Envolvimento do Sistema Endocanabinóide na fisiopatologia e tratamento da Esquizofrenia: a Linhagem SHR como Modelo Experimental
Data
2013
Autores
Levin, Raquel 
Orientadores
Abílio, Vanessa Costhek
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Achados farmacologicos e neuroquimicos indicam a participacao do sistema endocanabinoide na fisiopatologia da esquizofrenia. Verificamos em nosso laboratorio que a linhagem de ratos SHR apresenta alteracoes comportamentais que sao especificamente revertidas por antipsicoticos e potencializadas por manipulacoes æpro-esquizofrenicasÆ. Esses resultados sugerem que essa linhagem possa ser util para o estudo de diversos aspectos da esquizofrenia e do efeito de drogas com propriedades antipsicoticas. Os objetivos deste estudo foram: 1) avaliar a densidade de receptores CB1 em regioes cerebrais relacionadas a esquizofrenia, 2) avaliar os efeitos do WIN55-212,2 (agonista canabinoide direto), do rimonabanto (antagonista CB1), do AM404 (inibidor da recaptacao de anandamida) e do canabidiol (um composto derivado da Canabis sativa com propriedades antipsicoticas), sobre os deficits na tarefa de medo condicionado ao contexto (MCC u que mimetiza os prejuizos no entendimento de contexto emocionais) e no teste de inibicao pre-pulso (PPI u que mimetiza os prejuizos no funcionamento do filtro sensoriomotor) apresentados pela linhagem SHR em relacao a linhagem controle Wistar. Os animais da linhagem SHR apresentam um aumento significativo da densidade de receptores CB1 no cortex pre-limbico, cortex cingulado anterior e sub-regiao CA3 do hipocampo em relacao aos animais controle. A administracao de 1 mg/kg de WIN55212,2 reverteu o deficit de PPI presente na linhagem SHR. Em relacao a tarefa de MCC, esse farmaco produziu um efeito bifasico no tempo de congelamento, em ambas as linhagens, de acordo com as doses administradas (doses menores aumentaram o tempo de congelamento e doses maiores diminuiram essa resposta). O antagonista CB1, rimonabanto, reverteu o deficit de MCC da linhagem SHR (3 mg/kg), porem, potencializou o deficit de PPI presente nessa linhagem (0,75 mg/kg). Paralelamente, a menor dose de AM404 (1 mg/kg) reverteu o deficit de MCC na linhagem SHR, enquanto que a maior dose (10 mg/kg) prejudicou o desempenho da linhagem Wistar nessa tarefa. A administracao de AM404 nao alterou a resposta de PPI em ambas as linhagens. Por fim, o canabidiol foi capaz de reverter os deficit na tarefa de MCC (1mg/kg) e na resposta de PPI (30 e 60 mg/kg) na linhagem SHR e todas as doses testadas diminuiram o tempo de congelamento da linhagem Wistar. Nossos dados reforcam a participacao do sistema endocanabinoide na fisiopatologia da esquizofrenia e sugerem que manipulacoes nesse sistema podem ser beneficas para o tratamento dos prejuizos nos processamentos de informacao e de emocao relacionados a esquizofrenia. Por fim, nossos dados reforcam o potencial de utilizacao da linhagem SHR como modelo animal para o estudo de diversos aspectos relacionados a essa doenca
Clinical and neurobiological findings suggest that the endocannabinoid system may be implicated in the pathophysiology of schizophrenia. We have 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 were: 1) analyze the CB1 density in encephalic regions related to schizophrenia, 2) evaluate the effects of WIN55212,2 (direct cannabinoid agonist), rimonabant (CB1 antagonist), AM404 (anandamide uptake inhibitor) and cannabidiol (an alleged antipsychotic compound of Cannabis sativa) on the prepulse inhibition of startle (PPI the main paradigm used to study sensorimotor gating impairment related to schizophrenia) and on the contextual fear conditioning (CFC that mimics emotional processing impairment in schizophrenia) deficits presented by the SHR strain. The SHR strain has a higher CB1 density in the following encephalic regions: prelimbic cortex, anterior cingulate cortex and CA3 hippocampus subregion when compared to Wistar rats. Treatment with 1 mg/kg WIN55212,2 reversed the PPI deficit presented by SHR. Moreover, this drug produced a biphasic response in CFC in both strains, depending of the dose used (lower doses increased freezing response and higher doses decreased it). Rimonabant reversed the deficit in CFC (3 mg/kg) in SHR, but decreased (0,75 mg/kg) PPI response in this strain. The lower dose of AM404 (1 mg/kg) reversed the CFC deficit in SHR and the higher dose (10 mg/kg) worsened the freezing response in Wistar rats. AM404 did not modify PPI response in both strains. Finally, treatment with cannabidiol reversed the CFC (1 mg/kg) and the PPI (30 and 60 mg/kg) deficits presented by SHR and all doses tested decreased the freezing response in Wistar rats. Our results reinforce the role of endocannabinoid system in the pathophysiology of schizophrenia and point to cannabinoid drugs as potential therapeutic targets to treat the sensorimotor gating and the emotional processing impairments related to this disease. Finally, our data support the SHR strain as an animal model to study several aspects related to this disease.
Clinical and neurobiological findings suggest that the endocannabinoid system may be implicated in the pathophysiology of schizophrenia. We have 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 were: 1) analyze the CB1 density in encephalic regions related to schizophrenia, 2) evaluate the effects of WIN55212,2 (direct cannabinoid agonist), rimonabant (CB1 antagonist), AM404 (anandamide uptake inhibitor) and cannabidiol (an alleged antipsychotic compound of Cannabis sativa) on the prepulse inhibition of startle (PPI the main paradigm used to study sensorimotor gating impairment related to schizophrenia) and on the contextual fear conditioning (CFC that mimics emotional processing impairment in schizophrenia) deficits presented by the SHR strain. The SHR strain has a higher CB1 density in the following encephalic regions: prelimbic cortex, anterior cingulate cortex and CA3 hippocampus subregion when compared to Wistar rats. Treatment with 1 mg/kg WIN55212,2 reversed the PPI deficit presented by SHR. Moreover, this drug produced a biphasic response in CFC in both strains, depending of the dose used (lower doses increased freezing response and higher doses decreased it). Rimonabant reversed the deficit in CFC (3 mg/kg) in SHR, but decreased (0,75 mg/kg) PPI response in this strain. The lower dose of AM404 (1 mg/kg) reversed the CFC deficit in SHR and the higher dose (10 mg/kg) worsened the freezing response in Wistar rats. AM404 did not modify PPI response in both strains. Finally, treatment with cannabidiol reversed the CFC (1 mg/kg) and the PPI (30 and 60 mg/kg) deficits presented by SHR and all doses tested decreased the freezing response in Wistar rats. Our results reinforce the role of endocannabinoid system in the pathophysiology of schizophrenia and point to cannabinoid drugs as potential therapeutic targets to treat the sensorimotor gating and the emotional processing impairments related to this disease. Finally, our data support the SHR strain as an animal model to study several aspects related to this disease.
Descrição
Citação
LEVIN, Raquel. Envolvimento do Sistema Endocanabinóide na Fisiopatologia e Tratamento da Esquizofrenia: a Linhagem SHR como Modelo Experimental.2013. 86f. Tese (Doutorado em Farmacologia) – Escola Paulista de Medicina, Universidade Federal de São Paulo. São Paulo, 2013.