Comparable Acute Antidepressant-like Effects of Two Subanesthetic Ketamine Doses Are Associated with Divergent Region-Specific Molecular Responses After Adolescent Chronic Stress

Ketamine produces rapid antidepressant-like effects across a range of subanesthetic doses, yet how dose shapes behavioral efficacy and region-specific molecular signaling following adolescent chronic unpredictable stress (CUS) is not well understood. Here, we examined the behavioral and molecular consequences of two subanesthetic ketamine doses in adult mice with depression-like behavior induced by CUS. Male C57BL/6J mice were exposed to CUS during adolescence and developed depression-like behavior in adulthood. Adult mice received a single injection of vehicle or ketamine at 6 or 10 mg/kg, while non-stressed controls received vehicle. Both ketamine doses reduced immobility in the tail suspension test 24 h after treatment, indicating comparable acute antidepressant-like effects; however, this effect was not sustained one week later. Molecular analyses of the prefrontal cortex, hippocampus, and striatum were performed 24 h after behavioral testing, corresponding to 48 h after ketamine administration, to define region-specific ERK, mTOR, JNK, and BDNF signaling profiles. These analyses revealed dose- and region-dependent regulation of all four markers. The higher ketamine dose produced more extensive molecular changes without producing a greater reduction in tail-suspension test (TST) immobility, suggesting that the behavioral relevance of ketamine-induced signaling depends on regional context rather than the overall magnitude of pathway activation.