The effect of a potent agonistic LHRH analog D-Trp-6-LHRH on the hyperprolactinemia induced by haloperidol was tested in intact and ovariectomized female rats. The administration of D-Trp-6-LHRH at two dose levels (5 and 50 micrograms/day) for 20 days blocked the increase in serum PRL induced by haloperidol in intact as well as ovariectomized rats. The pituitary PRL concentration was also decreased by the administration of the analog in intact, but not ovariectomized, rats. Serum LH levels were significantly increased and the pituitary LH concentration was reduced by D-Trp-6-LHRH in intact rats. In ovariectomized rats, D-Trp-6-LHRH decreased serum as well as pituitary LH levels compared with levels in control rats. Another in vivo model to induce hyperprolactinemia consisted of grafting anterior pituitary glands under the kidney capsule in intact female rats. The administration of D-Trp-6-LHRH for 20 days (50 micrograms/day, sc) to rats bearing pituitary grafts blocked the hyperprolactinemia observed in similar animals injected with the vehicle only. Serum LH levels were increased after the administration of D-Trp-6-LHRH, whereas pituitary LH concentrations were significantly decreased in the rats treated with the analog. These results demonstrate that the LHRH agonist D-Trp-6-LHRH can counteract the hyperprolactinemic effect of haloperidol, and that this effect is not mediated by suppression of ovarian estrogens. The treatment with the analog blocked the hypersecretion of PRL by pituitary grafts, suggesting a direct effect of the analog on the pituitary gland to modulate PRL secretion.