Evidence to date suggests an inhibitory role for serotonin (5-HT) in the regulation of feeding behavior. In the present study, hypothalamic 5-HT was investigated for its anorexic potency under different feeding conditions. In fasted rats, 5-HT (1.1-4.4 micrograms) injected into the hypothalamic paraventricular nucleus (PVN), produced a reliable dose-dependent reduction in food consumption. Under satiated conditions, this inhibitory effect was significantly larger and apparent at lower doses (down to 0.1 micrograms), in animals induced to eat by PVN injection of norepinephrine (NE). Tests with receptor antagonists, injected into the PVN immediately prior to 5-HT, revealed a dose-dependent blockade of 5-HT's action by the serotonergic blockers, metergoline, methysergide and cinanserin. While the effect of 5-HT was somewhat attenuated by administration of certain beta-adrenergic and phenothiazine-type dopamine receptor antagonists, 5-HT was totally resistant to the actions of more selective dopamine blockers and of the cholinergic and histaminergic antagonists, atropine and dexbrompheniramine. PVN injection of various serotonergic compounds, known to inhibit feeding when peripherally administered, also suppressed NE-induced feeding in a dose-related manner (fluoxetine = dl-norfenfluramine greater than quipazine greater than chlorimipramine greater than dl-fenfluramine). Further tests with PVN administration of the dextro isomer and metabolite of fenfluramine showed a considerably stronger inhibitory effect with d-norfenfluramine as compared to dexfenfluramine, and a particular effectiveness of peripherally injected dexfenfluramine in NE-injected rats, at doses at least 10-fold higher than centrally effective doses.(ABSTRACT TRUNCATED AT 250 WORDS)