Fluspirilene, a neuroleptic drug which is used clinically to treat schizophrenic patients, is a dopamine D2 receptor antagonist. Besides its well-known actions on the dopamine receptors, fluspirilene also displays calcium channel-blocking activity. The aim of this study was to investigate the effect of fluspirilene on the 4-aminopyridine (4AP)-evoked glutamate release in the cerebrocortical nerve terminals (synaptosomes). Fluspirilene reduced 4AP-evoked glutamate release in a concentration-dependent manner. This inhibitory effect was associated with a decrease in the depolarization-evoked increase in the cytoplasmic free Ca2+ concentration ([Ca2+]C), which could be completely abolished by the Ca2+ channel blocker omega-CgTX GVIA. Furthermore, fluspirilene did not produce any effect on ionomycin-evoked glutamate release. These results suggest that fluspirilene inhibits glutamate release primarily by reducing presynaptic Ca2+ influx via N-type Ca2+ channels in rat cerebrocortical nerve terminals. This finding implies that presynaptic Ca2+ channel blockade concomitant with inhibition of glutamate release and possibly other neurotransmitters release may contribute to the antischizophrenic action of fluspirilene.
Copyright 2002 Wiley‐Liss, Inc.