The manner by which dopaminergic and TRH mechanisms interact to control PRL release is not known. Whilst dopamine receptor antagonists and TRH both release PRL, it is not known if the PRL released by these two mechanisms reflects similar aspects of physiological control, or if PRL responses to these mechanisms of release can be dissociated. We addressed this question by studying the PRL responses to maximal stimulatory dose of TRH and domperidone (a DA receptor antagonist), which were administered sequentially, simultaneously or separately on different occasions. Six normal volunteers undertook three sets of studies: (1) standard PRL stimulation tests to 400 micrograms TRH, 5 mg domperidone or simultaneous TRH/domperidone administration, (2) domperidone bolus-infusion study in which either 5 mg domperidone or 400 micrograms TRH was administered i.v. at 120 min during a 240 min infusion of domperidone (50 micrograms/min) which was preceded by a 5 mg i.v. bolus of the drug, and (3) TRH bolus-infusion study in which domperidone or TRH was administered i.v. at 120 min during a 240 min infusion of TRH (0.4 micrograms/min) which was preceded by a 400 micrograms i.v. bolus of the drug. In Study 1, simultaneous TRH/domperidone administration induced an incremental rise in PRL (5195 +/- 940 mIU/l) which was significantly greater (P less than 0.0005) than with either domperidone (3730 +/- 825 mIU/l) or TRH (1335 +/- 300 mIU/l) alone. In study 2, TRH administration at 120 min resulted in a significant rise (P less than 0.01) in PRL (delta PRL 960 +/- 232 mIU/l) whilst the second dose of domperidone did not, thus suggesting that the initial bolus and subsequent infusion had resulted in complete DA receptor blockade. In Study 3, domperidone administered at 120 min induced a marked rise in PRL (delta PRL 3609 +/- 963 mIU/l). In contrast, the corresponding TRH stimulus resulted in a small rise (delta PRL 142 +/- 32 mIU/l) suggesting that the PRL release induced by the initial bolus and subsequent infusion had been near maximal. Thus, TRH is able to induce significant PRL release in the presence of maximal DA receptor blockade, and domperidone, in the presence of maximal TRH stimulation, is also capable of inducing significant PRL release. These observations together with the ability of TRH/domperidone to induce a greater PRL response than either agent alone, suggest that each stimulus has a specific releasing action on a fraction of intracellular PRL which is not accessible to the other.(ABSTRACT TRUNCATED AT 400 WORDS)