Efeitos da administração repetida de zolpidem sobre as fases da memória em camundongos submetidos à restrição de sono
Data
2015-06-24
Autores
Zanin, Karina Agustini 
Orientadores
Poyares, Dalva Lucia Rollemberg
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Objetivos: O zolpidem (Zolp) é um fármaco seletivo para a subunidade alfa1 dos receptores GABAA com propriedades hipnóticas. Há relatos que sua administração pode induzir efeitos amnésticos. Até o presente momento nenhum estudo avaliou os efeitos cognitivos do Zolp em modelos experimentais de insônia. O objetivo desta Tese foi verificar os efeitos da administração repetida de Zolp (ou de sua retirada) sobre o processo de aprendizado/memória em camundongos submetidos à restrição de sono (RS). Métodos: Os camundongos foram submetidos à RS pelo método de gentle handling. Após a RS, os animais foram tratados com Zolp. Os paradigmas comportamentais utilizados foram a esquiva discriminativa em labirinto em cruz elevado (ED-LCE), a esquiva passiva (EP), reconhecimento de objetos (RO) e discriminação social (DS). O padrão de sono também foi analisado por meio do registro eletroencefalográfico. Resultados: A privação aguda de sono por 6 h promove amnésia, que é tolerada após a repetição do protocolo por 10 dias. Por outro lado, enquanto um curto período de privação de sono (3 h) não modificou a memória quando da sua ocorrência aguda, a repetição por 10 dias foi efetiva em prejudicar o desempenho na tarefa de ED-LCE. Ainda, todos os protocolos de privação de sono aumentaram a expressão de c-fos na amígdala basolateral e no giro denteado, estrutura que parece estar relacionada aos efeitos cognitivos da RS. Na tarefa de ED-LCE, a RS (3 h por 10 dias) promoveu déficits de memória quando realizada anteriormente ao treino ou ao teste. O prejuízo pré-treino foi revertido pela administração aguda de Zolp ou pela retirada do tratamento. O prejuízo de evocação foi revertido apenas após o tratamento repetido com a droga. Ainda na ED-LCE, o antagonista beta-cct reverteu o efeito agudo promnéstico do Zolp em animais submetidos à RS, mas não foi capaz de mimetizar os efeitos da retirada do tratamento. Na EP, uma tarefa de grande conteúdo emocional, a RS não foi capaz de promover déficits de retenção independente do momento em que ocorre. Já em paradigmas não-aversivos (RO e DS), a RS promoveu déficits de memória em ambos os modelos. O déficit de memória na tarefa de RO foi abolido pela administração de Zolp. Por outro lado, apenas a administração aguda dessa droga reverteu o prejuízo de memória induzido pela RS observado na tarefa de DS. Com relação ao padrão de sono, o protocolo de RS se mostrou efetivo em aumentar a vigília e, consequentemente, em reduzir significativamente o sono de ondas lentas (SOL), o sono paradoxal e o tempo total de sono. A administração de Zolp aumentou o SOL em ambas as fases do ciclo, mas diminuiu o sono paradoxal. Nos animais restritos de sono e tratados com Zolp, houve um aumento de SOL e de sono paradoxal e se manteve elevado no rebote. Conclusão: Os achados da presente Tese demonstram a importância da validação de modelos experimentais de insônia bem como a avaliação dos efeitos do tratamento com Zolp em condições de RS, uma vez que os efeitos dessa droga podem ser discrepantes dependendo das condições de sono e do método de avaliação empregado.
Purpose: Zolpidem (Zolp) is an imidazopyridine agent, which selectively binds to the alpha1 subunit into the GABAA receptors with mainly hypnotic properties. Zolp-induced amnestic effects have been reported. Cognitive effects of Zolp in animal models of insomnia remain poorly understood. Thus, the present work was tailored to examine the effects of the repeated administration of Zolp (or its withdrawal) on learning/memory phases in mice subjected to sleep restriction (SR). Methods: Mice were sleep restricted by gentle handling. After SR, animals were treated with Zolp. The behavioral paradigms employed were the plus-maze discriminative avoidance task (PM-DAT), the passive avoidance task (PAT), spontaneous object recognition (SOR) and social discrimination (SD). Sleep pattern was analyzed by electroencephalographic recording. Results: We observed that the deleterious effects of acute SR for 6 h may be tolerated when the protocol was repeated for 10 days. Oppositely, a shorter period of sleep deprivation (3 h) impaired memory in the PM-DAT when repeated during 10 days, but not when acutely employed. All of the SR protocols induced an increase in c-fos expression in the basolateral amygdala and dentate gyrus. Of note, c-fos expression in the dentate gyrus seems to be related to the cognitive effects of SR. In the PM-DAT, SR (3 h for 10 days) induced memory deficits when it occurred before training or testing. The pre-training impairment was abolished by the acute administration of Zolp or its withdrawal. Conversely, the retrieval deficit was abolished only after the repeated treatment with Zolp. The deleterious effects on memory were partially counteracted by the administration of the antagonist beta-cct. In the PAT, a paradigm with a higher emotional component, SR per se cannot promote retention deficits. In non-aversive paradigms (SOR and SD), SR promoted memory impairments in both tasks. The memory deficit in the SOR was abolished by Zolp administration. On the other hand, only the acute administration of this hypnotic counteracted the SR-induced memory impairment in the SD task. Regarding the sleep pattern, the SR protocol was effective in increasing wake time and consequently reducing slow-wave sleep (SWS), paradoxical sleep and total sleep time (TST). The acute administration of Zolp increased SWS in both cycle phases but decreased paradoxical sleep in control animals. An increase in SWS and paradoxical sleep were detected in sleep-restricted mice treated with Zolp, which persisted during rebound. Conclusion: The findings presented herein strengthen the importance to validate animal models of insomnia as well as the investigation of the effects of Zolp treatment under SR conditions since the effects of this drug may be dependable of the sleep conditions and the evaluation methods.
Purpose: Zolpidem (Zolp) is an imidazopyridine agent, which selectively binds to the alpha1 subunit into the GABAA receptors with mainly hypnotic properties. Zolp-induced amnestic effects have been reported. Cognitive effects of Zolp in animal models of insomnia remain poorly understood. Thus, the present work was tailored to examine the effects of the repeated administration of Zolp (or its withdrawal) on learning/memory phases in mice subjected to sleep restriction (SR). Methods: Mice were sleep restricted by gentle handling. After SR, animals were treated with Zolp. The behavioral paradigms employed were the plus-maze discriminative avoidance task (PM-DAT), the passive avoidance task (PAT), spontaneous object recognition (SOR) and social discrimination (SD). Sleep pattern was analyzed by electroencephalographic recording. Results: We observed that the deleterious effects of acute SR for 6 h may be tolerated when the protocol was repeated for 10 days. Oppositely, a shorter period of sleep deprivation (3 h) impaired memory in the PM-DAT when repeated during 10 days, but not when acutely employed. All of the SR protocols induced an increase in c-fos expression in the basolateral amygdala and dentate gyrus. Of note, c-fos expression in the dentate gyrus seems to be related to the cognitive effects of SR. In the PM-DAT, SR (3 h for 10 days) induced memory deficits when it occurred before training or testing. The pre-training impairment was abolished by the acute administration of Zolp or its withdrawal. Conversely, the retrieval deficit was abolished only after the repeated treatment with Zolp. The deleterious effects on memory were partially counteracted by the administration of the antagonist beta-cct. In the PAT, a paradigm with a higher emotional component, SR per se cannot promote retention deficits. In non-aversive paradigms (SOR and SD), SR promoted memory impairments in both tasks. The memory deficit in the SOR was abolished by Zolp administration. On the other hand, only the acute administration of this hypnotic counteracted the SR-induced memory impairment in the SD task. Regarding the sleep pattern, the SR protocol was effective in increasing wake time and consequently reducing slow-wave sleep (SWS), paradoxical sleep and total sleep time (TST). The acute administration of Zolp increased SWS in both cycle phases but decreased paradoxical sleep in control animals. An increase in SWS and paradoxical sleep were detected in sleep-restricted mice treated with Zolp, which persisted during rebound. Conclusion: The findings presented herein strengthen the importance to validate animal models of insomnia as well as the investigation of the effects of Zolp treatment under SR conditions since the effects of this drug may be dependable of the sleep conditions and the evaluation methods.
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Citação
ZANIN, Karina Agustini. Efeitos da administração repetida de zolpidem sobre as fases da memória em camundongos submetidos à restrição de sono. 2015. 229 f. Tese (Doutorado em Psicobiologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2015.