Selective inhibition by fluspirilene and pimozide of L-type Ca2+ channels

Atypical neuroleptics including fluspirilene and pimozide differ in their c linical actions from typical neuroleptics including haloperidol and chlorpr omazine. We have found that these two groups of neuroleptics differently af fect voltage-gated ion channels. In PC12 cells, a neuronal cell line derive d from a rat pheochromocytoma, fluspirilene and pimozide inhibit Ba2+ curre nt mediated through L-type Ca2+ channels at nanomolar or subnanomolar conce ntrations. These compounds also inhibit ionic current through voltage-gated K+ channels, but the concentration required for the K+ channel inhibition is much higher than that for the L-type Ca2+ channel inhibition. On the oth er-hand, haloperidol and chlorpromazine block both the L-type Ca2+ channels and the K+ channels at similar concentrations of micromolars. Pharmacologi cal characterization has indicated that the L-type Ca2+ channel inhibition is not due to the antagonism at dopamine receptors, a major mechanism under lying the relief by neuroleptics of the positive symptoms of schizophrenia. The inhibition by fluspirilene and pimozide of L-type Ca2+ is distinctive because no other types of Ca2+ channels are blocked by these compounds at s uch low concentrations. This selective inhibition of L-type Ca2+ channels m ay be related to the relief by atypical neuroleptics of the negative sympto ms of schizophrenia.