Chronic Chrysin, but Not Diazepam, Induces Anxiolytic-like Effects Without Behavioral Tolerance

Background: Chrysin (5-7-dihydroxyflavone) exerts anxiolytic-like effects via the GABAA/benzodiazepine receptor complex after acute administration, similar to diazepam. Chronic diazepam treatment produces pharmacological tolerance, likely due to structural receptor modification. Whether chronic chrysin treatment also produces pharmacological tolerance remains unknown. This study evaluated GABAA/benzodiazepine receptor-mediated behavioral responses after a pharmacological challenge with a sedative dose of diazepam (5 mg/kg) in rats chronically treated with chrysin or diazepam. Methods: Thirty-five male Wistar rats were divided into five groups: vehicle, chrysin (1, 2.5, or 5 mg/kg), and diazepam (2 mg/kg, pharmacological control). Treatments were injected intraperitoneally for 32 days. On day 28, rats were evaluated in the elevated plus maze and locomotor activity tests. On day 32, all groups received a pharmacological challenge with 5 mg/kg diazepam and were assessed via sedative scale and the rota-rod test. Results: Chronic Chrysin (5 mg/kg) but not diazepam, maintained anxiolytic-like effects. No doses of chrysin showed pharmacological cross-tolerance to 5 mg/kg of diazepam, which produced incoordination and sedation, similar to vehicle. Conclusions: Chronic treatment with chrysin (5 mg/kg) maintained their anxiolytic-like effects without pharmacological tolerance or cross-tolerance, unlike diazepam. This result supports the potential anxiolytic-like effects of chrysin in the long-term, as an alternative for anxiety disorders that require chronic treatment. This could contribute to the translational studies that could be applied to humans in the future.