It has been shown that histamine (HA) stimulates prolactin (PRL) secretion via H2 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 H2 receptor agonist dimaprit. Furthermore, during DA receptor blockade intracere-broventricular infusion of the H1 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 H1 receptor agonist 2-thiazolylethylamine. In fact, under these conditions intra-arterial infusion of HA or the H2-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 H2 receptors may stimulate PRL secretion partly via inhibition of the TIDA system and partly via other mechanisms. Furthermore, by activation of H1 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 H1 receptors stimulate PRL secretion preferentially via inhibition of the TIDA system, while the H2 receptor mediated PRL-inhibiting effect of intra-arterially infused HA may be related to other mechanis