The mechanism of the hyperglycemic response to intraperitoneally administered serotonin (5-HT) was studied in rats. 5-HT i.p.-induced hyperglycemia was strongly antagonized by the 5-HT2A receptor antagonist ketanserin. 5-HT did not affect the serum insulin levels and increased plasma glucagon levels only at the high dose of 10 mg/kg. 5-HT dose-dependently induced a remarkable increase in plasma adrenaline levels and these effects were antagonized by ketanserin. 5-HT-induced hyperglycemia was abolished by adrenodemedullation. These results suggest that the hyperglycemic effects of 5-HT are closely related to the release of adrenaline from the adrenal gland, mediated by 5-HT2A receptors.