Characterization of Inhibition by Risperidone of the Inwardly Rectifying K+ Current in Pituitary GH3 Cells

Abstract

The effects of risperidone on ionic currents in rat pituitary GH3 cells were investigated with the aid of the patch-clamp technique. Hyperpolarization-activated K+ currents in GH3 cells bathed in high-K+ Ca2+-free solution were studied to determine the effect of risperidone and other related compounds on the inwardly rectifying K+ current (IK(IR)). Risperidone (0.1–10 μM) suppressed the amplitude of IK(IR) in a concentration-dependent manner. The IC50 value for the risperidone-induced inhibition of IK(IR) was 1 μM. Risperidone (3 μM) was found to slow the rate of activation. An increase in current deactivation by the presence of risperidone was also observed. Haloperidol (10 μM) and thioridazine (10 μM) inhibited the amplitude of IK(IR) effectively, and clozapine slightly suppressed it; however, metoclopramide (10 μM) had no effect on it. Risperidone (10 μM) had no effect on voltage-dependent K+ and L-type Ca2+ currents. However, in the inside-out configuration, risperidone (10 μM) did not alter the single-channel conductance, but reduced the activity of large-conductance Ca2+-activated K+ (BKCa) channels. Under the current-clamp mode, risperidone (3 μM) 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 μM). The present study provides evidence that risperidone, in addition to the blockade of dopamine receptors, can produce a depressant effect on IK(IR) and BKCa channels, and implies that the blockade of these ionic currents by risperidone may affect membrane excitability and prolactin secretion in GH3 cells.