This study investigates the behavioral effects of fluoxetine in an animal model of anxiety/depression induced by chronic corticosterone treatment. The model successfully mimics anxiety and depressive-like behaviors, which are reversed by chronic antidepressant treatment. The study reveals that fluoxetine's efficacy is mediated by both neurogenesis-dependent and independent mechanisms. Specifically, in corticosterone-treated mice, fluoxetine's effects are blocked in some but not all behavioral paradigms, suggesting the involvement of multiple pathways. Additionally, the study identifies candidate genes, including β-arrestin 1, β-arrestin 2, and Gia2, whose expression is decreased by chronic corticosterone and normalized by fluoxetine treatment, particularly in the hypothalamus. Notably, β-arrestin 2 knockout mice show reduced responsiveness to fluoxetine in multiple behavioral tasks, indicating that β-arrestin signaling is crucial for the antidepressant effects of fluoxetine. These findings provide insights into the complex mechanisms underlying the therapeutic actions of fluoxetine and highlight the importance of both neurogenesis-dependent and independent pathways in its efficacy.This study investigates the behavioral effects of fluoxetine in an animal model of anxiety/depression induced by chronic corticosterone treatment. The model successfully mimics anxiety and depressive-like behaviors, which are reversed by chronic antidepressant treatment. The study reveals that fluoxetine's efficacy is mediated by both neurogenesis-dependent and independent mechanisms. Specifically, in corticosterone-treated mice, fluoxetine's effects are blocked in some but not all behavioral paradigms, suggesting the involvement of multiple pathways. Additionally, the study identifies candidate genes, including β-arrestin 1, β-arrestin 2, and Gia2, whose expression is decreased by chronic corticosterone and normalized by fluoxetine treatment, particularly in the hypothalamus. Notably, β-arrestin 2 knockout mice show reduced responsiveness to fluoxetine in multiple behavioral tasks, indicating that β-arrestin signaling is crucial for the antidepressant effects of fluoxetine. These findings provide insights into the complex mechanisms underlying the therapeutic actions of fluoxetine and highlight the importance of both neurogenesis-dependent and independent pathways in its efficacy.