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

Atypical neuroleptics including fluspirilene and pimozide differ in their clinical actions from typical neuroleptics including haloperidol and chlorpromazine. We have found that these two groups of neuroleptics differently affect voltage-gated ion channels. In PC12 cells, a neuronal cell line derived from a rat pheochromocytoma, fluspirilene and pimozide inhibit Ba2+ current mediated through L-type Ca2+ channels at nanomolar or subnanomolar concentrations. 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 other-hand, haloperidol and chlorpromazine block both the L-type Ca2+ channels and the K+ channels at similar concentrations of micromolars. Pharmacological characterization has indicated that the L-type Ca2+ channel inhibition is not due to the antagonism at dopamine receptors, a major mechanism underlying 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 such low concentrations. This selective inhibition of L-type Ca2+ channels may be related to the relief by atypical neuroleptics of the negative symptoms of schizophrenia.