Alterations in hypothalamic-pituitary-adrenal (HPA) function are associated with changes in mood and behavior. Protein kinase A (PKA), on activation, phosphorylates many important intracellular proteins and thereby plays a major role in mediating various physiological functions in brain. We systematically examined the relationship of altered HPA function with PKA modifications in rat brain after administering corticosterone to normal rats and by first adrenalectomizing rats and then simultaneously treating them with different doses of corticosterone. Rats were decapitated on day 1, 4, or 14. Subcutaneously implanted 50- or 100-mg corticosterone pellets in normal rats for 4 or 14 days significantly decreased PKA activity, B(max) of [3H]cyclic AMP binding, and protein levels of selective PKA regulatory (RIalpha, RIIbeta) and catalytic (Catbeta) subunit isoforms in cortex and hippocampus in a dose-dependent manner without any significant changes at day 1; these changes were more pronounced at day 14. However, adrenalectomy caused the opposite changes in these measures at day 4 or 14 in both cortex and hippocampus, and the magnitude of the changes was more pronounced at day 14. Simultaneous treatment with implanted corticosterone at 50- or 100-mg doses in adrenalectomized rats reversed the adrenalectomy-induced increases in PKA measures in a dose-dependent manner. These results suggest that endogenous glucocorticoid modifies the expression of RIalpha, RIIalpha, and Catbeta subunit isoforms of PKA, as well as the catalytic and regulatory activities of PKA, and that these alterations in PKA may in part explain HPA axis-mediated changes in mood and behavior.