It has been shown that histamine (HA) stimulates prolactin (PRL) secretion via H<sub>2</sub> receptors following intra-cerebroventricular infusion and via Hi receptors following systemic (intra-arterial) infusion. Since the effect of HA appears to be exerted at a suprapituitary level, we investigated the involvement of the tuberoinfundibular dopaminergic (TIDA) system in HA-induced PRL secretion in urethane-anesthetized male rats. HA infused intracerebroventricularly (30 µg) or intra-arterially (420 µg) decreased the dopamine (DA) concentration in pituitary portal blood by 30 and 23%, respectively. Blockade of DA receptors by pimozide did not prevent the stimulation of PRL secretion induced by intracere-broventricular infusion of HA or the H<sub>2</sub> receptor agonist dimaprit. Furthermore, during DA receptor blockade intracere-broventricular infusion of the H<sub>1</sub> receptor agonist 2-thiazolylethylamine inhibited PRL secretion. In contrast, pimozide prevented the stimulation of PRL secretion induced by intra-arterial infusion of HA and the H<sub>1</sub> receptor agonist 2-thiazolylethylamine. In fact, under these conditions intra-arterial infusion of HA or the H<sub>2</sub>-receptor agonist dimaprit inhibited PRL secretion. During treatment with α-methyl-p-tyrosine, which reduced the hypothalamic DA content by 50%, HA infused intracerebroventricularly stimulated PRL secretion, while HA infused intra-arterially inhibited the secretion, which is in accordance with the results obtained during pimozide treatment. Cholinergic blockade by atropine did not prevent the HA-induced PRL release, exluding the possibility that the observed effect of pimozide is due to its anticholinergic property. We suggest that intracerebroventricular infusion of HA by activation of H<sub>2</sub> receptors may stimulate PRL secretion partly via inhibition of the TIDA system and partly via other mechanisms. Furthermore, by activation of H<sub>1</sub> receptors, intracerebroventricularly infused HA seems to inhibit PRL secretion by a DA-independent mechanism. In contrast, intra-arterial infusion of HA may by activation of H<sub>1</sub> receptors stimulate PRL secretion preferentially via inhibition of the TIDA system, while the H<sub>2</sub> receptor mediated PRL-inhibiting effect of intra-arterially infused HA may be related to other mechanisms.