RESUMO
OBJECTIVES: This study investigated the involvement of heme oxygenase-1 (HO-1) in the antidepressant-like effects of ursolic acid (UA), a plant-derived compound with neuroprotective and antidepressant-like properties. METHODS: Mice received intracerebroventricular injections of zinc protoporphyrin IX (ZnPP) or cobalt protoporphyrin IX (CoPP) to inhibit or induce HO-1, respectively, together with effective (0.1 mg/kg, p.o.) or sub-effective (0.01 mg/kg, p.o.) doses of UA or fluoxetine (10 mg/kg, p.o.). Immobility time was assessed using the tail suspension test (TST) and the ambulatory behaviour with the open field test. HO-1 immunocontent was evaluated in mice hippocampus and prefrontal cortex. KEY FINDINGS: ZnPP prevented the anti-immobility effects of UA and fluoxetine. Combined treatment with a sub-effective dose of CoPP and UA synergistically exerted antidepressant-like effects in the TST. Acute administration of UA or CoPP, but not fluoxetine, increased the HO-1 immunocontent in the hippocampus. None of the treatments altered the HO-1 immunocontent in the prefrontal cortex. CONCLUSIONS: In conclusion, this work shows that increased hippocampal HO-1 content and activity mediate the antidepressant-like effect of UA in the TST.
Assuntos
Heme Oxigenase-1/metabolismo , Hipocampo/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Fluoxetina/farmacologia , Hipocampo/metabolismo , Camundongos , Fármacos Neuroprotetores/farmacologia , Preparações de Plantas/farmacologia , Resultado do Tratamento , Ácido UrsólicoRESUMO
Distresses may induce behavioral phenotypes constituting heuristic models for psychopharmacology studies. In several species, including Drosophila, antidepressants counteract stress-induced phenotypes allowing the use of these models to test new psychoactive drugs. Here, we developed a novel and time-efficient protocol to provoke stress-induced phenotypes in Drosophila for the study of psychopharmacological agents. In the first experiment, flies (n = 12/groups) were exposed to a random-sequence of different types of stresses during nearly 24 h (including social isolation, fasting, heat, and electric shock), a protocol named short-term variable stress (SVS). Second, flies were exposed to a single stressful stimulus (social isolation, fasting, heat shock or electric shock, n = 12/groups). Next, flies submitted to SVS protocol were treated with vehicle, diazepam or fluoxetine (n = 12/groups). At the end of the stress protocols, behavioral phenotypes were evaluated in the open field (OF) and sucrose preference tests. In comparison to the unstressed group, flies exposed to SVS exhibited hyperactivity, as well as shorter times exploring the boundaries of the OF. In contrast to fasting stress, SVS reduced sucrose preference in flies. By analyzing the effects of individual stimuli on fly behavior, fasting and electric shock appear to be the predominant influences on the SVS-induced behaviors. Although fluoxetine or diazepam reduced the initial locomotor activity of flies, no treatment prevented the sequelae of SVS. Altogether, this study provides a time-efficient model system for the study of stress-mediated hyperactivity and anhedonia-like state resistant to fluoxetine and diazepam. The applications of SVS in Drosophila to preclinical psychopharmacology require further studies. LAY SUMMARY Exposition to unpredictable stress plays a significant role in psychiatric disorder's onset. Behavioral traits of these disorders can be partially modeled in rodents aimed at developing psychopharmacological therapies. However, studies in rodents were questioned by ethical issues. Focused on 3Rs principles, we developed a preclinical model for stress and psychopharmacology research in Drosophila. Variable stress induced behavioral alterations, including hyperlocomotion and reduced preference for sucrose in flies. However, behavioral alterations were resistant to fluoxetine and diazepam.