Depressão experimental e tratamento agudo com cetamina : análise comportamental, neurometabólica e histofisiológica dopaminérgica
Autor(a) principal: | |
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Data de Publicação: | 2015 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da PUC_RS |
Texto Completo: | http://tede2.pucrs.br/tede2/handle/tede/6367 |
Resumo: | The major depressive disorder (MDD) is a psychiatric condition which profoundly alters with the brain metabolism and neurochemistry characterized by a state of deep, chronic sadness, accompanied by anhedonia, sensation of worthlessness and lack of motivation, often leading the patient to suicide. The ventral tegmental area (VTA) is an important dopaminergic region intimately associated with the pathophysiology of MDD. Ketamine is a drug that antagonizes the glutamatergic NMDA receptors which has been shown to exert an immediate antidepressant effect and the treatment with ketamine is a promising new alternative for MDD therapeutic. Furthermore, the small animal positron emission tomography (microPET) is a technique which allows the assessment of the temporal-spatial distribution of radiolabelled molecules in vivo, and the utilization of 18F-Fluorodeoxyglucose (18F-FDG) as a radiotracer for this analysis still needs standardization in our University. In this sense, this thesis has been divided into two stages. Firstly, we standardized the brain metabolic assessment technique using 18F-FDG associated with microPET in Wistar rats, and with it, we rendered a neurometabolic atlas of the distribution of 18F-FDG in 56 brain regions. We compared our neurometabolic data with data from five other scientific articles which assessed the biochemical and immunohistochemical activity of cytochrome c oxidase (COX), these techniques are traditionally used for assessment of ex vivo brain metabolism. Thus, we ranked the regions analyzed in our study and the regions from the selected COX studies, and correlated the rankings with the Spearman test for non-parametric ranked data correlation. In this study we detailed the distribution of 18F-FDG in the brain of Wistar rats. On four of the selected studies we did not find a correlation, only on Shumake at al.´s study we found a moderate correlation (r=0.56, p=0.023). In the second stage, we analyzed the influence of acute ketamine treatment on the depressive-like behavior, the glucose metabolism and tyrosine hydroxylase activity (TH) (a rate-limiting dopamine synthesis enzyme) in the VTA of animals exposed to the chronic unpredictable stress (CUS). In this study, 48 Wistar rats were divided into four groups: 1-Control, 2-Ketamine, 3-CUS, 4-CUS+Ketamine. The animals undergone the CUS protocol were expose to several stressors, twice-daily, for 28 consecutive days. The treatment consisted of a single intraperitoneal injection of 10mg/kg of ketamine. For the behavioral analysis the sucrose preference test, the open field test, and the forced swim test were executed. The glucose metabolism and TH immunoreactivity in the VTA were analyzed by 18F-FDG-microPET and immunohistochemistry for TH, respectively. The CUS groups showed a decrease in sucrose solution intake and an increase in the immobility time on the forced swim test, and ketamine treatment was able to reverted the depressive-like behavior (p<0.05. The CUS protocol and ketamine treatment did not influence upon the 18F-FDG uptake or the TH immunoreactivity in the VTA. The results obtained in this thesis aid on the standardizing of the use of 18F-FDG with microPET, for the analyses on brain metabolism in our university. Furthermore, with the CUS protocol, we confirmed the acute, antidepressant effect of ketamine, however, our finds indicated that this effect is not related to metabolic or dopaminergic physiology in the VTA. |
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Xavier, Léder Leal730.223.570-87http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4795990T9112.033.177-35http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4420019P6Baptista, Pedro Porto Alegre2015-10-26T11:19:38Z2015-08-31http://tede2.pucrs.br/tede2/handle/tede/6367The major depressive disorder (MDD) is a psychiatric condition which profoundly alters with the brain metabolism and neurochemistry characterized by a state of deep, chronic sadness, accompanied by anhedonia, sensation of worthlessness and lack of motivation, often leading the patient to suicide. The ventral tegmental area (VTA) is an important dopaminergic region intimately associated with the pathophysiology of MDD. Ketamine is a drug that antagonizes the glutamatergic NMDA receptors which has been shown to exert an immediate antidepressant effect and the treatment with ketamine is a promising new alternative for MDD therapeutic. Furthermore, the small animal positron emission tomography (microPET) is a technique which allows the assessment of the temporal-spatial distribution of radiolabelled molecules in vivo, and the utilization of 18F-Fluorodeoxyglucose (18F-FDG) as a radiotracer for this analysis still needs standardization in our University. In this sense, this thesis has been divided into two stages. Firstly, we standardized the brain metabolic assessment technique using 18F-FDG associated with microPET in Wistar rats, and with it, we rendered a neurometabolic atlas of the distribution of 18F-FDG in 56 brain regions. We compared our neurometabolic data with data from five other scientific articles which assessed the biochemical and immunohistochemical activity of cytochrome c oxidase (COX), these techniques are traditionally used for assessment of ex vivo brain metabolism. Thus, we ranked the regions analyzed in our study and the regions from the selected COX studies, and correlated the rankings with the Spearman test for non-parametric ranked data correlation. In this study we detailed the distribution of 18F-FDG in the brain of Wistar rats. On four of the selected studies we did not find a correlation, only on Shumake at al.´s study we found a moderate correlation (r=0.56, p=0.023). In the second stage, we analyzed the influence of acute ketamine treatment on the depressive-like behavior, the glucose metabolism and tyrosine hydroxylase activity (TH) (a rate-limiting dopamine synthesis enzyme) in the VTA of animals exposed to the chronic unpredictable stress (CUS). In this study, 48 Wistar rats were divided into four groups: 1-Control, 2-Ketamine, 3-CUS, 4-CUS+Ketamine. The animals undergone the CUS protocol were expose to several stressors, twice-daily, for 28 consecutive days. The treatment consisted of a single intraperitoneal injection of 10mg/kg of ketamine. For the behavioral analysis the sucrose preference test, the open field test, and the forced swim test were executed. The glucose metabolism and TH immunoreactivity in the VTA were analyzed by 18F-FDG-microPET and immunohistochemistry for TH, respectively. The CUS groups showed a decrease in sucrose solution intake and an increase in the immobility time on the forced swim test, and ketamine treatment was able to reverted the depressive-like behavior (p<0.05. The CUS protocol and ketamine treatment did not influence upon the 18F-FDG uptake or the TH immunoreactivity in the VTA. The results obtained in this thesis aid on the standardizing of the use of 18F-FDG with microPET, for the analyses on brain metabolism in our university. Furthermore, with the CUS protocol, we confirmed the acute, antidepressant effect of ketamine, however, our finds indicated that this effect is not related to metabolic or dopaminergic physiology in the VTA.O transtorno depressivo maior (MDD) é um distúrbio psiquiátrico que altera profundamente a neuroquímica e o metabolismo encefálico; caracterizado clinicamente por um estado de tristeza profunda crônica, acompanhada por anedonia, sensação de desvalia e falta de motivação, podendo levar o paciente a cometer suicídio. A área tegmental ventral (VTA) é uma importante região dopaminérgica intimamente relacionada com a patofisiologia do MDD. A cetamina é um fármaco antagonista de receptores NMDA glutamatérgicos que apresenta um rápido efeito antidepressivo e o tratamento agudo com cetamina é uma promissora alternativa terapêutica para os pacientes com MDD. Ademais, a tomografia por emissão de pósitrons para pequenos animais (microPET) é uma técnica que permite avaliar a distribuição temporal-espacial de moléculas radiomarcadas in vivo, e a utilização do 18F-Fluorodeoxiglicose (18F-FDG) como rádio-traçador para este tipo de análise ainda necessita ser padronizada junto a nossa Universidade. Deste modo, esta tese de doutorado foi dividida em duas etapas. Primeiramente, padronizamos a técnica de análise do metabolismo encefálico de ratos Wistar com uso de 18F-FDG associada ao microPET, e com isso confeccionamos um atlas neurometabólico detalhado da distribuição de 18F-FDG em 56 regiões encefálicas. Comparamos os dados neurometabólicos obtidos com dados de cinco artigos da literatura científica que realizaram avaliações bioquímicas e imunoistoquímicas da atividade do citocromo c oxidase (COX), técnicas tradicionalmente utilizadas para análise do metabolismo encefálico ex vivo. Para a comparação, ordenamos as regiões analisadas em nosso estudo e as regiões dos estudos de COX selecionados, então correlacionamos estas ordenações através do teste não paramétrico de correlação para dados ordenados de Spearman. Neste estudo detalhamos a distribuição de 18F-FDG no encéfalo de ratos Wistar. Em quatro dos estudos selecionados não encontramos correlação, somente com o estudo de Shumake et al. encontramos uma correlação moderada (r=0,56, p=0,023). Na segunda etapa, analisamos a influência do tratamento agudo com a cetamina sobre o comportamento símil-depressivo, o metabolismo de glicose e a atividade da enzima tirosina hidroxilase (TH) (uma enzima limitante na síntese de dopamina) na VTA de animais submetidos protocolo de estresse crônico imprevisível (CUS). Neste estudo, 48 ratos Wistar foram divididos em quatro grupos: 1-Controle, 2-Cetamina, 3-CUS, 4-CUS+Cetamina. Os animais submetidos ao protocolo CUS foram expostos a estressores variados, duas vezes ao dia, por 28 dias consecutivos. O tratamento foi uma única administração intraperitoneal de 10mg/kg de cetamina. Para análise comportamental foram realizados os testes de preferência a sacarose, campo aberto e nado forçado. O metabolismo da glicose e a imunorreatividade para TH na VTA foram analisadas por meio do 18F-FDG-microPET e imunoistoquímica para TH, respectivamente. Os grupos CUS apresentaram uma diminuição do consumo de solução de sacarose e um aumento no tempo de imobilidade no teste de nada forçado e o tratamento com cetamina foi capaz de reverter o comportamento símil-depressivo (p<0,05). O protocolo CUS e o tratamento com cetamina não exerceram influência sobre a captação de 18F-FDG e a imunorreatividade para TH na VTA. Os resultados obtidos com esta tese de doutorado possibilitaram a padronização do uso de 18F-FDG com microPET, para análise do metabolismo encefálico de ratos Wistar em nossa Universidade. Ademais, com o uso do protocolo CUS, confirmou-se o efeito antidepressivo agudo da cetamina, contudo nossos achados indicam que este não é relacionado a alterações metabólicas ou da histofisiologia dopaminérgica da VTA.Submitted by Setor de Tratamento da Informação - BC/PUCRS (tede2@pucrs.br) on 2015-10-26T11:19:38Z No. of bitstreams: 1 475882 - Texto Completo.pdf: 18258562 bytes, checksum: 5b76b66a03e3116f7e13505a183443a8 (MD5)Made available in DSpace on 2015-10-26T11:19:38Z (GMT). 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dc.title.por.fl_str_mv |
Depressão experimental e tratamento agudo com cetamina : análise comportamental, neurometabólica e histofisiológica dopaminérgica |
title |
Depressão experimental e tratamento agudo com cetamina : análise comportamental, neurometabólica e histofisiológica dopaminérgica |
spellingShingle |
Depressão experimental e tratamento agudo com cetamina : análise comportamental, neurometabólica e histofisiológica dopaminérgica Baptista, Pedro Porto Alegre BIOLOGIA CELULAR BIOLOGIA MOLECULAR DEPRESSÃO SEROTONINA ANTIDEPRESSIVOS CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
title_short |
Depressão experimental e tratamento agudo com cetamina : análise comportamental, neurometabólica e histofisiológica dopaminérgica |
title_full |
Depressão experimental e tratamento agudo com cetamina : análise comportamental, neurometabólica e histofisiológica dopaminérgica |
title_fullStr |
Depressão experimental e tratamento agudo com cetamina : análise comportamental, neurometabólica e histofisiológica dopaminérgica |
title_full_unstemmed |
Depressão experimental e tratamento agudo com cetamina : análise comportamental, neurometabólica e histofisiológica dopaminérgica |
title_sort |
Depressão experimental e tratamento agudo com cetamina : análise comportamental, neurometabólica e histofisiológica dopaminérgica |
author |
Baptista, Pedro Porto Alegre |
author_facet |
Baptista, Pedro Porto Alegre |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Xavier, Léder Leal |
dc.contributor.advisor1ID.fl_str_mv |
730.223.570-87 |
dc.contributor.advisor1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4795990T9 |
dc.contributor.authorID.fl_str_mv |
112.033.177-35 |
dc.contributor.authorLattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4420019P6 |
dc.contributor.author.fl_str_mv |
Baptista, Pedro Porto Alegre |
contributor_str_mv |
Xavier, Léder Leal |
dc.subject.por.fl_str_mv |
BIOLOGIA CELULAR BIOLOGIA MOLECULAR DEPRESSÃO SEROTONINA ANTIDEPRESSIVOS |
topic |
BIOLOGIA CELULAR BIOLOGIA MOLECULAR DEPRESSÃO SEROTONINA ANTIDEPRESSIVOS CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
description |
The major depressive disorder (MDD) is a psychiatric condition which profoundly alters with the brain metabolism and neurochemistry characterized by a state of deep, chronic sadness, accompanied by anhedonia, sensation of worthlessness and lack of motivation, often leading the patient to suicide. The ventral tegmental area (VTA) is an important dopaminergic region intimately associated with the pathophysiology of MDD. Ketamine is a drug that antagonizes the glutamatergic NMDA receptors which has been shown to exert an immediate antidepressant effect and the treatment with ketamine is a promising new alternative for MDD therapeutic. Furthermore, the small animal positron emission tomography (microPET) is a technique which allows the assessment of the temporal-spatial distribution of radiolabelled molecules in vivo, and the utilization of 18F-Fluorodeoxyglucose (18F-FDG) as a radiotracer for this analysis still needs standardization in our University. In this sense, this thesis has been divided into two stages. Firstly, we standardized the brain metabolic assessment technique using 18F-FDG associated with microPET in Wistar rats, and with it, we rendered a neurometabolic atlas of the distribution of 18F-FDG in 56 brain regions. We compared our neurometabolic data with data from five other scientific articles which assessed the biochemical and immunohistochemical activity of cytochrome c oxidase (COX), these techniques are traditionally used for assessment of ex vivo brain metabolism. Thus, we ranked the regions analyzed in our study and the regions from the selected COX studies, and correlated the rankings with the Spearman test for non-parametric ranked data correlation. In this study we detailed the distribution of 18F-FDG in the brain of Wistar rats. On four of the selected studies we did not find a correlation, only on Shumake at al.´s study we found a moderate correlation (r=0.56, p=0.023). In the second stage, we analyzed the influence of acute ketamine treatment on the depressive-like behavior, the glucose metabolism and tyrosine hydroxylase activity (TH) (a rate-limiting dopamine synthesis enzyme) in the VTA of animals exposed to the chronic unpredictable stress (CUS). In this study, 48 Wistar rats were divided into four groups: 1-Control, 2-Ketamine, 3-CUS, 4-CUS+Ketamine. The animals undergone the CUS protocol were expose to several stressors, twice-daily, for 28 consecutive days. The treatment consisted of a single intraperitoneal injection of 10mg/kg of ketamine. For the behavioral analysis the sucrose preference test, the open field test, and the forced swim test were executed. The glucose metabolism and TH immunoreactivity in the VTA were analyzed by 18F-FDG-microPET and immunohistochemistry for TH, respectively. The CUS groups showed a decrease in sucrose solution intake and an increase in the immobility time on the forced swim test, and ketamine treatment was able to reverted the depressive-like behavior (p<0.05. The CUS protocol and ketamine treatment did not influence upon the 18F-FDG uptake or the TH immunoreactivity in the VTA. The results obtained in this thesis aid on the standardizing of the use of 18F-FDG with microPET, for the analyses on brain metabolism in our university. Furthermore, with the CUS protocol, we confirmed the acute, antidepressant effect of ketamine, however, our finds indicated that this effect is not related to metabolic or dopaminergic physiology in the VTA. |
publishDate |
2015 |
dc.date.accessioned.fl_str_mv |
2015-10-26T11:19:38Z |
dc.date.issued.fl_str_mv |
2015-08-31 |
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por |
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por |
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Pontifícia Universidade Católica do Rio Grande do Sul |
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Programa de Pós-Graduação em Biologia Celular e Molecular |
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PUCRS |
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Brasil |
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Faculdade de Biociências |
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Pontifícia Universidade Católica do Rio Grande do Sul |
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