Imatinib-Induced Changes in Anxiety-Like Behaviors are Associated With Prefrontal Cortical Metabolic Remodeling in Mice.

BACKGROUND: Anxiety-related symptoms are frequently reported in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI) therapy. However, the role of TKIs, including imatinib, in development of anxiety remains unclear. The prefrontal cortex (PFC) is closely associated with anxiety-like behaviors, and its metabolic components, particularly lipid- and myelin-related metabolites, are involved in their regulation. Whether imatinib affects brain metabolism remains unknown. This study aimed to evaluate the effects of imatinib on anxiety-like behaviors and to investigate associated metabolic alterations in the PFC. METHODS: Anxiety-like behaviors were assessed using a battery of behavioral assays in imatinib-treated mice. PFC tissues from imatinib-treated and control mice were subjected to untargeted metabolomic analysis. RESULTS: Imatinib-treated mice exhibited selective alterations in anxiety-like behaviors. Metabolomic analysis revealed distinct metabolic profiles between the two groups, with significant changes in lipid-related pathways, particularly sphingolipid metabolism. These findings extend the current understanding of the metabolic basis of anxiety-like behaviors and suggest that TKI treatment may influence neuropsychiatric processes through metabolic remodeling of the PFC. CONCLUSIONS: This study highlights a potential link between TKI therapy and brain metabolism and provides a framework for understanding the neurobiological basis of anxiety-related effects. These findings may inform future research on the neuropsychiatric consequences of targeted cancer therapies.