It was the aim of this study to investigate the mechanisms responsible for changes in 3',5'-cyclic adenosine monophosphate (cAMP) in the rat adrenal medulla occuring after administration of carbamylcholine, histamine, ACTH and various phenylethylamines. Carbamylcholine, ACTH, histamine, noradrenaline and dopamine produced marked (500-900%) increases in adrenal cAMP which were very similar in both adrenal cortex and medulla both with respect to time-course and relative extent. Interestingly isoprenaline and adrenaline did not influence cAMP levels even at excessively high doses. In all cases studied transsection of the splanchnic fibers supplying the adrenals reduced the increase in medullary cAMP by not more than 25--30%, suggesting that cAMP levels in the adrenal medulla are predominantly regulated by non-neuronal mechanisms. This assumption was strongly supported by the observation that hypophysectomy completely abolished the 500--600% increase in cAMP produced by 50 mumol/kg of dopamine and reduced the 700% increase resulting from 4.4 mumol/kg of carbamylcholine to 70%. In spite of the marked increase in cAMP produced by single and repeated doses of dopamine in the adrenal medulla there was no subsequent induction of tyrosine hydroxylase (TH). Moreover carbamylcholine (8.2 mumol/kg) evoked TH induction only in innervated adrenals whereas after denervation, in spite of the large (+ 500%) and prolonged (more than 90 min) increase in cAMP, no TH induction could be observed. It is concluded that adrenal medullary cAMP is predominantly regulated by the pituitary gland via the adrenal cortex and only to a much smaller extent--if at all--by direct cholinergic mechanisms, which are responsible for the initiation of TH induction.