Characterization of inhibition by risperidone of the inwardly rectifying K+ current in pituitary GH(3) cells

The effects of risperidone on ionic currents in rat pituitary GH(3) cells w ere investigated with the aid of the patch-clamp technique. Hyperpolarizati on-activated K+ currents in GH(3) cells bathed in high-K+ Ca-2 -free soluti on were studied to determine the effect of risperidone and other related co mpounds on the inwardly rectifying K+ current (I-K(IR)). Risperidone (0.1-1 0 muM) suppressed the amplitude of I-K(IR) in a concentration-dependent man ner. The IC50 value for the risperidone-induced inhibition of I-K(IR) was 1 muM. Risperidone (3 muM) was found to slow the rate of activation. An incr ease in current deactivation by the presence of risperidone was also obeser ved. Haloperidol (10 muM) and thioridazine (10 muM) inhibited the amplitude of I-K(IR) effectively, and clozapine slightly suppressed it; however, met oclopramide (10 muM) had no effect on it. Risperidone (10 muM) had no effec t on voltage-dependent K+ and L-type Ca2+ currents. However, in the inside- out configuration, risperidone (10 muM) did not alter the single-channel co nductance, but reduced the activity of larconductance Ca2+-activated K+ (BK Ca) channels. Under the current-clamp mode, risperidone (3 muM) depolarized the membrane potential and increased the firing rate. With the and of the spectral analysis, cells that exhibited an irregular firing pattern were al so converted to those displaying a regular firing pattern after addition of risperidone (3 muM). The present study provides evidence that risperidone, in addition to the blockade of dopamine receptors, can produce a depressan t effect on I-K(IR) and BKCa channels, and implies that the blockade of the se ionic currents by risperidone may affect membrane excitability and prola ctin secretion in GH(3) cells. (C) 2000 American College of Neuropsychophar macology. Published by Elsevier Science Inc.