The effects of risperidone on ionic currents in rat pituitary GH(3) cells were investigated with the aid of the patch-clamp technique. Hyperpolarization-activated K(+) currents in GH(3) cells bathed in high-K(+) Ca(2+)-free solution were studied to determine the effect of risperidone and other related compounds on the inwardly rectifying K(+) current (I(K(IR))). Risperidone (0.1-10 microM) suppressed the amplitude of I(K(IR)) in a concentration-dependent manner. The IC(50) value for the risperidone-induced inhibition of I(K(IR)) was 1 microM. Risperidone (3 microM) was found to slow the rate of activation. An increase in current deactivation by the presence of risperidone was also observed. Haloperidol (10 microM) and thioridazine (10 microM) inhibited the amplitude of I(K(IR)) effectively, and clozapine slightly suppressed it; however, metoclopramide (10 microM) had no effect on it. Risperidone (10 microM) had no effect on voltage-dependent K(+) and L-type Ca(2+) currents. However, in the inside-out configuration, risperidone (10 microM) did not alter the single-channel conductance, but reduced the activity of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels. Under the current-clamp mode, risperidone (3 microM) depolarized the membrane potential and increased the firing rate. With the aid of the spectral analysis, cells that exhibited an irregular firing pattern were also converted to those displaying a regular firing pattern after addition of risperidone (3 microM). The present study provides evidence that risperidone, in addition to the blockade of dopamine receptors, can produce a depressant effect on I(K(IR)) and BK(Ca) channels, and implies that the blockade of these ionic currents by risperidone may affect membrane excitability and prolactin secretion in GH(3) cells.