The mechanisms of prolactin (PRL) unresponsiveness to repeated sulpiride (SUL) injections were investigated in 7 normal males. The experimental protocol consisted of two phases, separated by a 5 day interval. In both phases the administration of 1 mg/kg i.m. of SUL was followed 24 hours later, by the administration of the same dose of SUL together with either placebo (PL, 2 ml saline i.v.) or TRH (200 mcg i.v.). A control TRH test (200 mcg i.v.) was also performed. PRL showed a significant increase after the administration of SUL alone in both phases. Twenty-four hours later plasma PRL was still higher than the basal level and it was not significantly modified by administration of SUL + PL, or by SUL + TRH. The data seem to show that the lack of responsiveness of PRL to repeated administration of SUL is not due to refractoriness of dopaminergic receptors but probably to exhaustion of the hypophyseal PRL pool.