Responses of substantia nigra zona compacta neurons to nomifensine and amantadine were studied with intracellular recording techniques (current and voltage clamp) in in vitro slice preparation of rat mesencephalon. The application of nomifensine (1-10 microM) slightly hyperpolarized the cells and inhibited action potential discharge that occurs spontaneously. In voltage-clamp experiments (-50, -60 mV, holding potential) an outward current was observed. The membrane responses to exogenously-applied dopamine were potentiated by the concomitant superfusion of nomifensine. The effects of nomifensine were antagonized by (-)-sulpiride (1 microM), a D2 receptor antagonist. By contrast, the superfusion of amantadine (1-30 microM) on substantia nigra zona compacta cells was ineffective on firing rate, membrane potential or on sensitivity to exogenous dopamine. In the presence of high doses (300 microM to 1 mM) of amantadine a depolarization and an increase in firing activity was observed. While our results provide electrophysiological evidence for an inhibition of the dopamine uptake system by nomifensine, they do not support a dopaminergic mechanism for the actions of amantadine in the substantia nigra zona compacta.