, increasing the odds of fatal arrhythmias. Low adenosine levels might also lead to a small increase in overall mortality rates and a major increase in the sudden death rate. This hypothesis paves the way for further investigation of the increased cardiac mortality associated with schizophrenia. Potentially, a better characterization of adenosine related mechanisms of sudden death in schizophrenia could lead to new evidence of factors leading to sudden death in the general population.Univ Fed Sao Paulo, Dept Psiquiatria, LINC, Rua Pedro Toledo,669 Vila Clementino, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Psiquiatria, Programa Esquizofrenia, PROESQ, Rua Machado Bittencourt 222, BR-04044000 Sao Paulo, BrazilUniv Sao Paulo, Heart Inst InCor, Med Sch, Av Dr Endas Carvaiho Aguiar 44, BR-05403900 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Neurol Neurocirurgia, Disciplina Neurociencia, Rua Pedro Toledo,669 Vila Clementino, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Psiquiatria, LINC, Rua Pedro Toledo,669 Vila Clementino, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Psiquiatria, Programa Esquizofrenia, PROESQ, Rua Machado Bittencourt 222, BR-04044000 Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Neurol Neurocirurgia, Disciplina Neurociencia, Rua Pedro Toledo,669 Vila Clementino, BR-04039032 Sao Paulo, SP, BrazilWeb of Scienc

Sleep rebound attenuates context-dependent behavioural sensitization induced by amphetamine

We have recently demonstrated that paradoxical sleep deprivation (PSD) potentiates the induction of amphetamine (AMPH)-induced behavioural sensitization by increasing its conditioned component. in the present study, the effects of sleep rebound (induced by 24 h recovery period from PSD) were studied on AMPH-induced behavioural sensitization. Sleep rebound attenuated the acute locomotor-stimulating effect of AMPH. AMPH-induced behavioural sensitization was context-specific and was also attenuated by sleep rebound. These results strengthen the notion that sleep conditions can influence AMPH-incluced behavioural sensitization. (C) 2008 Elsevier Inc. All rights reserved.Universidade Federal de São Paulo, Dept Psychobiol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pharmacol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pharmacol, BR-04023062 São Paulo, BrazilWeb of Scienc

Effects of antipsychotics and amphetamine on social behaviors in spontaneously hypertensive rats

We have recently reported that spontaneously hypertensive rats (SHRs) exhibit a deficit in contextual fear conditioning that is specifically reversed by antipsychotic and potentiated by psychostimulants and other manipulations thought to produce schizophrenia-like states in rodents. Based on these findings, we suggested that this deficit in fear conditioning could be used as an experimental model of emotional processing impairments observed in schizophrenia. This strain has also been suggested as a model by which to study attention deficit/hyperactivity disorder (ADHD). Considering that schizophrenia and ADHD are both characterized by poor social function, this study aimed to investigate possible behavioral deficits of SHRs in a social context. Furthermore, we sought to examine the effects of typical and atypical antipsychotics (used for the treatment of schizophrenia) and a psychostimulant (used to treat ADHD) on these behaviors. Pairs of unfamiliar rats of the same or different (i.e., Wistar) strains were treated with one of the aforementioned drugs and placed in an open-field for 10 min. During this time, social behaviors, locomotion and rearing frequencies were scored. Atypical antipsychotics increased social interaction in Wistar rats (WRs) and improved the deficit in social interaction exhibited by SHRs. in addition, the SHR group displayed hyperlocomotion that was attenuated by all antipsychotics (quetiapine and clozapine also decreased locomotion in WRs) and potentiated by amphetamine (which also increased locomotion in WRs). Our results reveal that the behavioral profile of the SHR group demonstrates that this strain can be a useful animal model to study several aspects of schizophrenia. (C) 2011 Elsevier B.V. All rights reserved.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo, Dept Farmacol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, LINC, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Farmacol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, LINC, BR-04039032 São Paulo, BrazilWeb of Scienc