Efeitos da retirada de sacarose e de etanol sobre comportamentos relacionados à ansiedade e à depressão: investigação do papel da via das quinureninas

Abstract

Repeated and prolonged use of psychoactive substances causes neuroadaptations that favor the development of tolerance, chemical dependency and withdrawal symptoms in attempts to stop consumption. Such symptoms cause great psychological suffering and constitute negative reinforcement of use. The kynurenine pathway is a possible candidate for neuromodulation and contribution to the emotional behavioral changes of withdrawal due to indoleamine 2,3-dioxygenase (IDO), the main enzyme of the pathway, metabolizing a large part of the brain's tryptophan, interfering with the synthesis of serotonin and generate neuroactive and reactive metabolites. To analyze this hypothesis, this work investigated the effects of sucrose and ethanol withdrawal on behaviors related to anxiety and depression, on IDO activity and the serological profile of Wistar rats. Women are more vulnerable to developing emotional and eating disorders when compared to men. Furthermore, the prebiotic action of the dietary fiber inulin was investigated in rats exposed to withdrawal ethanol. It is known that ethanol causes damage to the microbiota and intestinal permeability, leading to inflammatory conditions that could interfere with neural activity and emotional responses. Therefore, in experimental stage 1, the rats were subjected to a liquid sucrose diet for 16 days and sucrose withdrawal in the short term (48h) or long term (21 days). Afterwards, they performed open field behavioral tests (OF - 72h and day 22 of abstinence) and forced swimming (FS - days 4 and 5, 23 and 24 of abstinence). In experimental stage 2, females were subjected to an exclusive liquid ethanol diet in increasing concentrations (2, 4 and 6%) for 21 days and abstinence for 22 days. They then underwent behavioral tests on days 22 (elevated plus maze - EPM), 23 (sucrose spray - SS), 24 (marble burying - MB), 25 (pre-FS) and 26 (FS) days of abstinence. Inulin treatment consisted of administering a solution (100 mg/kg or 300 mg/kg orally, gavage) from the 14th day of exposure to ethanol until the end of the behavioral tests. Finally, the animals were euthanized to collect blood, frontal cortex, striatum and hippocampus samples. No behavioral changes were seen in animals withdrawing sucrose, but rats exposed to sucrose continuously had reduced immobility in the FS. However, rats withdrawing from ethanol exhibited less exploration of open arms in the EPM, greater burying of glass balls in the MB and longer immobility time in the FS. When treated with inulin at a dose of 100 or 300 mg/kg, females undergoing ethanol withdrawal showed behavior similar to controls on exploring the open arms of the EPM. Furthermore, rats undergoing withdrawal and treatment with 300 mg/kg inulin showed behavior similar to controls in burying glass balls and immobility in the FS. There was no change in the level of kynurenines, markers of brain oxidative stress and markers of the serological profile of the animals, with the exception of those exposed to sucrose which showed an increase in plasma triglycerides. In conclusion, prolonged sucrose consumption demonstrated an antidepressant effect. Ethanol withdrawal promoted anxious and depressive-like behaviors that were mitigated by inulin treatment. The prebiotic inulin has demonstrated a potential candidate for the treatment of alcohol use disorder.