Desenvolvimento de modelos animais alternativos para avaliação dos efeitos comportamentais e metabólicos de antipsicóticos

• Ano de defesa: 2013
• Autor(a) principal: Vitor Bortolo de Rezende
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; UFMG
• Palavras-chave em Português: Caenorhabditis elegans; Metabolismo energético; Danio rerio; Zebrafish; antipsicóticos; Comportamento; Agentes antipsicóticos/efeitos adversos; Metabolismo; Nematóides; Sistema nervoso central/efeitos de drogas; Modelos animais; Microbiologia molecular; Drogas Resistencia em microorganismos; Comportamento animal; Peixe-zebra
• Link de acesso: http://hdl.handle.net/1843/BUBD-9FUJ4G

Although the discovery of psychiatric drugs and the study of their mechanisms of action in mammals is very effective, this strategy is hampered by factors such as high complexity of the organism, low-throughput experimentation and the high maintenance cost. Therefore, simpler animal models have emerged as an alternative due to the ability to be used in large scale assays, the low cost of maintenance and the lower complexity compared to mammals. Thus, the present study aimed to develop new strategies to evaluate the effects of antipsychotics using two alternative animal models: the teleost fish zebrafish (Danio rerio) and the nematode worm Caenorhabditis elegans. In regard to zebrafish as a model, tests were developed to assess both the metabolic effect of atypical antipsychotics and the behavioral effects of these drugs. To study the adverse metabolic effect, a method was developed to evaluate the effect of these drugs on the uptake of yolk by larval zebrafish using lipophilic fluorescent probe (nile red). Moreover, three tests were developed to assess the behavioral effects using zebrafish larvae: aggregation/dispersion of melanophores, flotation behavior and spontaneous locomotor activity. While the evaluation of yolk absorption failed to predict the metabolic effects of atypical antipsychotics, behavioral tests were sensitive to the effect of antipsychotics. Clozapine and haloperidol were able to disperse melanosomes of melanophores. Furthermore, the flotation behavior was intensely induced by clozapine and risperidone, what appears to be partially mediated through H1 and D2 receptor antagonism. Regarding the effect on spontaneous locomotor activity, the antipsychotic clozapine proved to be the most effective in reducing the displacement followed by risperidone and mepyramine. Regarding C. elegans, we tried to develop a model of social behavior to assess the effect of the antipsychotic clozapine. Therefore, it was chosen strains that exhibit social behavior, as indicated by a phenotype of aggregation. Clozapine was able to inhibit the social behavior of C. elegans in a concentration-dependent manner, indicating the possibility to use this model in antipsychotic evaluation. Therefore, the developed methods ! contribute to study the behavioral effects of antipsychotics, suggesting the use of alternative models as a strategy to study pharmacology.