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Glucocorticoids (GCs) are involved in many psychological, cellular and molecular mechanisms in humans, and are vital to the preservation of stress-related homeostasis through their regulation of metabolic and immune functions. Alterations in tissue sensitivity to GCs define vulnerability to numerous diseases, including depression, diabetes, and chronic obstructive airways disease. Using an established murine model of social disruption stress (SDR), in which a male mouse is repeatedly defeated by an aggressor, we have previously shown that splenocytes of SDR-treated mice are less sensitive to the anti-inflammatory effects of GCs and resist GC-induced apoptosis. Although GC insensitivity has been repeatedly observed in SDR-treated mice, the mechanism by which it develops has not yet been fully elucidated. The present study aimed to characterize the resistance of GC-insensitive splenocytes to apoptosis by investigating the role of caspase-3 activity in splenocytes of stressed mice. The gene expression levels of CASP3 and CASP9 were also measured because of their direct relationship with caspase-3 activation in the intrinsic apoptotic pathway. Interestingly, capsase-3 activity was found to be elevated in the splenocytes of SDR- treated mice. In addition, both CASP3 and CASP9 expression was increased in SDR- treated mice. Taken together, the results demonstrate that caspase-3 is fully expressed and active in socially stressed mice and that resistance to glucocorticoid-induced apoptosis may be caused by apoptosis dysregulation downstream of caspase-3.