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Neuroleptics with differential affinities at dopamine D 2 receptors and sigma receptors affect differently the N‐methyl‐D‐aspartate‐induced increase in intracellular calcium concentration: Involvement of protein kinase
Author(s) -
Hayashi Teruo,
Su TsungPing,
Kagaya Ariyuki,
Nishida Akira,
Shimizu Masami,
Yamawaki Shigeto
Publication year - 1999
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/(sici)1098-2396(199901)31:1<20::aid-syn4>3.0.co;2-2
Subject(s) - sulpiride , nmda receptor , dopamine receptor d2 , chemistry , dopamine , pharmacology , haloperidol , sigma receptor , dopamine receptor , receptor , medicine , endocrinology , dopaminergic , biology , biochemistry
This study examined the effect of chronic antipsychotic treatment on the NMDA‐elicited changes in intracellular free Ca 2+ concentration ([Ca 2+ ] i ) in the primary culture of rat frontal cortical neurons. Antipsychotics used in the study were chosen for their differential affinities at dopamine D 2 receptors and sigma receptors. The potential involvement of protein kinases in this action of antipsychotics were also examined. Chronic treatment of cells with antipsychotics (sulpiride, clozapine, and chlorpromazine) which are known to be potent dopamine D 2 receptor ligands, whereas possessing low or no appreciable affinity for sigma receptors, caused a dose‐dependent potentiation of the NMDA‐induced increase in [Ca 2+ ] i . On the contrary, haloperidol, which is as potent a sigma receptor ligand as a dopamine D 2 receptor ligand, did not affect the NMDA‐elicited increase in [Ca 2+ ] i . Sulpiride increased the maximum effect afforded by different concentrations of NMDA and shifted the dose–response curve of NMDA to the left (EC 50 value from 12.5 μM to 1.39 μM). Consistent with sulpiride's affinity at dopamine D 2 receptors, this action of sulpiride was stereoselective: S(−)‐sulpiride was active whereas R(+)‐sulpiride was inactive. Treatment of cells with dopamine (3 μM) tends to decrease the NMDA‐induced increase in [Ca 2+ ] i . Sulpiride at 1 μM totally abolished this action of dopamine and restored its potentiating action on the NMDA‐induced increase in [Ca 2+ ] i . Haloperidol, a potent dopamine D 2 and sigma receptor ligand, did not affect the sulpiride's potentiating action on the NMDA‐induced responses. On the other hand, chronic treatment of cells with a sigma receptor agonist, DTG, at a concentration producing no effect of its own (10 nM), led to an enhancement of the potentiating effect of sulpiride on NMDA‐induced increase in [Ca 2+ ] i . This action of DTG was abolished by haloperidol. Further, chronic, but not acute, treatment of cells with either a protein kinase inhibitor H‐7 or a cAMP‐dependent protein kinase (PKA) inhibitor H‐89 abolished this effect of sulpiride on the NMDA‐induced [Ca 2+ ] i changes. These results indicate that the action of NMDA in the primary cortical neurons are regulated differently by ligands with differential affinities at dopamine D 2 and sigma receptors. The results with protein kinase inhibitors indicate that the potentiation of NMDA responses by sulpiride involves intracellular biochemical events. Synapse 31:20–28, 1999. Published 1999 Wiley‐Liss, Inc.