Abstract
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.
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References
Bon C, Böhme GA, Doble A, Stutzmann J-M, Blanchard J-C (1992) A role for nitric oxide in long-term potentiation. Eur J Neurosci 4:420–424
Bredt DS, Snyder SH (1989) Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci USA 86:9030–9033
Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 87:682–685
Bredt DS, Ferris CD, Snyder SH (1992) Nitric oxide synthase regulatory sites. J Biol Chem 267:10976–10981
Brüne B, Lapetina EG (1989) Activation of a cytosolic ADP-ribosyltransferase by nitric oxide-generating agents. J Biol Chem 264:8455–8458
Busse R, Mülsch A (1990) Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett 265:133–136
Dawson VL, Dawson TM, London ED, Bredt DS, Synder SH (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 88:6368–6371
El-Fakahany EE, Richelson E (1980) Regulation of muscarinic receptor-mediated cyclic GMP synthesis by cultured mouse neuroblastoma cells. J Neurochem 35:941–948
Förstermann U, Schmidt HHHW, Pollock JS, Heller M, Murad F (1991) Enzyme synthesizing guanylate cyclase-activating factors in endothelial cells, neuroblastoma cells, and rat brain. J Cardiovasc Pharmacol 17 [suppl. 3]:S57-S64
Haley JE, Wilcox GL, Chapman PF (1992) The role of nitric oxide in hippocampal long-term potentiation. Neuron 8:211–216
Ignarro LJ (1992) Haem-dependent activation of cytosolic guanylate cyclase by nitric oxide: a widespread signal transduction mechanism. Biochem Soc Trans 20:465–469
Lau Y-S, Gnegy ME (1982) Chronic haloperidol treatment increased calcium-dependent phosphorylation in rat striatum. Life Sci 30:21–28
Loiacono RE, Beart PM (1992) Hippocampal lesion induced by microinjection of the nitric oxide donor nitroprusside. Eur J Pharmacol 216:331–333
Lowry O, Rosebrough NJ, Farr L, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142
Nowicki JP, Duval D, Poignet H, Scatton B (1991) Nitric oxide mediates neuronal death after focal cerebral ischemia in the mouse. Eur J Pharmacol 204:339–340
Pou WS, Pou S, Rosen GM, El-Fakahany EE (1990) EDRF release is a common pathway in the activation of guanylate cyclase by receptor agonists and calcium ionophores Eur J Pharmacol 182:393–394
Prozialeck WC, Weiss B (1982) Inhibition of calmodulin by phenothiazine and related drugs: structure-activity relationships. J Pharmacol Exp Ther 222:509–516
Richelson E (1985) Pharmacology of neuroleptics in use in the United States J Clin Psychiatry 46:8–14
Schini VB, Vanhoutte PM (1992) Inhibitors of calmidazolium impair the constitutive but not the inducible nitric oxide synthase activity in the rat aorta. J Pharmacol Exp Ther 261:553–559
Seeman P (1992) Dopamine receptor sequences, therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4 Neuropsychopharmacology 7:261–284
Snyder SH (1992) Nitric oxide: first in a new class of neurotransmitters? Science 257:494–496
Weiss B, Fertel R, Figlin R, Uzunov P (1974) selective alteration of the activity of the multiple forms of adenosine 3′,5′-monophosphate phosphodiesterase of rat cerebellum. Mol Pharmacol 10:615–625
Weiss B, Prozialeck WC, Wallace TL (1982) Interaction of drugs with calmodulin. Biochem Pharmacol 31:2217–2226
Williams MB, Li X, Gu X, Jope RS (1992) Modulation of endogenous ADP-ribosylation in rat brain. Brain Res 592:49–56
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Hu, J., Lee, JH. & El-Fakahany, E.E. Inhibition of neuronal nitric oxide synthase by antipsychotic drugs. Psychopharmacology 114, 161–166 (1994). https://doi.org/10.1007/BF02245458
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DOI: https://doi.org/10.1007/BF02245458