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 mu M) inhibited Ba2+ current permeating through Ca2+ channels. Fluspirilene and pimozide inhibited the Ba2+ current at lower concentrations (fluspirilene, 0.1 pM to 1 nM; pimozide 10 pM to 1 mu M). Effects of dopamine receptor antagonists and calmodulin antagonists were tested because antipsychotic drugs are known to exhibit these pharmacological activities. Sulpiride (1 and 10 mu M), an antagonist to dopamine D-2 receptors, and SCH-23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 1 and 10 mu M), an antagonist to dopamine D-2 receptors, also inhibited the Ba2+ current. As for calmodulin antagonists, W-7(N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; 10 and 100 mu M) as well as calmidazolium (10 nM to 1 mu M) 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.