Experiments were undertaken to examine the influence of dexamethasone administration on adrenergic receptor-mediated cAMP accumulation in rat brain cerebral cortical slices. While the initial response to continuous treatment with dexamethasone or ACTH was a decrease in the alpha-adrenergic receptor-mediated augmentation of isoproterenol-stimulated cAMP production, more prolonged administration of these substances also increased beta-adrenergic receptor-stimulated cAMP accumulation. Dose-response studies revealed a dose-dependent increase in beta-adrenergic receptor-stimulated cAMP production. Prolonged administration of either dexamethasone or ACTH also increased 2-chloradenosine-, vasoactive intestinal peptide (VIP)-, and forskolin-stimulated cAMP production in the brain slice. These results, together with previous findings, suggest that glucocorticoids have at least two effects on the brain neurotransmitter receptor-coupled cAMP generating system which may be important for maintaining homeostasis during times of stress.