The Comparative Effects Between Long‐Term and Short‐Term Treatment of Finasteride on Anxiety‐Like and Depression‐Like Behaviors in Early Senescent Male Rats

ABSTRACT This study aims to compare the efficacy of 5‐alpha‐reductase inhibitors (5ARIs) on anxiety and depression between long‐term and short‐term treatment followed by withdrawal in d ‐galactose (Dgal)–induced senescent male rats. Thirty‐two, 8‐week‐old, male Wistar rats were divided into two groups: control rats and Dgal‐treated rats (150 mg/kg/day; subcutaneously) for 18 weeks. At week 13, Dgal‐treated rats were subdivided into three subgroups: (1) vehicle (DgV), (2) long‐term treatment with 5ARIs, Finasteride 5 mg/kg/day, per oral for 6 weeks (DgF), (3) short‐term treatment with 5ARIs, Finasteride 5 mg/kg/day, per oral for 2 weeks followed by a 4‐week withdrawal period (DgW). Anxiety and depression were assessed using the elevated‐plus maze (EPM) and splash test (ST). Blood was collected for biochemical analysis. After euthanasia, the brains were removed to examine brain inflammation, oxidative stress, neuroactive steroids, brain metabolites, and brain senescent markers. We found that DgV rats exhibited metabolic disturbance with a reduced preference index of the EPM, and grooming duration in ST. Increased brain neurotoxic metabolites, along with increased brain inflammation/oxidative stress, and reduced microglia complexity were observed in the DgV rats. Both therapeutic approaches improved metabolic parameters and preference index in the open arm of EPM in Dgal‐treated rats, while grooming duration and microglia complexity were increased only in DgF rats. Our results indicate that Fin reduces depression‐like and anxiety‐like behaviors by reducing brain inflammation, oxidative stress, and brain senescent. In conclusion, long‐term treatment with 5ARIs is more effective in alleviating depression than short‐term treatment followed by withdrawal in Dgal‐induced early senescent male rats.