Pharmacological manipulation of H1 and H2 histamine receptors clearly indicates their participation in control of anterior pituitary secretion by the brain. Of particular interest is the PRL-releasing effect of H2 histamine receptor blocking agents like metiamide and cimetidine. The aim of the present study was to determine whether serotoninergic pathways, which exert a well known releasing effect on PRL secretion, were involved in the PRL-releasing action of cimetidine. As our first approach, the PRL-releasing effect of cimetidine was determined in developing male and female rats. Cimetidine failed to increase PRL in rats of 1 and 4 days of age. From 12 days onwards, the drug was able to cause a PRL increment in both sexes. There was a significant release of PRL at 20 and 28 days of age, and the response was greater in male than in female rats. The ontogeny of the cimetidine action, both in timing and sex differences, showed a close similarity with the development of the serotoninergic control of PRL secretion, and it was in clear contrast with the maturation of other controlling mechanisms, dopaminergic and TRH. In a second set of experiments, adult male rats were used. Methysergide, a serotonin receptor blocker, used in a dose and given by a route so that it did not modify the basal level of PRL, was able to completely prevent the PRL release evoked by cimetidine. Administration of p-chlorophenylalanine, a drug which reduces serotonin synthesis, was followed by a significant decline in the indole content of a portion of the brain which included the brain stem, the hypothalamus, and the preopticsuprachiasmatic area; and by a blockade of the PRL-releasing effect of cimetidine. Treatment of adult male rats with cimetidine, methysergide, or serotonin did not modify serum LH. It is concluded that a major serotoninergic input is involved in the PRL-releasing effect of cimetidine.