Sistema endocanabinóide em dois modelos animais: a anandamida na reconsolidação da memória associativa de reforço positivo e expressão de receptores CB2 em camundongos BTBR T+tf/J
Data
2015-04-29
Tipo
Tese de doutorado
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Resumo
Nas últimas três décadas houve um avanço significativo acerca do sistema endocanabinóide. Hoje, sabe-se que este sistema desempenha importantes funções, tanto no sistema nervoso central como na periferia. O endocanabinóide mais estudado na literatura é a anandamida, a qual interage com receptores canabinóides do tipo 1 (CB1R) e tipo 2 (CB2R) e também com o receptor vanilóide (TRPV1). A anandamida apresenta afinidade diferenciada por estes três receptores, sendo por ordem decrescente CB1R, TRPV1 e CB2R. Além disso, o sítio de interação com estes receptores ocorre via extracelular para os CB1R e CB2R e intracelular para o TRPV1. Acreditava-se que os CB2R não eram expressos de forma constitutiva no sistema nervoso central. No entanto, uma série de estudos recentes, mostram sua expressão constitutiva em algumas regiões do cérebro, e também que os CB2R estão relacionados com alguns transtornos neuropsiquiátricos. Nesta tese de doutorado, o sistema endocanabinóide foi estudado sob duas importantes vertentes. Na primeira, foi investigado o efeito do aumento de anandamida, através do uso do AM404 (um inibidor da recaptura extracelular de anandamida), sobre a reconsolidação da memória associativa de reforço positivo induzida pela morfina. Na segunda vertente, foi avaliada a expressão gênica dos receptores canabinóides do tipo 2 por PCR quantitativa (qPCR), no sistema nervoso central de camundongos BTBR T+tF/J (um modelo animal do espectro autista) em diferentes fases do neurodesenvolvimento. Os resultados aqui obtidos, demonstrando o papel da reconsolidação na atualização da memória, bem como, do papel da inibição da recaptura da anandamida neste modelo, assim como, a supra regulação da expressão gênica de receptores mCB2A em animais adultos com características autistas BTBR T+tF/J, colaboraram para a melhor compreensão acerca do envolvimento deste importante sistema de neurotrasmissão no contexto da drogadição e do espectro autista.
Rationale Drug addiction can be viewed as a pathological memory that is constantly retrieved and reconsolidated. Since drug abuse takes place in different contexts, it could be considered that reconsolidation plays a role in memory updating. There is consistent evidence regarding the role of reconsolidation in the maintenance and strengthening of appetitive associative memories induced by drugs of abuse. However, this role is not well established in memory updating. Objectives The purpose of the current study was to assess reconsolidation process over memory update Methods C57BL6 mice were subjected to the conventional morphine-induced conditioned place preference paradigm (CPP). After the first CPP test, animals were divided in experimental groups, according to the contextual characteristic of the re-exposure and a second CPP Test. Results (i) re-exposure in the original context is important to the maintenance of memory trace; (ii) re-exposure under discrete contextual changes leads to memory updating, although memory trace is maintained. Interestingly, cycloheximide had differential effects in our protocol. When the re-exposure was done under discrete contextual changes, cycloheximide administration just after re-exposure blocked memory updating, without changes in trace maintenance. When re-exposure was done under the original context, only two subsequent cycloheximide injections (3 and 6 h) disrupted memory trace. Conclusions Considering the temporal window of protein synthesis in consolidation and reconsolidation, our results suggests that re-exposure in the CPP could trigger both phenomena, according to the contextual profile of re-exposure. Furthermore, reconsolidation plays a pivotal role in memory updating, when new information is present on retrieval.
Rationale Drug addiction can be viewed as a pathological memory that is constantly retrieved and reconsolidated. Since drug abuse takes place in different contexts, it could be considered that reconsolidation plays a role in memory updating. There is consistent evidence regarding the role of reconsolidation in the maintenance and strengthening of appetitive associative memories induced by drugs of abuse. However, this role is not well established in memory updating. Objectives The purpose of the current study was to assess reconsolidation process over memory update Methods C57BL6 mice were subjected to the conventional morphine-induced conditioned place preference paradigm (CPP). After the first CPP test, animals were divided in experimental groups, according to the contextual characteristic of the re-exposure and a second CPP Test. Results (i) re-exposure in the original context is important to the maintenance of memory trace; (ii) re-exposure under discrete contextual changes leads to memory updating, although memory trace is maintained. Interestingly, cycloheximide had differential effects in our protocol. When the re-exposure was done under discrete contextual changes, cycloheximide administration just after re-exposure blocked memory updating, without changes in trace maintenance. When re-exposure was done under the original context, only two subsequent cycloheximide injections (3 and 6 h) disrupted memory trace. Conclusions Considering the temporal window of protein synthesis in consolidation and reconsolidation, our results suggests that re-exposure in the CPP could trigger both phenomena, according to the contextual profile of re-exposure. Furthermore, reconsolidation plays a pivotal role in memory updating, when new information is present on retrieval.
Descrição
Citação
ESCOSTEGUY NETO, Joao Carlos. Sistema endocanabinóide em dois modelos animais: a anandamida na reconsolidação da memória associativa de reforço positivo e expressão de receptores CB2 em camundongos BTBR T+tf/J. 2015. 123 f. Tese (Doutorado em Neurologia - Neurociências) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2015.