Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas

The aims of this work were the search for new atypical antipsychotics presenting low cost and the understanding of the mechanism of action leading to atypical antipsychotic profile. The results obtained are presented in two distinct parts based on their nature, namely, experimental (first part) or t...

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Autor principal:	Tort, Adriano Bretanha Lopes
Outros Autores:	Souza, Diogo Onofre Gomes de
Formato:	doctoralThesis
Idioma:	por
Publicado em:	Universidade Federal do Rio Grande do Sul
Assuntos:	Antipsicoticos Psicofarmacologia Dopamineregic system Psychopharmacology Antipsychotic agents Sistema dopaminérgico CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA
Endereço do item:	https://repositorio.ufrn.br/jspui/handle/123456789/24172
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id	ri-123456789-24172
record_format	dspace
institution	Repositório Institucional
collection	RI - UFRN
language	por
topic	Antipsicoticos Psicofarmacologia Dopamineregic system Psychopharmacology Antipsychotic agents Sistema dopaminérgico CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA
spellingShingle	Antipsicoticos Psicofarmacologia Dopamineregic system Psychopharmacology Antipsychotic agents Sistema dopaminérgico CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA Tort, Adriano Bretanha Lopes Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas
description	The aims of this work were the search for new atypical antipsychotics presenting low cost and the understanding of the mechanism of action leading to atypical antipsychotic profile. The results obtained are presented in two distinct parts based on their nature, namely, experimental (first part) or theoretical (second part). For the development of the first part, a webcam based software to measure locomotion of rodents was programmed. After that, it was investigated the effect of guanosine, flunarizine and cinnarizine on animal models of psychosis, as well as in other behavioral tasks. Guanosine was chosen because it has been shown to interact with the glutamatergic system – which is known to be involved in the pathophysiology of schizophrenia – by promoting astrocytic glutamate reuptake. Flunarizine and cinnarizine, two calcium channel blockers commonly used in many countries to treat vertigo and migraine, were chosen because they were shown to induce extrapyramidal signs in elder patients, which was later related to moderate antagonist properties at dopamine D2 receptors. Guanosine was able to reduce a NMDA antagonist (MK-801) induced hyperlocomotion, whereas it had no effect on the hyperlocomotion induced by amphetamine, and it is discussed that its utility as antipsychotic drug should be further evaluated. Both cinnarizine and flunarizine were able to reduce the hyperlocomotion induced by MK-801 and amphetamine at doses that presented no significant cataleptic behavior. It was therefore concluded that these compounds have a potential atypical antipsychotic profile, with the advantage of already approved for commercial use, presenting well tolerability and very low cost when compared to current commercially available atypical antipsychotics. The second part of this thesis presents some theoretical mathematical results that can be derived from the law of mass action theory applied to receptor binding linked with known PET experimental data. These results present insights to the understanding of the differences between typical and atypical profile of antipsychotics regarding the generation of extrapyramidal syndrome. It is argued that cultural and commercial aspects related to the nowadays employed posology of typical antipsychotics can be responsible for the difference seen in profile, once some typical antipsychotics are prescribed in proportionally higher doses in relation to their affinities, leading therefore to higher dopaminergic blockade. A short plasmatic half-life is also pointed as a possible important factor leading to an atipical profile. Moreover, the second part of this thesis also points to some misconception currently being used in the scientific literature regarding the time-course of dopaminergic occupation, such as the concept of receptor occupation half-life. As a last theoretical based result, it is proposed an algorithm for antipsychotic dose reduction in patients presenting extrapyramidal signs and symptoms.
author2	Souza, Diogo Onofre Gomes de
author_facet	Souza, Diogo Onofre Gomes de Tort, Adriano Bretanha Lopes
format	doctoralThesis
author	Tort, Adriano Bretanha Lopes
author_sort	Tort, Adriano Bretanha Lopes
title	Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas
title_short	Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas
title_full	Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas
title_fullStr	Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas
title_full_unstemmed	Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas
title_sort	sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas
publisher	Universidade Federal do Rio Grande do Sul
publishDate	2017
url	https://repositorio.ufrn.br/jspui/handle/123456789/24172
work_keys_str_mv	AT tortadrianobretanhalopes sistemasdopaminergicoseacaoantipsicoticaabordagensexperimentaiseteoricas AT tortadrianobretanhalopes dopaminergicsystemsandantipsychoticactionexperimentalandtheoreticalapproaches
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spelling	ri-123456789-241722017-11-07T05:35:37Z Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas Dopaminergic systems and antipsychotic action: experimental and theoretical approaches Tort, Adriano Bretanha Lopes Souza, Diogo Onofre Gomes de http://lattes.cnpq.br/3181888189086405 http://lattes.cnpq.br/9534019126486839 Lara, Diogo Rizzato http://lattes.cnpq.br/0468757957130419 Antipsicoticos Psicofarmacologia Dopamineregic system Psychopharmacology Antipsychotic agents Sistema dopaminérgico CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA The aims of this work were the search for new atypical antipsychotics presenting low cost and the understanding of the mechanism of action leading to atypical antipsychotic profile. The results obtained are presented in two distinct parts based on their nature, namely, experimental (first part) or theoretical (second part). For the development of the first part, a webcam based software to measure locomotion of rodents was programmed. After that, it was investigated the effect of guanosine, flunarizine and cinnarizine on animal models of psychosis, as well as in other behavioral tasks. Guanosine was chosen because it has been shown to interact with the glutamatergic system – which is known to be involved in the pathophysiology of schizophrenia – by promoting astrocytic glutamate reuptake. Flunarizine and cinnarizine, two calcium channel blockers commonly used in many countries to treat vertigo and migraine, were chosen because they were shown to induce extrapyramidal signs in elder patients, which was later related to moderate antagonist properties at dopamine D2 receptors. Guanosine was able to reduce a NMDA antagonist (MK-801) induced hyperlocomotion, whereas it had no effect on the hyperlocomotion induced by amphetamine, and it is discussed that its utility as antipsychotic drug should be further evaluated. Both cinnarizine and flunarizine were able to reduce the hyperlocomotion induced by MK-801 and amphetamine at doses that presented no significant cataleptic behavior. It was therefore concluded that these compounds have a potential atypical antipsychotic profile, with the advantage of already approved for commercial use, presenting well tolerability and very low cost when compared to current commercially available atypical antipsychotics. The second part of this thesis presents some theoretical mathematical results that can be derived from the law of mass action theory applied to receptor binding linked with known PET experimental data. These results present insights to the understanding of the differences between typical and atypical profile of antipsychotics regarding the generation of extrapyramidal syndrome. It is argued that cultural and commercial aspects related to the nowadays employed posology of typical antipsychotics can be responsible for the difference seen in profile, once some typical antipsychotics are prescribed in proportionally higher doses in relation to their affinities, leading therefore to higher dopaminergic blockade. A short plasmatic half-life is also pointed as a possible important factor leading to an atipical profile. Moreover, the second part of this thesis also points to some misconception currently being used in the scientific literature regarding the time-course of dopaminergic occupation, such as the concept of receptor occupation half-life. As a last theoretical based result, it is proposed an algorithm for antipsychotic dose reduction in patients presenting extrapyramidal signs and symptoms. Os objetivos da presente tese de doutorado foram os de buscar novos antipsicóticos atípicos de baixo preço comercial e também procurar entender o mecanismo de ação que leva a um perfil antipsicótico atípico. Os resultados da tese são divididos em duas partes, de acordo com sua natureza, em experimentais (primeira parte) e teóricos (segunda parte). Para o desenvolvimento da primeira parte, foi necessária primeiramente a programação de um software para medir locomoção em roedores após filmagem com webcam. A seguir, foram investigados os efeitos da guanosina, flunarizina e cinarizina em modelos animais de psicose, bem como em outros paradigmas comportamentais. A guanosina foi escolhida para estudo uma vez que tem se mostrado que ela interage com o sistema glutamatérgico – que sabidamente está envolvido na fisiopatologia da esquizofrenia – promovendo a captação astrocitária de glutamato. Já a flunarizina e a cinarizina, dois bloqueadores de canal de cálcio empregados para tratar enxaqueca e vertigem foram escolhidas pelo fato delas produzirem sinais e sintomas extrapiramidais em pacientes idosos, o que posteriormente foi relacionado às suas propriedades como antagonistas moderados dos receptores dopaminérgicos do tipo D2. A guanosina diminuiu o aumento de locomoção induzido por um antagonista NMDA (MK-801), enquanto que não apresentou efeito sobre o aumento de locomoção induzido por anfetamina, de forma que sua utilidade como potencial antipsicótico deve ser ainda melhor estudada. Tanto a flunarizina quanto a cinarizina foram capazes de diminuir o aumento de locomoção induzido por MK-801 e por anfetamina em doses que não causam efeitos catalépticos importantes. Portanto, foi concluído que estes dois compostos apresentam um potencial perfil de antipsicótico atípico, com as vantagens de já estarem disponíveis para uso comercial, boa tolerabilidade e baixo custo quando comparados com os antipsicóticos atípicos disponíveis comercialmente nos dias de hoje. A segunda parte da tese apresenta alguns resultados teóricos matemáticos que podem ser derivados da teoria da lei de ação das massas aplicada ao binding de receptores, utilizando também resultados experimentais já conhecidos de PET. Estes resultados apresentam insights ao entendimento das diferenças entre os perfis antipsicóticos atípicos e típicos em relação à geração de sinais extrapiramidais. É discutido que fatores culturais e comerciais relacionados à posologia atual empregada no tratamento com antipsicóticos típicos podem ser os responsáveis pelas diferenças de perfis, uma vez que alguns deles são prescritos em doses proporcionalmente maiores em relação à sua afinidade, atingindo assim maiores níveis de bloqueio dopaminérgico no estriado. Uma curta meia-vida plasmática também é apontada como um possível parâmetro importante na geração de um perfil atípico. É mostrado ainda alguns erros de concepção relacionados ao curso temporal da ocupação dopaminérgica que tem sido atualmente cometidos na literatura científica, como o conceito de meia-vida de ocupação de receptores. Como um último resultado teórico, é proposto um algoritmo para a redução de dose em pacientes tratados com antipsicóticos apresentando sinais e sintomas extrapiramidais. 2017-11-06T11:41:34Z 2017-11-06T11:41:34Z 2005-12 doctoralThesis TORT, Adriano Bretanha Lopes. Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas. 2005. 155 f. Tese (Doutorado) - Programa de Pós-graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, 2005. Disponível em: <http://hdl.handle.net/10183/5900>. Acesso em: 03 nov. 2017. https://repositorio.ufrn.br/jspui/handle/123456789/24172 por Acesso Aberto application/pdf Universidade Federal do Rio Grande do Sul Brasil UFRGS Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Departamento de Bioquímica

Sistemas dopaminérgicos e ação antipsicótica: abordagens experimentais e teóricas

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