Efeito da diciclomina sobre a evocação da memória recente e remota do condicionamento de medo e da esquiva inibitória
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Data
2014
Autores
Patricio, Rafael Rodisanski [UNIFESP]
Orientadores
Oliveira, Maria Gabriela Menezes de [UNIFESP]
Tipo
Dissertação de mestrado
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Resumo
Diversas evidencias sugerem um envolvimento do sistema colinergico muscarinico na modulacao dos processos de memoria em tarefas aversivamente motivadas. Estudos mostram prejuizo de memoria em ratos submetidos a tarefa de condicionamento de medo ao contexto quando da administracao de diciclomina (antagonista seletivo para receptores muscarinicos M1) nas doses de 16 e 32 mg/kg antes do teste, realizado 1 dia apos o treino, sugerindo atuacao desses receptores no processo de evocacao da memoria recente da tarefa. As mesmas doses de diciclomina nao produziram efeito sobre o condicionamento de medo ao som nem sobre a esquiva inibitoria. Uma vez que a evocacao da memoria recente e remota sao atribuidos diferentes substratos neurobiologicos, nao se e conhecido o efeito da diciclomina apos longo intervalo de tempo da realizacao do treino. O presente trabalho teve por objetivos, portanto, investigar os efeitos da administracao pre-teste de diciclomina sobre a evocacao da memoria recente e remota do condicionamento de medo e da esquiva inibitoria e identificar, atraves da analise imuno-histoquimica de Fos (metodo amplamente empregado no mapeamento funcional da atividade cerebral), as estruturas envolvidas nesse processo. Ratos Wistar machos de 3 a 4 meses de idade foram treinados e, apos um intervalo de 1 dia (memoria recente) ou 28 dias (memoria remota), injetados com diciclomina (16 ou 32 mg/kg, ip) e testados nas tarefas de condicionamento de medo ao contexto, condicionamento de medo ao som e esquiva inibitoria. A administracao da droga na dose de 32 mg/kg provocou prejuizo na evocacao das memorias recente e remota do condicionamento ao contexto e na evocacao da memoria remota do condicionamento ao som, sem interferir com a esquiva inibitoria em nenhum dos intervalos estudados. Esses resultados revelam que a modulacao exercida pelos receptores M1 sobre o processo de evocacao e distinta para essas tarefas, sugerindo que sejam mediadas por diferentes mecanismos neuroquimicos. O mapeamento da expressao de Fos nos animais submetidos ao condicionamento de medo ao contexto revelou aumento do numero de celulas Fos-positivas nos cortices pre-limbico e infra-limbico e na divisao lateral do nucleo central da amigdala dos animais testados 28 dias apos o condicionamento. Alem disso, verificou-se maior expressao de Fos no nucleo basolateral da amigdala dos grupos condicionados que receberam salina em relacao aqueles tratados com a droga. Essa diferenca pode estar associada ao efeito amnesico sobre a tarefa. Observou-se, tambem, aumento da expressao de Fos nos nucleos central da amigdala, supra-optico e paraventricular do hipotalamo, orgao subfornical, locus coeruleus, nucleo do trato solitario e area postrema dos animais tratados com diciclomina. Todavia, tais alteracoes parecem estar associadas a modificacoes de carater autonomico
Previous studies indicate the involvement of the muscarinic cholinergic system in the modulation of memory processes in aversively motivated tasks. In addition, other studies on memory impairment in rats subjected to contextual fear conditioning after administration of dicyclomine, a selective M1 muscarinic receptor antagonist, at doses of 16 and 32 mg/kg prior to testing (carried out 1 day after the training session) suggested that these receptors play a role in recent memory retrieval. The same doses of dicyclomine had no effect on auditory fear conditioning and on inhibitory avoidance. Considering that the retrieval of recent and remote memories are attributed to distinct neurobiological substrates, the effect of dicyclomine long after the completion of training is unknown. Therefore, the present study aimed to investigate the effects of pre-test administration of dicyclomine on the recent and remote memory retrieval of contextual fear conditioning and inhibitory avoidance, and identify the structures involved in this process via immunohistochemical analysis of Fos, which is a method widely used in the functional mapping of brain activity. Wistar male rats aged 3–4 months were trained. After an interval of 1 day (recent memory) or 28 days (remote memory), the rats received an intraperitoneal injection of dicyclomine (16 or 32 mg/kg) and then were tested in contextual fear conditioning, auditory fear conditioning, or inhibitory avoidance tasks. Dicyclomine administration at a dose of 32 mg/kg compromised the recent and remote memory retrieval of contextual fear conditioning and the remote memory retrieval of auditory fear conditioning. However, the drug did not affect inhibitory avoidance in any of the time intervals evaluated. These results indicated that the effect of modulation of the M1 receptor on memory retrieval was distinct for the tasks evaluated, suggesting that these processes were mediated by different neurochemical mechanisms. Mapping of Fos expression in animals submitted to contextual fear conditioning revealed an increase in the number of Fos-positive cells in the pre-limbic and infra-limbic cortices and in the lateral division of the central nucleus of the amygdala of animals tested 28 days after conditioning. In addition, Fos expression increased in the basolateral nucleus of the amygdala of the conditioned groups injected with saline compared with those treated with the drug. This difference may be associated with the amnesic effect on the task. Moreover, we observed an increase in Fos expression in the central nucleus of the amygdala, supraoptic nucleus, paraventricular nucleus of the hypothalamus, subfornical organ, locus coeruleus, nucleus of the solitary tract, and area postrema of the dicyclomine-treated animals. However, this modulation in Fos expression appears to be associated with autonomic changes.
Previous studies indicate the involvement of the muscarinic cholinergic system in the modulation of memory processes in aversively motivated tasks. In addition, other studies on memory impairment in rats subjected to contextual fear conditioning after administration of dicyclomine, a selective M1 muscarinic receptor antagonist, at doses of 16 and 32 mg/kg prior to testing (carried out 1 day after the training session) suggested that these receptors play a role in recent memory retrieval. The same doses of dicyclomine had no effect on auditory fear conditioning and on inhibitory avoidance. Considering that the retrieval of recent and remote memories are attributed to distinct neurobiological substrates, the effect of dicyclomine long after the completion of training is unknown. Therefore, the present study aimed to investigate the effects of pre-test administration of dicyclomine on the recent and remote memory retrieval of contextual fear conditioning and inhibitory avoidance, and identify the structures involved in this process via immunohistochemical analysis of Fos, which is a method widely used in the functional mapping of brain activity. Wistar male rats aged 3–4 months were trained. After an interval of 1 day (recent memory) or 28 days (remote memory), the rats received an intraperitoneal injection of dicyclomine (16 or 32 mg/kg) and then were tested in contextual fear conditioning, auditory fear conditioning, or inhibitory avoidance tasks. Dicyclomine administration at a dose of 32 mg/kg compromised the recent and remote memory retrieval of contextual fear conditioning and the remote memory retrieval of auditory fear conditioning. However, the drug did not affect inhibitory avoidance in any of the time intervals evaluated. These results indicated that the effect of modulation of the M1 receptor on memory retrieval was distinct for the tasks evaluated, suggesting that these processes were mediated by different neurochemical mechanisms. Mapping of Fos expression in animals submitted to contextual fear conditioning revealed an increase in the number of Fos-positive cells in the pre-limbic and infra-limbic cortices and in the lateral division of the central nucleus of the amygdala of animals tested 28 days after conditioning. In addition, Fos expression increased in the basolateral nucleus of the amygdala of the conditioned groups injected with saline compared with those treated with the drug. This difference may be associated with the amnesic effect on the task. Moreover, we observed an increase in Fos expression in the central nucleus of the amygdala, supraoptic nucleus, paraventricular nucleus of the hypothalamus, subfornical organ, locus coeruleus, nucleus of the solitary tract, and area postrema of the dicyclomine-treated animals. However, this modulation in Fos expression appears to be associated with autonomic changes.
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Citação
PATRICIO, Rafael Rodisanski. Efeito da diciclomina sobre a evocação da memória recente e remota do condicionamento de medo e da esquiva inibitória. Dissertação (Mestrado em Ciências) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2014.