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Intracellular Modulation of NMDA Receptor Function by Antipsychotic Drugs

Jean-Christophe Leveque¹, Wendy Macías¹, Anjali Rajadhyaksha², Richard R. Carlson², Amy Barczak¹, Stanley Kang¹, Xin-Min Li³, Joseph T. Coyle⁴, Richard L. Huganir⁵, Stephan Heckers⁴, and Christine Konradi^{1, 2, 4}

¹ Molecular and Developmental Neuroscience Laboratory and Department of Psychiatry, Massachusetts General Hospital East, Charlestown, Massachusetts 02129, ² Laboratory of Neuroplasticity, McLean Hospital, Belmont, Massachusetts 02478, ³ Department of Psychiatry, Royal University Hospital, Saskatoon, S7N 0W8 Canada, ⁴ Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, and ⁵ Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

The present study deals with the functional interaction of antipsychotic drugs and NMDA receptors. We show that both the conventional antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine mediate gene expression via intracellular regulation of NMDA receptors, albeit to different extents. Data obtained in primary striatal culture demonstrate that the intraneuronal signal transduction pathway activated by haloperidol, the cAMP pathway, leads to phosphorylation of the NR1 subtype of the NMDA receptor at ⁸⁹⁷Ser. Haloperidol treatment is likewise shown to increase ⁸⁹⁷Ser-NR1 phosphorylation in rats in vivo. Mutation of ⁸⁹⁶Ser and ⁸⁹⁷Ser to alanine, which prevents phosphorylation at both sites, inhibits cAMP-mediated gene expression. We conclude that antipsychotic drugs have the ability to modulate NMDA receptor function by an intraneuronal signal transduction mechanism. This facilitation of NMDA activity is necessary for antipsychotic drug-mediated gene expression and may contribute to the therapeutic benefits as well as side effects of antipsychotic drug treatment.

Key words: haloperidol; clozapine; D2 receptors; NMDA; c-fos; proenkephalin; striatum; CREB; tardive dyskinesia

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20114011-10$05.00/0

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