Gabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongos
Ano de defesa: | 2017 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | , , , |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
Centro de Ciências da Saúde |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Farmacologia
|
Departamento: |
Farmacologia
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/18649 |
Resumo: | Schizophrenia is a chronic and highly complex psychiatric illness that manifests with a wide spectrum of changes that include cognitive, negative and positive symptoms. The drugs available for the treatment (antagonists of dopamine D2 receptors) causes numerous metabolic and abnormal movements adverse effects, which leads the patients to abandon of the therapy, and therefore have symptomatic relapses. The manipulation of the dopaminergic system by using psychostimulant drugs such as amphetamine, or by long-term use of haloperidol, has served as experimental model for the screening of drugs with potential for pharmacological treatment of symptoms of schizophrenia and preventing adverse effects, respectively. It has been reported that drugs with a GABAergic agonist action may improve the positive and negative symptoms of schizophrenia or reduce the incidence of tardive dyskinesia (TD), thereby reducing dopaminergic activity. Thus, the aim of this study was to evaluate the possible modulatory and neuroprotective effects of gabapentin (GBP), a gamma-aminobutyric acid analog, on behavioral and biochemical alterations induced by the administration of amphetamine or haloperidol in mice. Firstly, the animals received vehicle (0,9% NaCl) or different doses of GBP (10, 30, 100 mg/kg) and, 30 minutes after, received a single dose of amphetamine (1.25 mg/kg), both by intraperitoneal route. Behavioral analyses in open field, stereotypy, Y maze and social interaction tests were performed 25 minutes after the administration of amphetamine. Amphetamine induced memory impairment, hyperlocomotion, stereotyped behavior and social withdrawal. GBP prevented the working memory and social interaction deficit as well as reduced stereotypies induced by amphetamine. However, GBP had no effect on hyperlocomotion. In addition, the effects of GBP were evaluated on haloperidol-induced orofacial dyskinesia (OD) model, an adverse effect of dopaminergic antagonists, where the animals received daily doses of haloperidol (1.25 mg/kg) and/or GBP (100 mg/kg) for 28 days and vacuous chewing movements (VCM) were recorded on the 1st (before the beginning of administrations) and on the 28th day as well as changes in the open field test on 28th day of treatment. Treatment with haloperidol increased the number of VCM and decreased the locomotor activity. Co-treatment with GBP prevented these effects. Biochemical parameters related to dopaminergic and gabaergic activity were evaluated. There was no statistically significant difference in tyrosine hydroxylase (TH) immunoreactivity, monoamine levels as well as the glutamate decarboxylase (GAD) immunoreactivity in the striatum of animals treated with both drugs. The results suggest that GBP may be a promising therapeutic agent in controlling the clinical symptoms of schizophrenia and to avoid the development of adverse effects by the current treatments resulting in improving the quality of life for patients. |
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2019-10-22T22:07:39Z2019-10-22T22:07:39Z2017-12-19http://repositorio.ufsm.br/handle/1/18649Schizophrenia is a chronic and highly complex psychiatric illness that manifests with a wide spectrum of changes that include cognitive, negative and positive symptoms. The drugs available for the treatment (antagonists of dopamine D2 receptors) causes numerous metabolic and abnormal movements adverse effects, which leads the patients to abandon of the therapy, and therefore have symptomatic relapses. The manipulation of the dopaminergic system by using psychostimulant drugs such as amphetamine, or by long-term use of haloperidol, has served as experimental model for the screening of drugs with potential for pharmacological treatment of symptoms of schizophrenia and preventing adverse effects, respectively. It has been reported that drugs with a GABAergic agonist action may improve the positive and negative symptoms of schizophrenia or reduce the incidence of tardive dyskinesia (TD), thereby reducing dopaminergic activity. Thus, the aim of this study was to evaluate the possible modulatory and neuroprotective effects of gabapentin (GBP), a gamma-aminobutyric acid analog, on behavioral and biochemical alterations induced by the administration of amphetamine or haloperidol in mice. Firstly, the animals received vehicle (0,9% NaCl) or different doses of GBP (10, 30, 100 mg/kg) and, 30 minutes after, received a single dose of amphetamine (1.25 mg/kg), both by intraperitoneal route. Behavioral analyses in open field, stereotypy, Y maze and social interaction tests were performed 25 minutes after the administration of amphetamine. Amphetamine induced memory impairment, hyperlocomotion, stereotyped behavior and social withdrawal. GBP prevented the working memory and social interaction deficit as well as reduced stereotypies induced by amphetamine. However, GBP had no effect on hyperlocomotion. In addition, the effects of GBP were evaluated on haloperidol-induced orofacial dyskinesia (OD) model, an adverse effect of dopaminergic antagonists, where the animals received daily doses of haloperidol (1.25 mg/kg) and/or GBP (100 mg/kg) for 28 days and vacuous chewing movements (VCM) were recorded on the 1st (before the beginning of administrations) and on the 28th day as well as changes in the open field test on 28th day of treatment. Treatment with haloperidol increased the number of VCM and decreased the locomotor activity. Co-treatment with GBP prevented these effects. Biochemical parameters related to dopaminergic and gabaergic activity were evaluated. There was no statistically significant difference in tyrosine hydroxylase (TH) immunoreactivity, monoamine levels as well as the glutamate decarboxylase (GAD) immunoreactivity in the striatum of animals treated with both drugs. The results suggest that GBP may be a promising therapeutic agent in controlling the clinical symptoms of schizophrenia and to avoid the development of adverse effects by the current treatments resulting in improving the quality of life for patients.A esquizofrenia é uma doença psiquiátrica crônica e altamente complexa que se manifesta com amplo espectro de alterações que incluem sintomas cognitivos, negativos e positivos. Os fármacos disponíveis para o tratamento (antagonistas de receptores dopaminérgicos D2) provocam inúmeros efeitos adversos metabólicos e motores, que leva os pacientes a abandonar o tratamento e, consequentemente, ter recidivas dos sintomas. A manipulação do sistema dopaminérgico pelo uso de drogas psicoestimulantes, como a anfetamina, ou pelo uso prolongado de haloperidol, tem servido como modelo experimental para o screening de fármacos com potencial farmacológico para o tratamento dos sintomas da esquizofrenia e prevenção de efeitos adversos, respectivamente. Tem-se relatado que fármacos com ação agonista no sistema gabaérgico podem melhorar os sintomas positivos e negativos da esquizofrenia ou mesmo diminuir a incidência de discinesia tardia (DT), reduzindo assim a atividade dopaminérgica. Desta forma, o objetivo deste estudo foi avaliar os possíveis efeitos modulatórios e neuroprotetores da gabapentina (GBP), um análogo do ácido gama-aminobutírico (GABA), sobre as alterações comportamentais e bioquímicas induzidas pela administração de anfetamina ou haloperidol em camundongos. Os animais receberam primeiramente veículo (NaCl 0,9%) ou diferentes doses de GBP (10, 30, 100 mg/kg) e, 30 minutos após, receberam uma dose única de anfetamina (1,25 mg/kg), ambas por via intraperitoneal. As análises comportamentais nos testes de campo aberto, estereotipia, labirinto em Y e teste de interação social foram realizadas 25 minutos após a administração de anfetamina. A anfetamina induziu prejuízo de memória, hiperlocomoção, comportamento estereotipado bem como retraimento social. A GBP preveniu o déficit de memória de trabalho e de interação social como também reduziu as estereotipias induzidas pela anfetamina. No entanto, observou-se que a GBP não apresentou efeito sobre a hiperlocomoção. Além disso, foi avaliado o efeito da GBP no modelo de discinesia orofacial (DO) induzida por tratamento com haloperidol, um efeito adverso motor de antagonistas dopaminérgicos, onde os animais receberam doses diárias de haloperidol (1,25 mg/kg) e/ou GBP (100 mg/kg) por 28 dias e foram contabilizados os movimentos de mascar no vazio (MMV) no 1º (antes do início das administrações) e no 28º dia assim como alterações no teste do campo aberto no 28º dia do tratamento. O tratamento com haloperidol aumentou o número de MMV e diminuiu a atividade locomotora dos animais. O co-tratamento com gabapentina preveniu esses efeitos. Na sequência foram avaliados parâmetros bioquímicos relacionados à atividade dopaminérgica e gabaérgica. Não houve diferença na imunorreatividade da tirosina hidroxilase (TH) e nos níveis de monoaminas bem como na imunorreatividade da glutamato descarboxilase (GAD) no estriado dos animais tratados com ambos os fármacos. Os resultados sugerem que a GBP possa ser um agente terapêutico promissor no controle dos sintomas clínicos da esquizofrenia bem como prevenir o desenvolvimento de efeitos adversos motores desenvolvidos pelos tratamentos atuais resultando na melhora da qualidade de vida dos pacientes.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em FarmacologiaUFSMBrasilFarmacologiaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessEsquizofreniaDiscinesia orofacialMovimentos de mascar no vazioDopaminaSistema gabaérgicoSchizophreniaOrofacial dyskinesiaVacuous chewing movementsDopamineGabaergic systemCNPQ::CIENCIAS DA SAUDE::FARMACIAGabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongosEffects of gabapentin on behavioural and neurochemical alterations induced by amphetamine or haloperidol in miceinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisFachinetto, Roseleihttp://lattes.cnpq.br/7203076675431306Oliveira, Sara Marchesan dehttp://lattes.cnpq.br/6574555059806902Puntel, Robson Luizhttp://lattes.cnpq.br/1134532326779900Wagner, Carolinehttp://lattes.cnpq.br/4004565241849091Zugno, Alexandra Ioppihttp://lattes.cnpq.br/7501286919190831http://lattes.cnpq.br/9568916195296116Ceretta, Ana Paula Chiapinotto400300000005600e99bf03a-61e7-46c9-97d1-a7255476d47f47a5e4a4-1c96-469d-808e-37ecb0ce296aae9ccccd-6c23-46a1-abda-fa450ef31e4f8e59b59c-ede5-4961-849a-262aa1a21a6fd7dc21db-e508-4e38-b2e9-c73d2ec6592799255cd8-ebf8-4465-bd8b-cf7a98bd1b68reponame:Biblioteca Digital de Teses e Dissertações do UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGFARMACOLOGIA_2017_CERETTA_ANA.pdfTES_PPGFARMACOLOGIA_2017_CERETTA_ANA.pdfTese de Doutoradoapplication/pdf3542208http://repositorio.ufsm.br/bitstream/1/18649/1/TES_PPGFARMACOLOGIA_2017_CERETTA_ANA.pdff95bddf27c517b072225ab86581ded6dMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Gabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongos |
dc.title.alternative.eng.fl_str_mv |
Effects of gabapentin on behavioural and neurochemical alterations induced by amphetamine or haloperidol in mice |
title |
Gabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongos |
spellingShingle |
Gabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongos Ceretta, Ana Paula Chiapinotto Esquizofrenia Discinesia orofacial Movimentos de mascar no vazio Dopamina Sistema gabaérgico Schizophrenia Orofacial dyskinesia Vacuous chewing movements Dopamine Gabaergic system CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Gabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongos |
title_full |
Gabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongos |
title_fullStr |
Gabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongos |
title_full_unstemmed |
Gabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongos |
title_sort |
Gabapentina previne alterações comportamentais induzidas por anfetamina ou haloperidol em camundongos |
author |
Ceretta, Ana Paula Chiapinotto |
author_facet |
Ceretta, Ana Paula Chiapinotto |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Fachinetto, Roselei |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/7203076675431306 |
dc.contributor.referee1.fl_str_mv |
Oliveira, Sara Marchesan de |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/6574555059806902 |
dc.contributor.referee2.fl_str_mv |
Puntel, Robson Luiz |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/1134532326779900 |
dc.contributor.referee3.fl_str_mv |
Wagner, Caroline |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/4004565241849091 |
dc.contributor.referee4.fl_str_mv |
Zugno, Alexandra Ioppi |
dc.contributor.referee4Lattes.fl_str_mv |
http://lattes.cnpq.br/7501286919190831 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/9568916195296116 |
dc.contributor.author.fl_str_mv |
Ceretta, Ana Paula Chiapinotto |
contributor_str_mv |
Fachinetto, Roselei Oliveira, Sara Marchesan de Puntel, Robson Luiz Wagner, Caroline Zugno, Alexandra Ioppi |
dc.subject.por.fl_str_mv |
Esquizofrenia Discinesia orofacial Movimentos de mascar no vazio Dopamina Sistema gabaérgico |
topic |
Esquizofrenia Discinesia orofacial Movimentos de mascar no vazio Dopamina Sistema gabaérgico Schizophrenia Orofacial dyskinesia Vacuous chewing movements Dopamine Gabaergic system CNPQ::CIENCIAS DA SAUDE::FARMACIA |
dc.subject.eng.fl_str_mv |
Schizophrenia Orofacial dyskinesia Vacuous chewing movements Dopamine Gabaergic system |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
Schizophrenia is a chronic and highly complex psychiatric illness that manifests with a wide spectrum of changes that include cognitive, negative and positive symptoms. The drugs available for the treatment (antagonists of dopamine D2 receptors) causes numerous metabolic and abnormal movements adverse effects, which leads the patients to abandon of the therapy, and therefore have symptomatic relapses. The manipulation of the dopaminergic system by using psychostimulant drugs such as amphetamine, or by long-term use of haloperidol, has served as experimental model for the screening of drugs with potential for pharmacological treatment of symptoms of schizophrenia and preventing adverse effects, respectively. It has been reported that drugs with a GABAergic agonist action may improve the positive and negative symptoms of schizophrenia or reduce the incidence of tardive dyskinesia (TD), thereby reducing dopaminergic activity. Thus, the aim of this study was to evaluate the possible modulatory and neuroprotective effects of gabapentin (GBP), a gamma-aminobutyric acid analog, on behavioral and biochemical alterations induced by the administration of amphetamine or haloperidol in mice. Firstly, the animals received vehicle (0,9% NaCl) or different doses of GBP (10, 30, 100 mg/kg) and, 30 minutes after, received a single dose of amphetamine (1.25 mg/kg), both by intraperitoneal route. Behavioral analyses in open field, stereotypy, Y maze and social interaction tests were performed 25 minutes after the administration of amphetamine. Amphetamine induced memory impairment, hyperlocomotion, stereotyped behavior and social withdrawal. GBP prevented the working memory and social interaction deficit as well as reduced stereotypies induced by amphetamine. However, GBP had no effect on hyperlocomotion. In addition, the effects of GBP were evaluated on haloperidol-induced orofacial dyskinesia (OD) model, an adverse effect of dopaminergic antagonists, where the animals received daily doses of haloperidol (1.25 mg/kg) and/or GBP (100 mg/kg) for 28 days and vacuous chewing movements (VCM) were recorded on the 1st (before the beginning of administrations) and on the 28th day as well as changes in the open field test on 28th day of treatment. Treatment with haloperidol increased the number of VCM and decreased the locomotor activity. Co-treatment with GBP prevented these effects. Biochemical parameters related to dopaminergic and gabaergic activity were evaluated. There was no statistically significant difference in tyrosine hydroxylase (TH) immunoreactivity, monoamine levels as well as the glutamate decarboxylase (GAD) immunoreactivity in the striatum of animals treated with both drugs. The results suggest that GBP may be a promising therapeutic agent in controlling the clinical symptoms of schizophrenia and to avoid the development of adverse effects by the current treatments resulting in improving the quality of life for patients. |
publishDate |
2017 |
dc.date.issued.fl_str_mv |
2017-12-19 |
dc.date.accessioned.fl_str_mv |
2019-10-22T22:07:39Z |
dc.date.available.fl_str_mv |
2019-10-22T22:07:39Z |
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/1/18649 |
url |
http://repositorio.ufsm.br/handle/1/18649 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
400300000005 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
e99bf03a-61e7-46c9-97d1-a7255476d47f 47a5e4a4-1c96-469d-808e-37ecb0ce296a ae9ccccd-6c23-46a1-abda-fa450ef31e4f 8e59b59c-ede5-4961-849a-262aa1a21a6f d7dc21db-e508-4e38-b2e9-c73d2ec65927 99255cd8-ebf8-4465-bd8b-cf7a98bd1b68 |
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.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Farmacologia |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Farmacologia |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações do UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
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Universidade Federal de Santa Maria (UFSM) |
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UFSM |
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UFSM |
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Biblioteca Digital de Teses e Dissertações do UFSM |
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Biblioteca Digital de Teses e Dissertações do UFSM |
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Biblioteca Digital de Teses e Dissertações do UFSM - Universidade Federal de Santa Maria (UFSM) |
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atendimento.sib@ufsm.br||tedebc@gmail.com |
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