Validação de um novo modelo animal no estudo da ansiedade e depressão em camundongos induzido por uma dose única de pilocarpina

Abstract

Animal models used to study anxiety and depression disorders are important tools for understanding the pathophysiology and developing new pharmacological therapies. Recently, studies have shown that subconvulsant doses of pilocarpine (PILO; nonselective muscarinic receptor agonist) produce short- and long-term anxiogenic-like behavior in male Wistar rats. Our research group extended these data by demonstrating that Swiss mice of both sexes exhibit anxiogenic- and depressive-like behavior after treatment with PILO (75 mg/kg); where females are more responsive than males to long-term effects. This study aimed to pharmacologically validate this new animal model of anxiety and depression, in addition to investigating neuronal death in the hippocampus and serological levels of corticosterone after the administration of a single dose of PILO in female mice. For pharmacological validity, female Swiss mice were treated with PILO (75 mg/kg, ip) and 24 hours after or for 30 consecutive days treated with diazepam (DZP; 1.5 mg/kg, ip) or fluoxetine (FLU; 10 mg/kg, ip). After 30 minutes of the last treatment, animals were submitted to the elevated plus maze (EPM) and forced swim (FST) tests to evaluate the short- (24h) and long-effects (30d) on related behaviors with anxiety and depression, respectively. The spontaneous locomotor activity of the animals was evaluated in the open-field (OF). After the tests, animals the blood and brain were collected for the analysis of serological levels of corticosterone and hippocampal neurodegeneration (by Fluoro-Jade C; FJ-C). Our results demonstrated that DZP blocked short- and long-term anxiogenic-like behavior, but not depressive-like behavior in PILO-induced FST. While FLU only blocked long-term anxiogenic and depressive-like behavior induced by PILO. Animals treated with PILO and later with DZP or FLU showed no change in spontaneous locomotion in the OF. Treatment with PILO increased serum corticosterone levels in the short-term. After 24 h or 30 d, animals treated with PILO did not show hippocampal neurodegeneration (FJ-C- ). Taken together, these results suggest that PILO-induced anxiogenic- and depressivelike behaviors are blocked by standard anxiolytic and antidepressant drugs, contributing to the pharmacological validation of this new model. Furthermore, the behavioral changes caused by PILO are not related to hippocampal neurodegeneration, distancing this dose from the convulsive dose, which is characterized by neuronal death in this brain region. In summary, the administration of a single dose of PILO in female mice proved to be, after behavioral and pharmacological validation, a good and promising animal model for the study of anxiety and depression.