The synchrony of PRL and cortisol release with feeding is now well established. To delineate further the neuroendocrine mechanisms involved, meal-related pituitary and adrenal cortical activities were investigated in seven normal men in a series of experiments conducted in random sequence at 1-week intervals. Ingestion of a standardized mixed meal elicited a consistent acute release of PRL and cortisol at noon (1200 h), but not at breakfast (0800 h). No measurable changes in other pituitary hormones were observed. The relative magnitudes of PRL and cortisol release in response to lunch were not significantly influenced by a preceding breakfast. These responses appear unrelated to the cephalic or oral phases of food ingestion. However, the composition of the meals was found to be important. Whereas carbohydrate meals had no discernible effects, high protein meals induced a large increase in both PRL and cortisol; high fat meals caused selective release of PRL. Ingestion of L-tyrosine and L-tryptophan induced remarkable increments in serum concentrations of both PRL and cortisol, suggesting that these essential amino acids may be active components of the high protein meal. Choline had no effect. Meal-mediated PRL and cortisol release was unaffected by prior receptor blockade of the opioidergic and cholinergic systems with naloxone and atropine, respectively. These observations indicate that the protein component of the meal was responsible for the midday surges of PRL and cortisol and that the cephalic-vagal pathway was not required in food-entrained pituitary hormone release. Further, our data suggest that the neurotransmitter substrates in the protein meal may serve to link the gut and brain by modifying central catecholamine and serotonin biosynthesis, and thereby influence the hypothalamic factors controlling pituitary PRL and ACTH secretion. The possibility that gastrointestinal hormones may also influence the hypothalamic-pituitary system remains to be explored.