Inhibition of neuronal nitric oxide synthase by antipsychotic drugs.
There is rapidly accumulating evidence that generation of nitric oxide (NO) through a Ca2+ and calmodulin-dependent pathway plays various important roles in the central nervous system. In the present study, effects of several antipsychotics on the activity of NO synthase were investigated in rat cerebellum and neuroblastoma N1E-115 cells, due to the known ability of these agents to inhibit calmodulin. In cytosolic preparations of rat cerebellum, the antipsychotic drugs inhibited the conversion of [3H]L-arginine into [3H]L-citrulline by NO synthase in a concentration-dependent manner. This inhibition was noncompetitive in nature, and it exhibited an excellent correlation with blockade of calmodulin activity. Furthermore, these drugs attenuated cyclic GMP formation induced by a calcium ionophore in N1E-115 cells, a response which takes place as a consequence of NO generation. Taken together, our data demonstrate that antipsychotic drugs inhibit NO formation in vitro. It is unlikely, however, that these actions might contribute to their therapeutic and/or side effects, since they take place at relatively high concentrations.
Hu
J
J
Division of Neuroscience Research in Psychiatry, University of Minnesota Medical School, Minneapolis 55455.
Lee
J H
JH
el-Fakahany
E E
EE
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D019001:Nitric Oxide Synthase; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D014150:Antipsychotic Agents; D002147:Calmodulin; D010726:Phosphodiesterase Inhibitors; D002956:Citrulline; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP