Histamine (HA) is likely to participate in the neuroendocrine regulation of prolactin (PRL) secretion. We, therefore, studied the possible involvement of HA in the stress-induced release of PRL in conscious male rats. HA (30 µg) infused intracerebroventricularly 15 min before decapitation elevated PRL plasma levels from 5 + 1 to 54 ± 6 ng/ml (p < 0.01). Intracerebroventricular infusion of the H2 receptor antagonists cimetidine (CIM; 100 µg) or ranitidine (RAN; 125 µg) abolished the PRL response to HA (p < 0.01), while intracerebroventricular infusion of the H1 receptor antagonist mepyramine (MEP; 100 µg) inhibited the response only 40% (p < 0.05). Intra-arterial infusion of CIM (2,000 µg) or RAN (2,500 µg) inhibited the HA-stimulated PRL secretion 52% (p < 0.01) or 63% (p < 0.01), respectively. The H1 receptor antagonists MEP (1,000 µg) and SKF-93944 (1,500 µg) had no effect following intra-arterial administration. Restraint stress increased the PRL level to 84 ± 6 ng/ml (p < 0.01 vs. control). This effect was prevented by intracerebroventricular infusion of CIM or RAN (p < 0.01) and inhibited 75% by MEP (p < 0.01). Intra-arterial infusion of CIM, MEP, and SKF-93944 inhibited the stress response about 50% (p < 0.01), while RAN decreased the response only 25% (p < 0.05). Ether stress elevated the plasma PRL concentration to 46 ± 5 ng/ml (p < 0.01 vs. control). When infused intracerebroventricularly, CIM or RAN prevented the response (p < 0.01), while MEP had no effect. Intra-arterial infusion of CIM or RAN attenuated the response approximately 50% (p < 0.01), while intra-arterial infusion of MEP or SKF-93944 inhibited the response 80% (p < 0.01). We conclude that restraint as well as ether stress stimulates the secretion of PRL via release of neuronal HA. The effect of HA seems primarily mediated through activation of H2 receptors, whereas H1 receptors appear to play a