Inhibition by antipsychotic drugs of L-type Ca2+ channel current in PC12 cells

Inhibition by antipsychotic drugs of voltage-gated L-type Ca2+ channels was characterized in rat neuronal cell line pheochromocytoma PC12 cells. Under whole-cell voltage-clamp, haloperidol and chlorpromazine (1-100 microM) inhibited Ba2+ current permeating through Ca2+ channels. Fluspirilene and pimozide the Ba2+ current at lower concentrations (fluspirilene, 0.1 pM to 1 nM; pimozide 10 pM to 1 microM). Effects of dopamine receptor antagonists and calmodulin antagonists were tested because antipsychotic drugs are known to exhibit these pharmacological activities. Sulpiride (1 and 10 microM), an antagonist to dopamine D2 receptors, and SCH-23390 (R(+)-7-chloro-8-hydroxy-3-methyl-l-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine; 1 and 10 microM), an antagonist to dopamine D1 receptors, also inhibited the Ba2+ current. As for calmodulin antagonists, W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; 10 and 100 microM) as well as calmidazolium (10 nM to 1 microM) reduced the Ba2+ current. The inhibition by haloperidol or fluspirilene of the Ba2+ current was not affected when GTP in intracellular solution was replaced with GDP beta S. These properties of the Ca2+ channel inhibition are discussed by comparing with those of the K+ channel inhibition and in relation to therapeutic relevance.