The physiological relevance of the recently described prolactin-releasing peptides (PrRPs) has yet to be established. Here, we demonstrate the low potency of the PrRPs (minimum effective dose: 100 nM), compared to that observed for thyrotropin-releasing hormone (TRH, minimum effective dose: 1.0 nM), to stimulate prolactin (PRL) release from cultured pituitary cells harvested from lactating female rats. Anatomic studies question the role of these peptides in neuroendocrine control of lactotroph function. Instead, peptide and peptide receptor mapping studies suggest potential actions in hypothalamus and brainstem unrelated to the control of anterior pituitary hormone secretion. Intracerebroventricular (i.c.v. ) administration of both PrRP-20 and PrRP-31 (0.4 and 4.0 nmol) resulted in significantly increased mean arterial blood pressure in conscious, unrestrained rats [peak elevations vs. baseline: PrRP-20, 10% and 16%, low and high dose peptide; PrRP-31, 7% and 10%; compared to the response to 0.1 nmol angiotensin II (A II), 15-17%]. Similar doses of peptide did not significantly alter water drinking in response to overnight fluid deprivation, or thirst or salt appetite in response to an isotonic hypovolemic challenge. Thus, the effect on blood pressure appeared relatively specific. We suggest that these peptides, identified originally as ligands for a receptor found in abundance in pituitary gland, play a broader role in brain function and that the ability of them to stimulate PRL release may not represent their primary biologic function.