The effects of physalaemin on thyrotropin-releasing hormone (TRH) and thyrotropin (TSH) secretion were studied in rats. Physalaemin (150 micrograms/kg) was injected iv, and the rats were serially decapitated. TRH, TSH and thyroid hormone were measured by radioimmunoassay. The hypothalamic immunoreactive TRH (ir-TRH) contents increased significantly after physalaemin injection, whereas its plasma concentrations tended to decrease, but not significantly. The plasma TSH levels decreased significantly in a dose-related manner with a nadir at 30 min. The plasma ir-TRH and TSH responses to cold were inhibited by physalaemin, but the plasma TSH response to TRH was not affected. The plasma thyroid hormone levels did not change significantly. In the pimozide- or para-chlorophenylalanine-pretreated group, the inhibitory effect of physalaemin on TSH levels was prevented, but not in the L-DOPA- or 5-hydroxytryptophan-pretreated group. These drugs alone did not affect plasma TSH levels in terms of the dose used. The inactivation of TRH immunoreactivity by the hypothalamus or plasma in vitro after physalaemin injection did not differ from that of the control. These findings suggest that physalaemin acts on the hypothalamus to inhibit TRH release, and its effects are at least partially modified by amines of the central nervous system.