In investigating the feedback effects of circulating hormones on the brain, we showed previously that adrenalectomy (ADX) increases vasoactive intestinal peptide (VIP)-stimulated cAMP generation in slices from rat hippocampus, a brain structure with high levels of glucocorticoid receptors. This effect is reversed by replacement with glucocorticoids such as dexamethasone (DEX) and corticosterone (CORT). Here we report that, like ADX, hypophysectomy (HYPOX) also elevates VIP-stimulated cAMP generation, compared with sham-operated controls. Moreover, like glucocorticoid replacement, administration of ACTH to HYPOX rats causes a decrease in cAMP stimulation by VIP. Furthermore, ACTH had no effect when given to HYPOX + ADX rats, indicating that the effects of ACTH require the presence of adrenal steroid secretion. However, we find that ACTH may have a permissive role in this glucocorticoid effect because, in the absence of the pituitary, DEX treatment does not decrease VIP-stimulated cAMP levels in the hippocampus. In addition, hippocampal beta-adrenergic-stimulated cAMP accumulation was not suppressed by DEX treatment of HYPOX rats, which again is different from the effect of DEX treatment on ADX animals. These results are discussed in terms of possible synergism between pituitary hormones and steroid hormones in exerting feedback actions on brain function.