Stress-induced gene expression and corticosterone release in adolescent and adult male and female rats after acute or repeated restraint

Adolescence is a sensitive window for the maturation of hypothalamic-pituitary-adrenal (HPA) axis function; however, the timing and mechanisms underlying this transition remain unclear, particularly in females and in response to repeated homotypic stress. We measured corticosterone (CORT) release and glucocorticoid-related gene expression in postpubertal (P45) and adult (P75) male and female rats after acute or repeated restraint. In males, adolescents elicited higher CORT responses than adults did after acute stress, although both ages showed habituation to repeated restraint. In contrast, females exhibited adult-like CORT responses by P45 and no evidence of habituation. At the molecular level, adolescents of both sexes displayed distinct medial prefrontal cortex and ventral hippocampus expression profiles of glucocorticoid receptor (<i>Nr3c1</i>) and co-chaperones (<i>Fkbp4</i>, <i>Fkbp5</i>) relative to adults, though these effects were more pronounced in females, for whom there were also age- and stress-dependent changes in mineralocorticoid receptor (<i>Nr3c2</i>) expression. These findings suggest that while hormonal stress responses mature earlier in females than in males, sex-specific trajectories of molecular regulation continue to develop into late adolescence, potentially shaping long-term vulnerability to stress-related disorders.