Inhibition of nicotinic acetylcholine receptors and calcium channels by clozapine in bovine adrenal chromaffin cells

Abstract

The effects of clozapine on the activities of nicotinic acetylcholine receptors (nAChRs) and voltage-sensitive calcium channels (VSCCs) were investigated and compared with those of chlorpromazine (CPZ) in bovine adrenal chromaffin cells. [H-3]Norepinephrine ([H-3]NE) secretion induced by activation of nAChRs was inhibited by clozapine and CPZ with half-maximal inhibitory concentrations (IC50) of 10.4 +/- 1.1 and 3.9. +/- 0.2 muM, respectively. Both cytosolic calcium increase and inward current in the absence of extracellular calcium induced by nicotinic stimulation were also inhibited by clozapine and CPZ, but the greater inhibition was achieved by CPZ. In addition, [H-3]nicotine binding to chromaffin cells was inhibited by clozapine and CPZ with IC50 values of approximately 19 and 2 muM, respectively. On the other hand, [H-3]NE secretion induced by high K+ was inhibited by clozapine and CPZ with similar IC50 values of 15.5 +/- 3.8 and 17.1 +/- 3.9 muM, respectively. Our results suggest that clozapine, as well as CPZ, inhibits nAChRs and VSCCs, thereby causing inhibition of catecholamine secretion, and that clozapine is much less potent than CPZ in inhibiting nAChRs. (C) 2001 Elsevier Science Inc. All rights reserved.