O exercício físico reduz parâmetros comportamentais e moleculares envolvidos na drogadição por anfetamina em ratos: envolvimento da via opioide endógena
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/30369 |
Resumo: | The mesolimbic dopaminergic system constitutes a drug target circuit, whose neuroplasticity alteration is involved in the development of drug addiction. Due to this neuromodulation, currently available treatments only relieve the initial symptoms of drug withdrawal, not reaching the molecular basis of the disease. Based on this, our group has investigated the beneficial influence of physical exercise (PE) on drug addiction, by activating the release of endogenous opioids (EO). Furthermore, it is pointed out that psychostimulant drugs are also capable of favoring the release of EO, thus arousing interest in the study of this mechanism. Therefore, it is necessary to elucidate the relationship between the practice of PE and the administration of psychostimulants, such as amphetamine (AMPH), considering the activation of the EO system, in search of support for new treatments for drug addiction. Thus, the studies that make up the present thesis were developed through 3 experimental protocols: I) exposure of rats to the conditioned place preference protocol (CPP) with AMPH, the practice of PE during drug abstinence and concomitant administration of naloxone (NAL), to inhibit the activation of the EO system induced by PE, evaluation of drug relapse, as well as of dopaminergic molecular markers, in the mesolimbic region (Ventral Tegmental Area (VTA) and Nucleus accumbens (NAc)); II) exposure of rats to AMPH, to the PE protocol with the EO system inhibited by the administration of NAL, reexposed to AMPH and evaluation of neurotrophic molecular markers in VTA and NAc; III) the blockade of the EO system, with administration of NAL, was performed before conditioning with AMPH in the CPP, in which the preference for the drug and the levels of monoamines in the VTA and NAc were evaluated. In addition to the behavioral assessments of preference and relapse by AMPH, locomotor, and memory performance were also quantified, to monitor any artifact that could falsify the hedonic response to the drug. Taken together, the studies that make up this thesis showed that the activation of the EO system induced by PE was able to prevent AMPH relapse behaviors and increase the immunoreactivity of dopaminergic molecular markers and neurotrophins in VTA, reducing them in the NAc. In addition, conditioning with AMPH also allowed us to confirm the activation of the OE system, which we interpreted as a modulatory response of the organism in search of a balance of the psychostimulant activity induced by the drug. This response was evidenced through the quantification of monoamines in the mesolimbic system, whose metabolite levels showed agreement with the hedonic effects observed in the CPP. In this context, it is possible to deduce that the reduction in drug-seeking relapse behavior induced by PE was consequent to the modulation of the EO system in the mesolimbic area, thus disfavoring drug addiction. Considering that drug addiction is a serious public health problem, whose pharmacological treatments do not have the desired efficacy, unraveling neural mechanisms and their adjacent molecular bases will contribute to the achievement of future therapeutic approaches for drug addiction. |
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O exercício físico reduz parâmetros comportamentais e moleculares envolvidos na drogadição por anfetamina em ratos: envolvimento da via opioide endógenaPhysical exercise reduces behavioral and molecular parameters involved in amphetamine drug addiction in rat: involvement of the endogenous opioid pathwayDrogas aditivasExercício físicoTerapia não-farmacológicaSistema dopaminérgicoFatores neurotróficosAdditive drugsPhysical exercisePhysical exerciseNon-pharmacological therapyDopaminergic systemNeurotrophic factorsCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAThe mesolimbic dopaminergic system constitutes a drug target circuit, whose neuroplasticity alteration is involved in the development of drug addiction. Due to this neuromodulation, currently available treatments only relieve the initial symptoms of drug withdrawal, not reaching the molecular basis of the disease. Based on this, our group has investigated the beneficial influence of physical exercise (PE) on drug addiction, by activating the release of endogenous opioids (EO). Furthermore, it is pointed out that psychostimulant drugs are also capable of favoring the release of EO, thus arousing interest in the study of this mechanism. Therefore, it is necessary to elucidate the relationship between the practice of PE and the administration of psychostimulants, such as amphetamine (AMPH), considering the activation of the EO system, in search of support for new treatments for drug addiction. Thus, the studies that make up the present thesis were developed through 3 experimental protocols: I) exposure of rats to the conditioned place preference protocol (CPP) with AMPH, the practice of PE during drug abstinence and concomitant administration of naloxone (NAL), to inhibit the activation of the EO system induced by PE, evaluation of drug relapse, as well as of dopaminergic molecular markers, in the mesolimbic region (Ventral Tegmental Area (VTA) and Nucleus accumbens (NAc)); II) exposure of rats to AMPH, to the PE protocol with the EO system inhibited by the administration of NAL, reexposed to AMPH and evaluation of neurotrophic molecular markers in VTA and NAc; III) the blockade of the EO system, with administration of NAL, was performed before conditioning with AMPH in the CPP, in which the preference for the drug and the levels of monoamines in the VTA and NAc were evaluated. In addition to the behavioral assessments of preference and relapse by AMPH, locomotor, and memory performance were also quantified, to monitor any artifact that could falsify the hedonic response to the drug. Taken together, the studies that make up this thesis showed that the activation of the EO system induced by PE was able to prevent AMPH relapse behaviors and increase the immunoreactivity of dopaminergic molecular markers and neurotrophins in VTA, reducing them in the NAc. In addition, conditioning with AMPH also allowed us to confirm the activation of the OE system, which we interpreted as a modulatory response of the organism in search of a balance of the psychostimulant activity induced by the drug. This response was evidenced through the quantification of monoamines in the mesolimbic system, whose metabolite levels showed agreement with the hedonic effects observed in the CPP. In this context, it is possible to deduce that the reduction in drug-seeking relapse behavior induced by PE was consequent to the modulation of the EO system in the mesolimbic area, thus disfavoring drug addiction. Considering that drug addiction is a serious public health problem, whose pharmacological treatments do not have the desired efficacy, unraveling neural mechanisms and their adjacent molecular bases will contribute to the achievement of future therapeutic approaches for drug addiction.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESO sistema mesolímbico dopaminérgico constitui um circuito-alvo de drogas, cuja alteração da neuroplasticidade está envolvida no desenvolvimento de drogadição. Devido a essa neuromodulação, os tratamentos atualmente disponíveis aliviam apenas os sintomas inicias de retirada da droga, não alcançando as bases moleculares da doença. Baseando-se nisso, nosso grupo tem investigado a influência benéfica do exercício físico (EF) frente à drogadição, por ativar a liberação de opioides endógenos (OE). Ademais, aponta-se que drogas psicoestimulantes também são capazes de favorecer a liberação de OE, despertando assim, o interesse no estudo deste mecanismo. Assim sendo, faz-se necessário elucidar a relação entre a prática de EF e a administração de psicoestimulantes, tais como a anfetamina (ANF), considerando a ativação sistema OE, em busca de suporte para novos tratamentos para a drogadição. Deste modo, os estudos que compõe a presente tese foram desenvolvidos através de 3 protocolos experimentais: I) exposição de ratos ao protocolo de preferência de lugar condicionado (PLC) com ANF, prática de EF durante a abstinência da droga e administração concomitante de naloxona (NAL), a fim de inibir a ativação do sistema OE induzido pelo EF, avaliação da recaída a droga, assim como dos marcadores moleculares dopaminérgicos, na região mesolímbica (Área tegmental ventral (ATV) e Nucleus accumbens (NAc)); II) exposição de ratos a ANF, ao protocolo de EF com o sistema EO inibido pela administração de NAL, reexpostos a ANF e avaliação dos marcadores moleculares neurotroficos na ATV e NAc; III) o bloqueio do sistema OE, com administração de NAL foi realizado antes do condicionamento com ANF no PLC, no qual, foi avaliada a preferencia pela droga e os níveis de monomaminas na VTA e NAc. Além das avaliações comportamentais de preferência e recaida pela ANF, a performance locomotora e de memória foram também quantificados, afim de monitorar algum artefato que pudesse falsear a resposta hedônicas da droga. Tomados em conjunto, os estudos que compôem a presente tese, mostraram que a ativação do sistema OE induzido pelo EF, foi capaz de prevenir comportamentos de recaída à ANF, aumentar a imunoreatividade de marcadores moleculares dopaminérgicos e de neurotrofinas na ATV, reduzindo os mesmos no NAc. Além disso, o condicionamento com ANF também permitiunos confirmar a ativação do sistema OE, a qual nós interpretamos como uma resposta modulatória do organismo em busca de um equilíbrio da atividade psicoestimulante induzida pela droga. Tal resposta foi evidenciada através da quantificação de monoaminas no sistema mesolimbico, cujos níveis dos metabólitos manifestaram concordância com os efeitos hedônicos observados no PLC. Nesse contexto, é possível deduzir que a redução do comportamento de recaída à busca pela droga induzida pelo EF foi consequente à modulação do sistema OE na área mesolímbica, desfavorecendo assim a drogadição. Considerando que a drogadição é um grave problema de saúde pública, cujos tratamentos farmacológicos não apresentam a eficácia desejada, desvendar mecanismos neurais e suas bases moleculares adjacentes contribuirá para o alcance de futuras abordagens terapêuticas para a drogadição.Universidade Federal de Santa MariaBrasilFarmacologiaUFSMPrograma de Pós-Graduação em FarmacologiaCentro de Ciências da SaúdeBurger, Marilise Escobarhttp://lattes.cnpq.br/9128090974948413Brüning, César AugustoRoyes, Luiz Fernando FreireRambo, Leonardo MagnoBrucker, NatáliaRosa, Higor Zuquetto2023-10-19T11:37:53Z2023-10-19T11:37:53Z2023-09-15info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/30369porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2023-10-19T11:37:53Zoai:repositorio.ufsm.br:1/30369Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2023-10-19T11:37:53Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
O exercício físico reduz parâmetros comportamentais e moleculares envolvidos na drogadição por anfetamina em ratos: envolvimento da via opioide endógena Physical exercise reduces behavioral and molecular parameters involved in amphetamine drug addiction in rat: involvement of the endogenous opioid pathway |
title |
O exercício físico reduz parâmetros comportamentais e moleculares envolvidos na drogadição por anfetamina em ratos: envolvimento da via opioide endógena |
spellingShingle |
O exercício físico reduz parâmetros comportamentais e moleculares envolvidos na drogadição por anfetamina em ratos: envolvimento da via opioide endógena Rosa, Higor Zuquetto Drogas aditivas Exercício físico Terapia não-farmacológica Sistema dopaminérgico Fatores neurotróficos Additive drugs Physical exercise Physical exercise Non-pharmacological therapy Dopaminergic system Neurotrophic factors CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
O exercício físico reduz parâmetros comportamentais e moleculares envolvidos na drogadição por anfetamina em ratos: envolvimento da via opioide endógena |
title_full |
O exercício físico reduz parâmetros comportamentais e moleculares envolvidos na drogadição por anfetamina em ratos: envolvimento da via opioide endógena |
title_fullStr |
O exercício físico reduz parâmetros comportamentais e moleculares envolvidos na drogadição por anfetamina em ratos: envolvimento da via opioide endógena |
title_full_unstemmed |
O exercício físico reduz parâmetros comportamentais e moleculares envolvidos na drogadição por anfetamina em ratos: envolvimento da via opioide endógena |
title_sort |
O exercício físico reduz parâmetros comportamentais e moleculares envolvidos na drogadição por anfetamina em ratos: envolvimento da via opioide endógena |
author |
Rosa, Higor Zuquetto |
author_facet |
Rosa, Higor Zuquetto |
author_role |
author |
dc.contributor.none.fl_str_mv |
Burger, Marilise Escobar http://lattes.cnpq.br/9128090974948413 Brüning, César Augusto Royes, Luiz Fernando Freire Rambo, Leonardo Magno Brucker, Natália |
dc.contributor.author.fl_str_mv |
Rosa, Higor Zuquetto |
dc.subject.por.fl_str_mv |
Drogas aditivas Exercício físico Terapia não-farmacológica Sistema dopaminérgico Fatores neurotróficos Additive drugs Physical exercise Physical exercise Non-pharmacological therapy Dopaminergic system Neurotrophic factors CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Drogas aditivas Exercício físico Terapia não-farmacológica Sistema dopaminérgico Fatores neurotróficos Additive drugs Physical exercise Physical exercise Non-pharmacological therapy Dopaminergic system Neurotrophic factors CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
The mesolimbic dopaminergic system constitutes a drug target circuit, whose neuroplasticity alteration is involved in the development of drug addiction. Due to this neuromodulation, currently available treatments only relieve the initial symptoms of drug withdrawal, not reaching the molecular basis of the disease. Based on this, our group has investigated the beneficial influence of physical exercise (PE) on drug addiction, by activating the release of endogenous opioids (EO). Furthermore, it is pointed out that psychostimulant drugs are also capable of favoring the release of EO, thus arousing interest in the study of this mechanism. Therefore, it is necessary to elucidate the relationship between the practice of PE and the administration of psychostimulants, such as amphetamine (AMPH), considering the activation of the EO system, in search of support for new treatments for drug addiction. Thus, the studies that make up the present thesis were developed through 3 experimental protocols: I) exposure of rats to the conditioned place preference protocol (CPP) with AMPH, the practice of PE during drug abstinence and concomitant administration of naloxone (NAL), to inhibit the activation of the EO system induced by PE, evaluation of drug relapse, as well as of dopaminergic molecular markers, in the mesolimbic region (Ventral Tegmental Area (VTA) and Nucleus accumbens (NAc)); II) exposure of rats to AMPH, to the PE protocol with the EO system inhibited by the administration of NAL, reexposed to AMPH and evaluation of neurotrophic molecular markers in VTA and NAc; III) the blockade of the EO system, with administration of NAL, was performed before conditioning with AMPH in the CPP, in which the preference for the drug and the levels of monoamines in the VTA and NAc were evaluated. In addition to the behavioral assessments of preference and relapse by AMPH, locomotor, and memory performance were also quantified, to monitor any artifact that could falsify the hedonic response to the drug. Taken together, the studies that make up this thesis showed that the activation of the EO system induced by PE was able to prevent AMPH relapse behaviors and increase the immunoreactivity of dopaminergic molecular markers and neurotrophins in VTA, reducing them in the NAc. In addition, conditioning with AMPH also allowed us to confirm the activation of the OE system, which we interpreted as a modulatory response of the organism in search of a balance of the psychostimulant activity induced by the drug. This response was evidenced through the quantification of monoamines in the mesolimbic system, whose metabolite levels showed agreement with the hedonic effects observed in the CPP. In this context, it is possible to deduce that the reduction in drug-seeking relapse behavior induced by PE was consequent to the modulation of the EO system in the mesolimbic area, thus disfavoring drug addiction. Considering that drug addiction is a serious public health problem, whose pharmacological treatments do not have the desired efficacy, unraveling neural mechanisms and their adjacent molecular bases will contribute to the achievement of future therapeutic approaches for drug addiction. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-10-19T11:37:53Z 2023-10-19T11:37:53Z 2023-09-15 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/30369 |
url |
http://repositorio.ufsm.br/handle/1/30369 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Farmacologia Centro de Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Farmacologia Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
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1805922131802849280 |