Efeitos do SKF 38393 e da α-metil-p-tirosina na preferência condicionada por lugar induzida por cocaína em camundongos: aspectos comportamentais e neurobiológicos
Arquivos
Data
2013
Autores
Sabioni, Pamela 
Orientadores
Galduróz, José Carlos Fernandes
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A cocaina produz potentes efeitos reforcadores devido ao bloqueio de transportadores dopaminergicos, causando um grande e rapido aumento de dopamina na fenda sinaptica. Este aumento de dopamina no sistema mesolimbico e provavelmente o maior responsavel pelo abuso da droga, que pode levar a dependencia. No entanto, ate o momento, nao foi estabelecido nenhum tratamento para a dependencia de cocaina. Neste sentido, este estudo foi proposto a fim de avaliar o efeito de duas drogas sobre a preferencia condicionada por lugar (PCL) induzida por cocaina, o agonista parcial de receptores D1, SKF 38393, e o inibidor da sintese de dopamina, α-metil-p-tirosina (AMPT). Camundongos machos adultos C57BL/6J foram condicionados a um ambiente com administracao de cocaina (10 mg/kg) via intraperitoneal (i.p.) em dias alternados em um procedimento obiasedo. Apos o teste de preferencia pos-condicionamento, os animais foram submetidos a tres dias de tratamento com SKF 38393 (10 mg/kg) ou AMPT (250 mg/kg) ou com a associacao das duas drogas. O tratamento com SKF 38393 foi capaz de reverter a PCL induzida pela cocaina. Contrariamente, a administracao repetida de AMPT potencializou este comportamento. A associacao de SKF 38393 e AMPT bloqueou o comportamento previamente estabelecido pela cocaina. Adicionalmente, foi avaliado o efeito do SKF 38393 sobre os niveis de BDNF no nucleo accumbens (NAcc) e na area tegmental ventral (ATV) apos o procedimento de PCL induzido por cocaina. Houve aumento de BDNF na ATV tanto pela administracao repetida de cocaina quanto de SKF 38393, sendo que a associacao destas duas drogas potencializou o aumento de BDNF nesta regiao. No entanto, nao foram verificadas alteracoes nos niveis de BDNF no NAcc em nenhum grupo. Este estudo fornece indicios de que os receptores D1 participam diretamente do mecanismo de reforco condicionado no modelo de PCL induzida por cocaina; e que a ativacao parcial destes receptores concomitante ao uso da cocaina desencadeia alteracoes neurobiologicas que podem ser a chave para o desenvolvimento de medicamentos para a dependencia de cocaina
Cocaine produces potent reward effects by the block age of dopamine transporters. This blockage triggers a fast and large increase of dopamine levels in the synaptic cleft. This increase of dopamine in the mesolimbic system is probably the major responsible for the drug abuse that may lead to add iction. However, until now, it was not yet established a treatment for cocaine addicti on. Therefore, the aims of this study were to evaluate the effects of the partial D 1 agonist SKF 38393 and of the dopamine synthesis inhibitor α -metil- p -tyrosine (AMPT) on cocaine-conditioned place preference (CPP). Male adult C57BL/6J mice were con ditioned with cocaine (10 mg/kg; i.p.) each other day in a biased procedure. After the post-conditioning test, the mice were submitted to three consecutive days of tr eatment with SKF 38393 (10 mg/kg; i.p.) or AMPT (250 mg/kg; i.p.), or the asso ciation of the two drugs. After the post-treatment preference test, it was demonstrated that the SKF 38393 reversed the CPP; while conversely, AMPT potentiated it. The ass ociation of the two drugs was able to block the effects of cocaine-induced CPP. A dditionally, we investigated the effects of the three days of treatment with SKF 383 93 (10 mg/kg) on the BDNF levels in the ventral tegmental area (VTA) and nucleus acc umbens (NAcc) after the cocaine-induced CPP procedure. Both cocaine and SKF 38393 treatments increased the BDNF levels in the VTA. The increase of BDNF wa s potentialized with the association of cocaine and SKF 38393 in this area. However there were no changes in BDNF levels in the NAcc in any experimental grou p. This study provides evidences that D1 receptors are directly involved with the co nditioned reward mechanism in cocaine-induced CPP. Moreover, the partial activati on of D1 receptors concomitant with cocaine use triggers neurobiological changes t hat may be the key role for the development of a treatment for cocaine addiction
Cocaine produces potent reward effects by the block age of dopamine transporters. This blockage triggers a fast and large increase of dopamine levels in the synaptic cleft. This increase of dopamine in the mesolimbic system is probably the major responsible for the drug abuse that may lead to add iction. However, until now, it was not yet established a treatment for cocaine addicti on. Therefore, the aims of this study were to evaluate the effects of the partial D 1 agonist SKF 38393 and of the dopamine synthesis inhibitor α -metil- p -tyrosine (AMPT) on cocaine-conditioned place preference (CPP). Male adult C57BL/6J mice were con ditioned with cocaine (10 mg/kg; i.p.) each other day in a biased procedure. After the post-conditioning test, the mice were submitted to three consecutive days of tr eatment with SKF 38393 (10 mg/kg; i.p.) or AMPT (250 mg/kg; i.p.), or the asso ciation of the two drugs. After the post-treatment preference test, it was demonstrated that the SKF 38393 reversed the CPP; while conversely, AMPT potentiated it. The ass ociation of the two drugs was able to block the effects of cocaine-induced CPP. A dditionally, we investigated the effects of the three days of treatment with SKF 383 93 (10 mg/kg) on the BDNF levels in the ventral tegmental area (VTA) and nucleus acc umbens (NAcc) after the cocaine-induced CPP procedure. Both cocaine and SKF 38393 treatments increased the BDNF levels in the VTA. The increase of BDNF wa s potentialized with the association of cocaine and SKF 38393 in this area. However there were no changes in BDNF levels in the NAcc in any experimental grou p. This study provides evidences that D1 receptors are directly involved with the co nditioned reward mechanism in cocaine-induced CPP. Moreover, the partial activati on of D1 receptors concomitant with cocaine use triggers neurobiological changes t hat may be the key role for the development of a treatment for cocaine addiction
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Citação
SABIONI, Pamela. Efeitos do SKF 38393 e da α-metil-p-tirosina na preferência condicionada por lugar induzida por cocaína em camundongos: aspectos comportamentais e neurobiológicos. 2013. 105 f. Tese (Doutorado em Ciências) – Escola Paulista de Medicina, Universidade Federal de São Paulo. São Paulo, 2013.