Kappa-Opioid Receptor Antagonism Prolongs the Antidepressant Effects of Ketamine in Adult Mice with Depression-like Behavior Induced by Adolescent Chronic Unpredictable Stress.

Major depressive disorder (MDD) is a highly prevalent psychiatric illness for which rapid-acting antidepressants such as ketamine provide only transient benefit. Because κ-opioid receptor (KOR) signaling contributes to stress-related dysphoria and impaired neuroplasticity, we examined whether KOR antagonism could prolong ketamine's antidepressant-like effects in a mouse model of adolescent chronic unpredictable stress (CUS). Male C57BL/6J mice (n = 10 per group for behavioral analyses) were exposed to CUS during adolescence and developed persistent depression-like behavior in adulthood. Mice with depressive-like behavior received a single injection of ketamine, the selective KOR antagonist norbinaltorphimine (nBNI), or their combination. Behavioral testing showed that all treatments reduced immobility in the tail suspension test (TST) 24 h post-administration; however, only the combined ketamine/nBNI treatment maintained antidepressant-like effects one week post-treatment. Molecular analyses (n = 4-8 per group) were conducted at this single time point, one week post-treatment, to characterize region-specific signaling states in the prefrontal cortex, hippocampus, and striatum, focusing on ERK, AKT, JNK, mTOR, and BDNF pathways. These molecular findings represent correlates of sustained behavioral effects rather than evidence of causal mechanisms. Together, the data indicate that concurrent KOR antagonism is associated with prolonged antidepressant response to ketamine in stress-exposed male mice and with distinct region-dependent signaling profiles at one week post-treatment. Further studies are needed to establish mechanistic causality and confirm the possible applicability of these findings.