Peixe-zebra como modelo animal para estudo de transtornos neuropsiquiátricos : manipulação farmacológica de receptores dopaminérgicos e avaliação do envolvimento do sistema purinérgico
Autor(a) principal: | |
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Data de Publicação: | 2021 |
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/9628 |
Resumo: | Neuropsychiatric disorders are disabling diseases that affect a significant number of people. Although its biological basis is not fully understood, it is known that changes in neurotransmission systems play an important role in its pathogenesis. The dopaminergic and purinergic systems are involved in numerous brain functions, and are associated with many disorders. Pharmacological agents that interact with the neurotransmission systems allow investigating cellular and molecular responses mediated by them, which may elucidate the patophysiology of such disorders. Quinpirole, a dopamine D2/D3 receptor agonist, allows the study of mechanisms underlying neuropsychiatric disorders, using animal models. The zebrafish is widely used in translational biomedical research and has been successfully used in psychopharmacology studies. In the present study, three quinpirole administration protocols were performed in zebrafish and behavioral, morphological and biochemical analysis were performed. Quinpirole exposure (5.5, 16.7, 50 μM) during 1h in larvae (6 days post-fertilization, dpf) induced hyperactivity, anxiety-like behavior, erratic and repetitive movements, and impair optomotor responses. The effects observed were dependent upon feeding status, only fed animals showed behavioral alterations. Adult zebrafish (6 months) received two intraperitoneal injections of quinpirole with an inter-injection interval of 48h (0.5, 1.0, 2.0 mg/kg), and exhibited hypolocomotion, anxiety-like behavior, erratic and stereotypic movements, and memory impairment. The quinpirole treatment induced increased brain neurotrophic factor and glutamate levels, and decreased levels of serotonin. In the third protocol, exposure to quinpirole during 24h (5.5, 16.7, 50 μM) at 5 dpf led to late alterations. At 120 dpf, animals exposed to quinpirole exhibited anxiety-like behavior, erratic and stereotypic movements, and impaired memory. The enzymatic activity of ectonucleotidases, adenosine deaminase (ADA) and the ATP metabolism were evaluated. For larvae, quinpirole altered the nucleoside triphosphate diphosphohydrolase (NTPDase) activities by promoting a decrease in ADP hydrolysis, and induced increased ATP, AMP, ADO and INO levels. In adults, decrease in ADP hydrolysis and adenosine deamination was observed, indicating alterations on NTPDase and ADA activities. Additionally, increased ADP and decreased AMP, ADO and INO levels were observed. The analysis performed at 120 dpf after quinpirole exposure during development had no alterations on enzymatic activity. However, decreased levels for the nucleotide and nucleosides evaluated were observed. In summary, the behavioral alterations observed are part of the behavioral spectrum of several neuropsychiatric disorders. Furthermore, the results with larvae indicate that the behavioral effects of quinpirole exposure are depended upon feeding status – food intake, a naturally rewarding stimulus known to engage the dopaminergic system, became the receptors more susceptible to quinpirole’s effects. The protocol in adult zebrafish showed that more than behavioral alterations, quinpirole administration led to neuroplastic changes in the central nervous system of zebrafish. Furthermore, the third protocol showed that quinpirole exposure can lead to late behavioral alterations. Last, the findings of this study demonstrated that quinpirole administration may inhibit NTPDases and ADA activities, modulating nucleotide and nucleoside levels, indicating the involvement of purinergic signaling on neurological disorders. Thus, the present study shows that the use of quinpirole exposure may be an appropriate tool for the analysis of mechanics underlying neuropsychiatric disorders. |
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Bonan, Carla DeniseNabinger, Débora Dreher2021-05-17T18:42:11Z2021-03-08http://tede2.pucrs.br/tede2/handle/tede/9628Neuropsychiatric disorders are disabling diseases that affect a significant number of people. Although its biological basis is not fully understood, it is known that changes in neurotransmission systems play an important role in its pathogenesis. The dopaminergic and purinergic systems are involved in numerous brain functions, and are associated with many disorders. Pharmacological agents that interact with the neurotransmission systems allow investigating cellular and molecular responses mediated by them, which may elucidate the patophysiology of such disorders. Quinpirole, a dopamine D2/D3 receptor agonist, allows the study of mechanisms underlying neuropsychiatric disorders, using animal models. The zebrafish is widely used in translational biomedical research and has been successfully used in psychopharmacology studies. In the present study, three quinpirole administration protocols were performed in zebrafish and behavioral, morphological and biochemical analysis were performed. Quinpirole exposure (5.5, 16.7, 50 μM) during 1h in larvae (6 days post-fertilization, dpf) induced hyperactivity, anxiety-like behavior, erratic and repetitive movements, and impair optomotor responses. The effects observed were dependent upon feeding status, only fed animals showed behavioral alterations. Adult zebrafish (6 months) received two intraperitoneal injections of quinpirole with an inter-injection interval of 48h (0.5, 1.0, 2.0 mg/kg), and exhibited hypolocomotion, anxiety-like behavior, erratic and stereotypic movements, and memory impairment. The quinpirole treatment induced increased brain neurotrophic factor and glutamate levels, and decreased levels of serotonin. In the third protocol, exposure to quinpirole during 24h (5.5, 16.7, 50 μM) at 5 dpf led to late alterations. At 120 dpf, animals exposed to quinpirole exhibited anxiety-like behavior, erratic and stereotypic movements, and impaired memory. The enzymatic activity of ectonucleotidases, adenosine deaminase (ADA) and the ATP metabolism were evaluated. For larvae, quinpirole altered the nucleoside triphosphate diphosphohydrolase (NTPDase) activities by promoting a decrease in ADP hydrolysis, and induced increased ATP, AMP, ADO and INO levels. In adults, decrease in ADP hydrolysis and adenosine deamination was observed, indicating alterations on NTPDase and ADA activities. Additionally, increased ADP and decreased AMP, ADO and INO levels were observed. The analysis performed at 120 dpf after quinpirole exposure during development had no alterations on enzymatic activity. However, decreased levels for the nucleotide and nucleosides evaluated were observed. In summary, the behavioral alterations observed are part of the behavioral spectrum of several neuropsychiatric disorders. Furthermore, the results with larvae indicate that the behavioral effects of quinpirole exposure are depended upon feeding status – food intake, a naturally rewarding stimulus known to engage the dopaminergic system, became the receptors more susceptible to quinpirole’s effects. The protocol in adult zebrafish showed that more than behavioral alterations, quinpirole administration led to neuroplastic changes in the central nervous system of zebrafish. Furthermore, the third protocol showed that quinpirole exposure can lead to late behavioral alterations. Last, the findings of this study demonstrated that quinpirole administration may inhibit NTPDases and ADA activities, modulating nucleotide and nucleoside levels, indicating the involvement of purinergic signaling on neurological disorders. Thus, the present study shows that the use of quinpirole exposure may be an appropriate tool for the analysis of mechanics underlying neuropsychiatric disorders.Transtornos neuropsiquiátricos são doenças incapacitantes que atingem um número significativo de pessoas. Suas bases biológicas não são completamente compreendidas, mas sabe-se que alterações em sistemas de neurotransmissão desempenham importante papel na sua patogênese. Os sistemas dopaminérgico e purinérgico estão envolvidos em inúmeras funções cerebrais e são associados a muitos transtornos. Agentes farmacológicos que interagem com sistemas de neurotransmissão permitem investigar respostas celulares e moleculares mediadas por estes, podendo elucidar a fisiopatologia de tais transtornos. O quinpirole, agonista dopaminérgico dos receptores D2/D3, permite o estudo de mecanismos subjacentes a distúrbios neuropsiquiátricos, através de modelos animais. O peixezebra é amplamente utilizado na pesquisa biomédica translacional e empregado com sucesso em estudos psicofarmacológicos. Neste estudo, três protocolos de administração de quinpirole foram realizados em peixe-zebra e avaliações comportamentais, morfológicas e bioquímicas foram estudadas. A exposição larval (6 dias pós-fertilização, dpf) ao quinpirole (5,5, 16,7, 50 μM) por 1h induziu hiperatividade, comportamento do tipo ansioso, movimentos erráticos e repetitivos e prejudicou respostas optomotoras. Os efeitos observados foram dependentes do estado nutricional, apenas animais alimentados apresentaram alterações comportamentais. Peixes-zebra adultos (6 meses) receberam duas injeções intraperitoneais de quinpirole com intervalo de 48h (0,5, 1,0, 2,0 mg/kg), e exibiram hipolocomoção, comportamento do tipo ansioso, movimentos erráticos e estereotipados e comprometimento de memória. Quinpirole induziu aumento dos níveis do fator neurotrófico derivado do cérebro e glutamato e diminuição de serotonina. No terceiro protocolo, a exposição ao quinpirole por 24h (5,5, 16,7, 50 μM) aos 5 dpf causou alterações tardias. Aos 120 dpf, animais expostos apresentaram comportamento do tipo ansioso, movimentos erráticos e estereotipados e comprometimento de memória. A atividade enzimática das ectonucleotidases, adenosina desaminase (ADA) e metabolismo de ATP foram avaliados. Para larvas, o quinpirole alterou a atividade das nucleosídeo trifosfato difosfoidrolases (NTPDases), diminuindo a hidrólise de ADP, e induziu aumento dos níveis de ATP, AMP, ADO e INO. Em animais adultos, diminuição da hidrólise de ADP e desaminação de adenosina foi observado, indicando alteração das NTPDases e ADA. Além disso, foi observado aumento de ADP e diminuição de AMP, ADO e INO. A análise aos 120 dpf após a exposição ao quinpirole na fase larval não alterou a atividade enzimática. Entretanto, uma diminuição dos níveis dos nucleotídeos e nucleosídeos avaliados foi observada. Em resumo, as alterações comportamentais observadas compreendem o espectro comportamental de diversos transtornos neuropsiquiátricos. Ainda, os resultados com larvas indicam que as alterações comportamentais observadas dependem do estado nutricional - consumo de alimento, um estímulo naturalmente recompensador relacionado ao sistema dopaminérgico, tornou os receptores mais suscetíveis ao quinpirole. O protocolo em peixes-zebra adultos demonstrou, além das alterações comportamentais, modificações neuroplásticas no sistema nervoso central do peixe-zebra. Além disso, alterações comportamentais tardias foram observadas após exposição ao quinpirole na fase larval. Ainda, foi observado que o quinpirole pode inibir as atividades das NTPDases e ADA, modulando níveis de nucleotídeos e nucleosídeos, indicando o envolvimento da sinalização purinérgica em distúrbios neurológicos. Assim, o presente estudo demonstra que a exposição ao quinpirole em peixe-zebra pode ser uma ferramenta apropriada para análise de mecanismos subjacentes aos transtornos neuropsiquiátricos.Submitted by PPG Biologia Celular e Molecular (bcm@pucrs.br) on 2021-05-04T12:53:08Z No. of bitstreams: 1 DEBORA_DREHER_NABINGER_TES.pdf: 5139105 bytes, checksum: 4848313d591f305ded678d56fd3d2aba (MD5)Approved for entry into archive by Caroline Xavier (caroline.xavier@pucrs.br) on 2021-05-17T18:30:01Z (GMT) No. of bitstreams: 1 DEBORA_DREHER_NABINGER_TES.pdf: 5139105 bytes, checksum: 4848313d591f305ded678d56fd3d2aba (MD5)Made available in DSpace on 2021-05-17T18:42:11Z (GMT). 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dc.title.por.fl_str_mv |
Peixe-zebra como modelo animal para estudo de transtornos neuropsiquiátricos : manipulação farmacológica de receptores dopaminérgicos e avaliação do envolvimento do sistema purinérgico |
title |
Peixe-zebra como modelo animal para estudo de transtornos neuropsiquiátricos : manipulação farmacológica de receptores dopaminérgicos e avaliação do envolvimento do sistema purinérgico |
spellingShingle |
Peixe-zebra como modelo animal para estudo de transtornos neuropsiquiátricos : manipulação farmacológica de receptores dopaminérgicos e avaliação do envolvimento do sistema purinérgico Nabinger, Débora Dreher Transtornos Neuropsiquiátricos Sistema Dopaminérgico Sistema Purinérgico Peixe-zebra Quinpirole Neuropsychiatric Disorders Dopaminergic System Purinergic System Zebrafish Quinpirole CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
title_short |
Peixe-zebra como modelo animal para estudo de transtornos neuropsiquiátricos : manipulação farmacológica de receptores dopaminérgicos e avaliação do envolvimento do sistema purinérgico |
title_full |
Peixe-zebra como modelo animal para estudo de transtornos neuropsiquiátricos : manipulação farmacológica de receptores dopaminérgicos e avaliação do envolvimento do sistema purinérgico |
title_fullStr |
Peixe-zebra como modelo animal para estudo de transtornos neuropsiquiátricos : manipulação farmacológica de receptores dopaminérgicos e avaliação do envolvimento do sistema purinérgico |
title_full_unstemmed |
Peixe-zebra como modelo animal para estudo de transtornos neuropsiquiátricos : manipulação farmacológica de receptores dopaminérgicos e avaliação do envolvimento do sistema purinérgico |
title_sort |
Peixe-zebra como modelo animal para estudo de transtornos neuropsiquiátricos : manipulação farmacológica de receptores dopaminérgicos e avaliação do envolvimento do sistema purinérgico |
author |
Nabinger, Débora Dreher |
author_facet |
Nabinger, Débora Dreher |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Bonan, Carla Denise |
dc.contributor.author.fl_str_mv |
Nabinger, Débora Dreher |
contributor_str_mv |
Bonan, Carla Denise |
dc.subject.por.fl_str_mv |
Transtornos Neuropsiquiátricos Sistema Dopaminérgico Sistema Purinérgico Peixe-zebra Quinpirole |
topic |
Transtornos Neuropsiquiátricos Sistema Dopaminérgico Sistema Purinérgico Peixe-zebra Quinpirole Neuropsychiatric Disorders Dopaminergic System Purinergic System Zebrafish Quinpirole CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
dc.subject.eng.fl_str_mv |
Neuropsychiatric Disorders Dopaminergic System Purinergic System Zebrafish Quinpirole |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
description |
Neuropsychiatric disorders are disabling diseases that affect a significant number of people. Although its biological basis is not fully understood, it is known that changes in neurotransmission systems play an important role in its pathogenesis. The dopaminergic and purinergic systems are involved in numerous brain functions, and are associated with many disorders. Pharmacological agents that interact with the neurotransmission systems allow investigating cellular and molecular responses mediated by them, which may elucidate the patophysiology of such disorders. Quinpirole, a dopamine D2/D3 receptor agonist, allows the study of mechanisms underlying neuropsychiatric disorders, using animal models. The zebrafish is widely used in translational biomedical research and has been successfully used in psychopharmacology studies. In the present study, three quinpirole administration protocols were performed in zebrafish and behavioral, morphological and biochemical analysis were performed. Quinpirole exposure (5.5, 16.7, 50 μM) during 1h in larvae (6 days post-fertilization, dpf) induced hyperactivity, anxiety-like behavior, erratic and repetitive movements, and impair optomotor responses. The effects observed were dependent upon feeding status, only fed animals showed behavioral alterations. Adult zebrafish (6 months) received two intraperitoneal injections of quinpirole with an inter-injection interval of 48h (0.5, 1.0, 2.0 mg/kg), and exhibited hypolocomotion, anxiety-like behavior, erratic and stereotypic movements, and memory impairment. The quinpirole treatment induced increased brain neurotrophic factor and glutamate levels, and decreased levels of serotonin. In the third protocol, exposure to quinpirole during 24h (5.5, 16.7, 50 μM) at 5 dpf led to late alterations. At 120 dpf, animals exposed to quinpirole exhibited anxiety-like behavior, erratic and stereotypic movements, and impaired memory. The enzymatic activity of ectonucleotidases, adenosine deaminase (ADA) and the ATP metabolism were evaluated. For larvae, quinpirole altered the nucleoside triphosphate diphosphohydrolase (NTPDase) activities by promoting a decrease in ADP hydrolysis, and induced increased ATP, AMP, ADO and INO levels. In adults, decrease in ADP hydrolysis and adenosine deamination was observed, indicating alterations on NTPDase and ADA activities. Additionally, increased ADP and decreased AMP, ADO and INO levels were observed. The analysis performed at 120 dpf after quinpirole exposure during development had no alterations on enzymatic activity. However, decreased levels for the nucleotide and nucleosides evaluated were observed. In summary, the behavioral alterations observed are part of the behavioral spectrum of several neuropsychiatric disorders. Furthermore, the results with larvae indicate that the behavioral effects of quinpirole exposure are depended upon feeding status – food intake, a naturally rewarding stimulus known to engage the dopaminergic system, became the receptors more susceptible to quinpirole’s effects. The protocol in adult zebrafish showed that more than behavioral alterations, quinpirole administration led to neuroplastic changes in the central nervous system of zebrafish. Furthermore, the third protocol showed that quinpirole exposure can lead to late behavioral alterations. Last, the findings of this study demonstrated that quinpirole administration may inhibit NTPDases and ADA activities, modulating nucleotide and nucleoside levels, indicating the involvement of purinergic signaling on neurological disorders. Thus, the present study shows that the use of quinpirole exposure may be an appropriate tool for the analysis of mechanics underlying neuropsychiatric disorders. |
publishDate |
2021 |
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2021-05-17T18:42:11Z |
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2021-03-08 |
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