Thirty five nmoles of pyrilamine (a H1-histamine antagonist) or metiamide (a H2-histamine antagonist) in 1 microliter of saline solution were injected into the preoptic-anterior hypothalamic area (POA-AHA) of estrogen-treated ovariectomized rats. Forty-eight hours later animals were bled between 15:00 and 20:00 hr. Prolactin (PRL) plasma levels were measured by RIA. The anti-histamine treatment altered the PRL surge normally observed 72 hr after the estrogen injection in these animals under this experimental schedule. Rats receiving metiamide showed a normal PRL surge but the hormone levels remained high at the end of the sampling period. Rats receiving pyrilamine instead, showed depressed PRL levels at 16:00-18:00 hr but sustained high hormone levels at 19:00-20:00 hr. Pyrilamine administration at lower doses (17.5 and 8.75 nmoles/microliter) still interfered with the PRL surge. The present data suggest that histamine receptors present in the POA-AHA are involved in the PRL release due to estrogen and that both H1 and H2-histamine receptors may be mediators of this response.