The involvement of histaminergic neurons in the neuroendocrine regulation of the release of the pro-opiomelanocortin-derived peptides adrenocorticotropin (ACTH; anterior pituitary lobe) and α-melanocyte-stimulating hormone (α-MSH; intermediate pituitary lobe) was studied in conscious male rats. Pretreatment with the histamine (HA) synthesis inhibitor (S)-α-fluoromethylhistidine (100 µmol/kg i.p. at -6 h or 400 µmol/kg i.p. at –20 and –6 h) had no effect on basal ACTH release but decreased basal α-MSH release. The two doses of (S)-α-fluoromethylhistidine inhibited by 35 and 50% the ACTH response to 5 min of restraint stress and almost prevented the stress-induced α-MSH release. (S)-α-fiuoromethylhistidine (100 µmol/kg) inhibited the ACTH and α-MSH response to ether stress by 50 and 70%, respectively. Intracerebroventricular administration of the HA metabolism inhibitor SKF 91488 (400 or 800 nmol at-15 min) stimulated basal secretion of ACTH and α-MSH dose-dependently and augmented slightly the restraint- and ether-stress-induced release of ACTH and α-MSH. Intracerebroventricular infusion of the H<sub>1</sub> receptor antagonist mepyramine (0.37 µmol) or the H<sub>2</sub> receptor antagonists cimetidine (0.40 µmol) or ranitidine (0.40 µmol) inhibited or prevented the α-MSH response to intracerebroventricular administration of HA (0.27 µmol), restraint or ether stress. Pretreatment with the dopamine receptor agonist bromocriptine or the β-adrenergic receptor antagonist propranolol inhibited the α-MSH response to HA or stress. The results indicate that hypothalamic histaminergic neurons participate in the neuroendocrine regulation of the pro-opiomelanocortin-derived peptides from the anterior (ACTH) and intermediate (α-MSH) pituitary lobe of male rats. The effect of HA and stress is caused via activation of H<sub>1</sub> and H<sub>2</sub> receptors, and may – concerning the effect on α-MSH secretion – be mediated by tuberohypophysial dopaminergic neurons and peripheral circulating epinephrine.