The effect of thyrotropin-releasing hormone (TRH) on the responses to excitatory amino acids was investigated in hypoglossal motoneurones in an in vitro preparation of the brainstem from guinea pigs using current clamp and discontinuous single electrode voltage clamp (dSEVC). Bath application of 20-50 microM TRH markedly potentiated the response to iontophoretically applied NMDA, whereas no potentiation of the response to glutamate, aspartate or quisqualic acid was seen. Voltage clamp experiments showed that TRH did not increase the current flowing through NMDA channels, thus a direct modulatory role of TRH on NMDA channels was not a likely explanation of the potentiation. Voltage clamp studies of the current-voltage relationship showed that the potentiation of the response to NMDA and lack of potentiation of the response to quisqualic acid was a result of an interaction between the actions of TRH and the amino acids on the electroresponsive profile of the membrane. Endogenous NMDA receptor activation was produced by tetanic stimulation of the reticular formation dorsolaterally to the hypoglossal nucleus, evoking large APV sensitive EPSPs in the presence of CNQX, a non-NMDA blocker. The amplitude and duration of these potentials were increased at more positive membrane potentials in response to TRH. It is concluded that TRH can act as a neuromodulator-potentiating the response to NMDA receptor activation-simply by changing the electroresponsive properties of the membrane.