Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina
Ano de defesa: | 2022 |
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Autor(a) principal: | |
Outros Autores: | |
Orientador(a): | |
Banca de defesa: | , , |
Tipo de documento: | Dissertação |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade do Estado do Rio de Janeiro
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Programa de Pós-Graduação: |
Programa de Pós-Graduação em Fisiopatologia Clínica e Experimental
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Departamento: |
Centro Biomédico::Faculdade de Ciências Médicas
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://www.bdtd.uerj.br/handle/1/20995 |
Resumo: | Schizophrenia affects 0.9% of the world population. It is considered a neurodevelopmental disorder, although its full manifestation and diagnosis occur often between late adolescence and early adulthood. After its establishment, three types of symptoms are observed: positive, negative, and cognitive. There are marked sexual differences in schizophrenia, with a higher and earlier incidence in men, who also have more severe negative and cognitive symptoms and a worse response to antipsychotics. Despite these differences, no established animal models mimic them, making it difficult to understand the sex-dependent pathophysiologic mechanisms of schizophrenia and to develop more efficient treatments. Thus, in this study, we used a developmental model of schizophrenia by the neonatal administration of phencyclidine (nPCP), an NMDA receptor antagonist, to investigate whether it induces behavioral and neurochemical changes in a sex-dependent manner. We also evaluated the impact of olanzapine, an atypical antipsychotic, on these changes. C57BL/6 mice of both sexes received subcutaneous injections of phencyclidine at doses of 5, 10, or 20mg/kg (nPCP5, nPCP10, nPCP20), or saline, at postnatal days (PN) 7, 9, and 11. A Naïve group was used to assess the impact of stress associated with injections. At PN30, early adolescence, we quantified by Western Blotting, the NR1 subunit of the NMDA receptor and the postsynaptic protein PSD-95 in the frontal cortex and hippocampus. From PN48 to PN50, the animals were submitted to the following behavioral tests: open field (OF), to check for locomotor hyperactivity associated with positive symptoms; social interaction (SI) to measure a change associated with a negative symptom; and prepulse inhibition (PPI) to assess sensorimotor gate integrity. Olanzapine was administered 30min before each test. There were no differences between Naive and Salina animals, which were pooled in subsequent analyses. In the OF, both nPCP males and females were hypoactive, but males were more sensitive, expressing hypoactivity even at the lowest dose of nPCP. In the SI, impairments in social interaction were identified only in males; in nPCP5 and nPCP20 animals. In the PPI, nPCP males and females showed deficits, with signs of greater severity in males, as they showed a reduction in the percentage of inhibition by the pre-pulse of lower intensity. Olanzapine failed to reverse the behavioral changes caused by nPCP and, in some situations, its administration intensified the effects of the neonatal model. Olanzapine caused more severe hypolocomotion in nPCP males and, particularly in the SI, nPCP10 males only showed deficits if exposed to this antipsychotic. Consistent with the data obtained in the behavioral assessments, we identified a decrease in NR1 protein expression in the frontal cortex only in males. These results suggest that nPCP can be used to model sex-dependent differences identified in patients with schizophrenia. The ineffectiveness and the behavioral damage associated with the protocol adopted for the administration of olanzapine also suggest the need for further studies with the aim of investigating the efficacy and safety of this drug during adolescence |
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Villaça, Yael de Abreuhttp://lattes.cnpq.br/2110538573461886Tavares, Ana Carolina Dutrahttp://lattes.cnpq.br/4054979030578737Filgueiras, Cláudio Carneirohttp://lattes.cnpq.br/4038653479176687Montes, Guilherme Carneirohttp://lattes.cnpq.br/5552317664330255Neves, Gilda Angelahttp://lattes.cnpq.br/1352255992428449http://lattes.cnpq.br/5360472411764361Souza, Thainá Pereira dethainasouza2@gmail.com2024-01-26T20:33:21Z2022-09-27SOUZA, Thainá Pereira de. Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina. 2022. 82 f. Dissertação (Mestrado em Fisiopatologia Clínica e Experimental) – Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2022.http://www.bdtd.uerj.br/handle/1/20995Schizophrenia affects 0.9% of the world population. It is considered a neurodevelopmental disorder, although its full manifestation and diagnosis occur often between late adolescence and early adulthood. After its establishment, three types of symptoms are observed: positive, negative, and cognitive. There are marked sexual differences in schizophrenia, with a higher and earlier incidence in men, who also have more severe negative and cognitive symptoms and a worse response to antipsychotics. Despite these differences, no established animal models mimic them, making it difficult to understand the sex-dependent pathophysiologic mechanisms of schizophrenia and to develop more efficient treatments. Thus, in this study, we used a developmental model of schizophrenia by the neonatal administration of phencyclidine (nPCP), an NMDA receptor antagonist, to investigate whether it induces behavioral and neurochemical changes in a sex-dependent manner. We also evaluated the impact of olanzapine, an atypical antipsychotic, on these changes. C57BL/6 mice of both sexes received subcutaneous injections of phencyclidine at doses of 5, 10, or 20mg/kg (nPCP5, nPCP10, nPCP20), or saline, at postnatal days (PN) 7, 9, and 11. A Naïve group was used to assess the impact of stress associated with injections. At PN30, early adolescence, we quantified by Western Blotting, the NR1 subunit of the NMDA receptor and the postsynaptic protein PSD-95 in the frontal cortex and hippocampus. From PN48 to PN50, the animals were submitted to the following behavioral tests: open field (OF), to check for locomotor hyperactivity associated with positive symptoms; social interaction (SI) to measure a change associated with a negative symptom; and prepulse inhibition (PPI) to assess sensorimotor gate integrity. Olanzapine was administered 30min before each test. There were no differences between Naive and Salina animals, which were pooled in subsequent analyses. In the OF, both nPCP males and females were hypoactive, but males were more sensitive, expressing hypoactivity even at the lowest dose of nPCP. In the SI, impairments in social interaction were identified only in males; in nPCP5 and nPCP20 animals. In the PPI, nPCP males and females showed deficits, with signs of greater severity in males, as they showed a reduction in the percentage of inhibition by the pre-pulse of lower intensity. Olanzapine failed to reverse the behavioral changes caused by nPCP and, in some situations, its administration intensified the effects of the neonatal model. Olanzapine caused more severe hypolocomotion in nPCP males and, particularly in the SI, nPCP10 males only showed deficits if exposed to this antipsychotic. Consistent with the data obtained in the behavioral assessments, we identified a decrease in NR1 protein expression in the frontal cortex only in males. These results suggest that nPCP can be used to model sex-dependent differences identified in patients with schizophrenia. The ineffectiveness and the behavioral damage associated with the protocol adopted for the administration of olanzapine also suggest the need for further studies with the aim of investigating the efficacy and safety of this drug during adolescenceA esquizofrenia atinge 0,9% da população mundial. É considerada um transtorno do neurodesenvolvimento, embora sua manifestação plena e seu diagnóstico ocorram frequentemente entre o final da adolescência e o início da fase adulta. Após seu estabelecimento, são observados três tipos de sintomas: positivos, negativos e cognitivos. Existem marcantes diferenças sexuais na esquizofrenia, sendo sua incidência maior e mais precoce em homens, os quais também apresentam sintomas negativos e cognitivos mais severos e pior resposta aos antipsicóticos. Apesar dessas diferenças, não há modelos animais estabelecidos que as mimetizem, o que dificulta o entendimento dos mecanismos sexo-dependentes envolvidos na fisiopatologia da esquizofrenia e o desenvolvimento de tratamentos mais eficientes. Assim, nesse estudo, utilizamos o modelo de esquizofrenia pela administração neonatal de fenciclidina (nPCP), um antagonista de receptores NMDA, visando investigar se este modelo induz alterações comportamentais e neuroquímicas de forma sexo-dependente. Avaliamos também o impacto da olanzapina, um antipsicótico atípico, sobre essas alterações. Camundongos C57BL/6 de ambos os sexos receberam injeções subcutâneas de fenciclidina nas doses de 5, 10 ou 20mg/kg (nPCP5, nPCP10, nPCP20), ou salina aos 7, 9 e 11 dias de vida pós-natal (PN). Para avaliar o impacto do estresse associado às injeções, foi utilizado um grupo Naive. Em PN30, início da adolescência, quantificamos por Western Blotting a subunidade NR1 do receptor NMDA e a proteína pós-sináptica PSD-95 no córtex frontal e hipocampo. De PN48 a PN50, os animais foram submetidos aos seguintes testes comportamentais: campo aberto (CA), para medir a hiperatividade locomotora associada aos sintomas positivos; interação social (IS), para mensurar uma alteração associada a um sintoma negativo; e inibição pelo pré-pulso (IPP), para avaliar a integridade do filtro sensório-motor. A olanzapina foi administrada 30 minutos antes de cada teste. Não houve diferenças entre animais Naive e Salina, os quais foram agrupados nas análises subsequentes. No CA, identificamos hipoatividade em animais nPCP de ambos os sexos, mas machos se mostraram mais sensíveis, expressando hipoatividade mesmo na menor dose de nPCP. No IS, prejuízos na interação social foram identificados somente em machos, em animais nPCP5 e nPCP20. No IPP, machos e fêmeas nPCP apresentaram déficits, com maior severidade em machos, pois estes apresentaram redução do percentual de inibição pelo pré-pulso de menor intensidade. A olanzapina não reverteu as alterações comportamentais provocadas pela nPCP e, em algumas situações, sua administração intensificou os efeitos da nPCP. A olanzapina causou hipolocomoção mais severa em machos nPCP e, particularmente no IS, machos nPCP10 somente apresentaram déficits se expostos a esse antipsicótico. Consistente com os dados obtidos nas avaliações comportamentais, identificamos diminuição da expressão da proteína NR1 no córtex frontal apenas em machos. Esses resultados sugerem que a nPCP pode ser usada para modelar as diferenças sexo-dependentes identificadas em pacientes com esquizofrenia. A ineficácia e indicação de danos comportamentais associados ao protocolo adotado para administração de olanzapina sugere ainda a necessidade de mais estudos com o objetivo de investigar a eficácia e segurança deste fármaco na adolescênciaSubmitted by Felipe CB/A (felipebibliotecario@gmail.com) on 2024-01-26T20:33:21Z No. of bitstreams: 1 Dissertação - Thainá Pereira Souza- 2022 - Completa.pdf: 1386754 bytes, checksum: b0f3e01116bb0bc57c9588c79131d446 (MD5)Made available in DSpace on 2024-01-26T20:33:21Z (GMT). No. of bitstreams: 1 Dissertação - Thainá Pereira Souza- 2022 - Completa.pdf: 1386754 bytes, checksum: b0f3e01116bb0bc57c9588c79131d446 (MD5) Previous issue date: 2022-09-27Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPqCoordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESFundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro - FAPERJapplication/pdfporUniversidade do Estado do Rio de JaneiroPrograma de Pós-Graduação em Fisiopatologia Clínica e ExperimentalUERJBrasilCentro Biomédico::Faculdade de Ciências MédicasSchizophreniaPhencyclidineBehaviorSexual dimorphismAdolescenceEsquizofrenia – Tratamento farmacológicoFenciclidina – Antagonistas e inibidoresComportamento do adolescenteCaracteres SexuaisDimorfismo sexualAdolescênciaCIENCIAS BIOLOGICAS::FISIOLOGIA::FISIOLOGIA DE ORGAOS E SISTEMAS::NEUROFISIOLOGIAEfeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidinaSex-dependent effects of a mouse model of schizophrenia induced by neonatal exposure to phencyclidineinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UERJinstname:Universidade do Estado do Rio de Janeiro (UERJ)instacron:UERJORIGINALDissertação - Thainá Pereira Souza- 2022 - Completa.pdfDissertação - Thainá Pereira Souza- 2022 - Completa.pdfapplication/pdf1386754http://www.bdtd.uerj.br/bitstream/1/20995/2/Disserta%C3%A7%C3%A3o+-+Thain%C3%A1+Pereira+Souza-+2022+-+Completa.pdfb0f3e01116bb0bc57c9588c79131d446MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82123http://www.bdtd.uerj.br/bitstream/1/20995/1/license.txte5502652da718045d7fcd832b79fca29MD511/209952024-02-26 16:36:27.207oai:www.bdtd.uerj.br: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Biblioteca Digital de Teses e Dissertaçõeshttp://www.bdtd.uerj.br/PUBhttps://www.bdtd.uerj.br:8443/oai/requestbdtd.suporte@uerj.bropendoar:29032024-02-26T19:36:27Biblioteca Digital de Teses e Dissertações da UERJ - Universidade do Estado do Rio de Janeiro (UERJ)false |
dc.title.por.fl_str_mv |
Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina |
dc.title.alternative.eng.fl_str_mv |
Sex-dependent effects of a mouse model of schizophrenia induced by neonatal exposure to phencyclidine |
title |
Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina |
spellingShingle |
Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina Souza, Thainá Pereira de Schizophrenia Phencyclidine Behavior Sexual dimorphism Adolescence Esquizofrenia – Tratamento farmacológico Fenciclidina – Antagonistas e inibidores Comportamento do adolescente Caracteres Sexuais Dimorfismo sexual Adolescência CIENCIAS BIOLOGICAS::FISIOLOGIA::FISIOLOGIA DE ORGAOS E SISTEMAS::NEUROFISIOLOGIA |
title_short |
Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina |
title_full |
Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina |
title_fullStr |
Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina |
title_full_unstemmed |
Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina |
title_sort |
Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina |
author |
Souza, Thainá Pereira de |
author_facet |
Souza, Thainá Pereira de thainasouza2@gmail.com |
author_role |
author |
author2 |
thainasouza2@gmail.com |
author2_role |
author |
dc.contributor.advisor1.fl_str_mv |
Villaça, Yael de Abreu |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/2110538573461886 |
dc.contributor.advisor-co1.fl_str_mv |
Tavares, Ana Carolina Dutra |
dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/4054979030578737 |
dc.contributor.referee1.fl_str_mv |
Filgueiras, Cláudio Carneiro |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/4038653479176687 |
dc.contributor.referee2.fl_str_mv |
Montes, Guilherme Carneiro |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/5552317664330255 |
dc.contributor.referee3.fl_str_mv |
Neves, Gilda Angela |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/1352255992428449 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/5360472411764361 |
dc.contributor.author.fl_str_mv |
Souza, Thainá Pereira de thainasouza2@gmail.com |
contributor_str_mv |
Villaça, Yael de Abreu Tavares, Ana Carolina Dutra Filgueiras, Cláudio Carneiro Montes, Guilherme Carneiro Neves, Gilda Angela |
dc.subject.eng.fl_str_mv |
Schizophrenia Phencyclidine Behavior Sexual dimorphism Adolescence |
topic |
Schizophrenia Phencyclidine Behavior Sexual dimorphism Adolescence Esquizofrenia – Tratamento farmacológico Fenciclidina – Antagonistas e inibidores Comportamento do adolescente Caracteres Sexuais Dimorfismo sexual Adolescência CIENCIAS BIOLOGICAS::FISIOLOGIA::FISIOLOGIA DE ORGAOS E SISTEMAS::NEUROFISIOLOGIA |
dc.subject.por.fl_str_mv |
Esquizofrenia – Tratamento farmacológico Fenciclidina – Antagonistas e inibidores Comportamento do adolescente Caracteres Sexuais Dimorfismo sexual Adolescência |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::FISIOLOGIA::FISIOLOGIA DE ORGAOS E SISTEMAS::NEUROFISIOLOGIA |
description |
Schizophrenia affects 0.9% of the world population. It is considered a neurodevelopmental disorder, although its full manifestation and diagnosis occur often between late adolescence and early adulthood. After its establishment, three types of symptoms are observed: positive, negative, and cognitive. There are marked sexual differences in schizophrenia, with a higher and earlier incidence in men, who also have more severe negative and cognitive symptoms and a worse response to antipsychotics. Despite these differences, no established animal models mimic them, making it difficult to understand the sex-dependent pathophysiologic mechanisms of schizophrenia and to develop more efficient treatments. Thus, in this study, we used a developmental model of schizophrenia by the neonatal administration of phencyclidine (nPCP), an NMDA receptor antagonist, to investigate whether it induces behavioral and neurochemical changes in a sex-dependent manner. We also evaluated the impact of olanzapine, an atypical antipsychotic, on these changes. C57BL/6 mice of both sexes received subcutaneous injections of phencyclidine at doses of 5, 10, or 20mg/kg (nPCP5, nPCP10, nPCP20), or saline, at postnatal days (PN) 7, 9, and 11. A Naïve group was used to assess the impact of stress associated with injections. At PN30, early adolescence, we quantified by Western Blotting, the NR1 subunit of the NMDA receptor and the postsynaptic protein PSD-95 in the frontal cortex and hippocampus. From PN48 to PN50, the animals were submitted to the following behavioral tests: open field (OF), to check for locomotor hyperactivity associated with positive symptoms; social interaction (SI) to measure a change associated with a negative symptom; and prepulse inhibition (PPI) to assess sensorimotor gate integrity. Olanzapine was administered 30min before each test. There were no differences between Naive and Salina animals, which were pooled in subsequent analyses. In the OF, both nPCP males and females were hypoactive, but males were more sensitive, expressing hypoactivity even at the lowest dose of nPCP. In the SI, impairments in social interaction were identified only in males; in nPCP5 and nPCP20 animals. In the PPI, nPCP males and females showed deficits, with signs of greater severity in males, as they showed a reduction in the percentage of inhibition by the pre-pulse of lower intensity. Olanzapine failed to reverse the behavioral changes caused by nPCP and, in some situations, its administration intensified the effects of the neonatal model. Olanzapine caused more severe hypolocomotion in nPCP males and, particularly in the SI, nPCP10 males only showed deficits if exposed to this antipsychotic. Consistent with the data obtained in the behavioral assessments, we identified a decrease in NR1 protein expression in the frontal cortex only in males. These results suggest that nPCP can be used to model sex-dependent differences identified in patients with schizophrenia. The ineffectiveness and the behavioral damage associated with the protocol adopted for the administration of olanzapine also suggest the need for further studies with the aim of investigating the efficacy and safety of this drug during adolescence |
publishDate |
2022 |
dc.date.issued.fl_str_mv |
2022-09-27 |
dc.date.accessioned.fl_str_mv |
2024-01-26T20:33:21Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
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SOUZA, Thainá Pereira de. Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina. 2022. 82 f. Dissertação (Mestrado em Fisiopatologia Clínica e Experimental) – Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2022. |
dc.identifier.uri.fl_str_mv |
http://www.bdtd.uerj.br/handle/1/20995 |
identifier_str_mv |
SOUZA, Thainá Pereira de. Efeitos sexo-dependentes do modelo de esquizofrenia pela exposição neonatal de camundongos à fenciclidina. 2022. 82 f. Dissertação (Mestrado em Fisiopatologia Clínica e Experimental) – Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2022. |
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http://www.bdtd.uerj.br/handle/1/20995 |
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Universidade do Estado do Rio de Janeiro |
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Programa de Pós-Graduação em Fisiopatologia Clínica e Experimental |
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UERJ |
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Brasil |
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Centro Biomédico::Faculdade de Ciências Médicas |
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Universidade do Estado do Rio de Janeiro |
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