The prolactin (PRL)-releasing effect of domperidone (DOM), a blocker of dopamine receptors which does not cross the blood-brain barrier, was studied in unanesthetized male rats and compared to that of the classic neuroleptic agent haloperidol (HAL). DOM proved to be a potent PRL releaser since striking and long-lasting (120 min) rises in plasma PRL were elicited by 50 and 100 μg/kg of the compound. Comparison with HAL showed that DOM was 5 times as potent as HAL as a PRL releaser (ED250 = 0.084 vs. 0.42 mg/kg, respectively). Apomorphine (APO) fully counteracted the PRL-releasing effect of DOM (0.1 mg/kg i.p.) only at the dose of 3 mg/kg s.c, while the PRL-releasing effect of HAL (0.1 mg/kg i.p.) was blocked by APO at the dose of 1 mg/kg s.c. The effect of DOM (0.1 mg/ kg i.p.) on PRL release was also suppressed by another DA-agonist drug, bromocriptine (5 mg/kg s.c). Evaluation of the affinity of DOM and HAL on [3H]-spiperone binding to striatal and pituitary homogenates showed a slightly higher affinity for DOM than HAL on both tissue. Systemic administration of DOM (50 and 100 μg/kg i.p.) left homo-vanillic acid (HVA) concentrations unchanged in the caudate nucleus while, as expected, HAL (0.5 and 1.0 mg/kg i.p.) induced a striking rise in striatal HVA content. These results indicate that DOM, by acting at the level of ‘peripheral’ DA receptors, is a strong PRL-releasing