Home LiteratureArticle Details
PMID: 10818136 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Intracellular modulation of NMDA receptor function by antipsychotic drugs.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 20 ·No. 11 ·2000-06-01 ·Pages 4011-20

Leveque JC, Macías W, Rajadhyaksha A, Carlson RR, Barczak A, Kang S, Li XM, Coyle JT, Huganir RL, Heckers S, Konradi C

Abstract

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 (897)Ser. Haloperidol treatment is likewise shown to increase (897)Ser-NR1 phosphorylation in rats in vivo. Mutation of (896)Ser and (897)Ser 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.

MeSH Terms
Animals Antipsychotic Agents/antagonists & inhibitors,pharmacology Blotting, Northern Cells, Cultured Clozapine/antagonists & inhibitors,pharmacology Cycloserine/pharmacology Dizocilpine Maleate/pharmacology Excitatory Amino Acid Agonists/pharmacology Excitatory Amino Acid Antagonists/pharmacology Gene Expression Regulation/drug effects Genes, fos/genetics Haloperidol/antagonists & inhibitors,pharmacology Male Neostriatum/drug effects,metabolism Neurons/drug effects,metabolism Phosphorylation Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate/biosynthesis,drug effects,genetics Signal Transduction/drug effects
Chemicals
Antipsychotic Agents Excitatory Amino Acid Agonists Excitatory Amino Acid Antagonists Receptors, N-Methyl-D-Aspartate Dizocilpine Maleate Cycloserine Clozapine Haloperidol
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Leveque J C
Molecular and Developmental Neuroscience Laboratory and Department of Psychiatry, Massachusetts General Hospital East, Charlestown, Massachusetts 02129, USA.
Macías W
Rajadhyaksha A
Carlson R R
Barczak A
Kang S
Li X M
Coyle J T
Huganir R L
Heckers S
Konradi C
References (49)
49 references, click to expand
  1. Isolation of RNA.
    Methods Enzymol. 1989;180:3-13 PMID: 2482420
  2. Competitive antagonists and partial agonists at the glycine modulatory site of the mouse N-methyl-D-aspartate receptor.
    J Physiol. 1990 Nov;430:189-212 PMID: 1707965
  3. Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine.
    Neuroscience. 1992;46(2):315-28 PMID: 1347406
  4. L-Type Ca(2+) channels are essential for glutamate-mediated CREB phosphorylation and c-fos gene expression in striatal neurons.
    J Neurosci. 1999 Aug 1;19(15):6348-59 PMID: 10414964
  5. Regulation of NMDA receptor phosphorylation by alternative splicing of the C-terminal domain.
    Nature. 1993 Jul 1;364(6432):70-3 PMID: 8316301
  6. The cAMP-response-element-binding protein interacts, but Fos protein does not interact, with the proenkephalin enhancer in rat striatum.
    Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7005-9 PMID: 8346209
  7. p1B15: a cDNA clone of the rat mRNA encoding cyclophilin.
    DNA. 1988 May;7(4):261-7 PMID: 3293952
  8. A DNA cassette containing a trimerized SV40 polyadenylation signal which efficiently blocks spurious plasmid-initiated transcription.
    Biotechniques. 1989 Mar;7(3):276-80 PMID: 2561060
  9. Calcium influx via the NMDA receptor induces immediate early gene transcription by a MAP kinase/ERK-dependent mechanism.
    J Neurosci. 1996 Sep 1;16(17):5425-36 PMID: 8757255
  10. Tardive dyskinesia and substrates of energy metabolism in CSF.
    Am J Psychiatry. 1995 Dec;152(12):1730-6 PMID: 8526238
  11. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects.
    Arch Gen Psychiatry. 1992 Jul;49(7):538-44 PMID: 1352677
  12. Proteins bound at adjacent DNA elements act synergistically to regulate human proenkephalin cAMP inducible transcription.
    EMBO J. 1988 Dec 1;7(12):3793-805 PMID: 2850173
  13. NMDA receptor antagonists inhibit catalepsy induced by either dopamine D1 or D2 receptor antagonists.
    Eur J Pharmacol. 1993 Jun 11;237(1):1-7 PMID: 8359205
  14. Analysis of the proenkephalin second messenger-inducible enhancer in rat striatal cultures.
    J Neurochem. 1995 Sep;65(3):1007-15 PMID: 7643080
  15. D2 dopamine receptor antagonists induce fos and related proteins in rat striatal neurons.
    Neuroscience. 1990;37(2):287-94 PMID: 1966822
  16. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine.
    Nature. 1991 Apr 18;350(6319):610-4 PMID: 1840645
  17. A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia.
    Arch Gen Psychiatry. 1999 Jan;56(1):21-7 PMID: 9892252
  18. Glutamate receptor phosphorylation and synaptic plasticity.
    Curr Opin Neurobiol. 1994 Jun;4(3):383-8 PMID: 7919933
  19. Differential expression of c-fos and zif268 in rat striatum after haloperidol, clozapine, and amphetamine.
    Proc Natl Acad Sci U S A. 1992 May 15;89(10):4270-4 PMID: 1374894
  20. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia.
    Cell. 1999 Aug 20;98(4):427-36 PMID: 10481908
  21. Characterization of protein kinase A and protein kinase C phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit using phosphorylation site-specific antibodies.
    J Biol Chem. 1997 Feb 21;272(8):5157-66 PMID: 9030583
  22. A cyclic AMP- and phorbol ester-inducible DNA element.
    Nature. 1986 Sep 25-Oct 1;323(6086):353-6 PMID: 3020428
  23. Cyclic AMP-dependent protein kinase and protein kinase C phosphorylate N-methyl-D-aspartate receptors at different sites.
    J Biol Chem. 1997 May 2;272(18):12107-15 PMID: 9115280
  24. Loss of haloperidol induced gene expression and catalepsy in protein kinase A-deficient mice.
    Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12157-61 PMID: 9342379
  25. Effects of chronic haloperidol and clozapine treatment on neurotensin and c-fos mRNA in rat neostriatal subregions.
    J Pharmacol Exp Ther. 1994 Oct;271(1):460-71 PMID: 7965747
  26. Modulation of striatal enkephalinergic neurons by antipsychotic drugs.
    Fed Proc. 1985 Jun;44(9):2535-9 PMID: 3838946
  27. Intracellular cAMP regulates the response to NMDA in hippocampal neurons.
    Neuroreport. 1991 Nov;2(11):673-6 PMID: 1667271
  28. Dose-finding trial of D-cycloserine added to neuroleptics for negative symptoms in schizophrenia.
    Am J Psychiatry. 1995 Aug;152(8):1213-5 PMID: 7625475
  29. Haloperidol-induced Fos expression in striatum is dependent upon transcription factor cyclic AMP response element binding protein.
    Neuroscience. 1995 Apr;65(4):1051-61 PMID: 7617161
  30. Quantitative light microscopic demonstration of increased pallidal and striatal met5-enkephalin-like immunoreactivity in rats following chronic treatment with haloperidol but not with clozapine: implications for the pathogenesis of neuroleptic-induced movement disorders.
    Exp Neurol. 1992 Jul;117(1):17-27 PMID: 1618284
  31. Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation.
    Nature. 1992 Apr 9;356(6369):521-3 PMID: 1373227
  32. MK 801 reverses haloperidol-induced catalepsy from both striatal and extrastriatal sites in the rat brain.
    Eur J Pharmacol. 1997 Aug 6;332(2):153-60 PMID: 9286616
  33. An overview of the mechanism of action of clozapine.
    J Clin Psychiatry. 1994 Sep;55 Suppl B:47-52 PMID: 7961573
  34. Induction patterns of Fos-like immunoreactivity in the forebrain as predictors of atypical antipsychotic activity.
    J Pharmacol Exp Ther. 1994 Nov;271(2):1058-66 PMID: 7965768
  35. Regulation of NMDA receptors by tyrosine kinases and phosphatases.
    Nature. 1994 May 19;369(6477):233-5 PMID: 7514272
  36. Glutamate agonist activity: implications for antipsychotic drug action and schizophrenia.
    Neuroreport. 1995 Dec 15;6(18):2500-4 PMID: 8741750
  37. Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum.
    J Comp Neurol. 1996 Oct 7;374(1):70-83 PMID: 8891947
  38. Dopamine receptor gene expression by enkephalin neurons in rat forebrain.
    Proc Natl Acad Sci U S A. 1990 Jan;87(1):230-4 PMID: 2296581
  39. D-cycloserine added to clozapine for patients with schizophrenia.
    Am J Psychiatry. 1996 Dec;153(12):1628-30 PMID: 8942463
  40. Cloned glutamate receptors.
    Annu Rev Neurosci. 1994;17:31-108 PMID: 8210177
  41. Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex.
    Science. 1999 Jul 2;285(5424):93-6 PMID: 10390370
  42. Molecular components of striatal plasticity: the various routes of cyclic AMP pathways.
    Dev Neurosci. 1998;20(2-3):204-15 PMID: 9691194
  43. Regulated subcellular distribution of the NR1 subunit of the NMDA receptor.
    Science. 1995 Sep 22;269(5231):1734-7 PMID: 7569904
  44. Glycine potentiates the NMDA response in cultured mouse brain neurons.
    Nature. 1987 Feb 5-11;325(6104):529-31 PMID: 2433595
  45. New insights into how antipsychotic drugs might work.
    Harv Rev Psychiatry. 1993 May-Jun;1(1):68-9 PMID: 9384831
  46. Striatal N-methyl-D-aspartate receptors in haloperidol-induced catalepsy.
    Eur J Pharmacol. 1991 Oct 15;203(2):173-80 PMID: 1686859
  47. The NMDA receptor antagonist MK-801 markedly reduces the induction of c-fos gene by haloperidol in the mouse striatum.
    Neurosci Lett. 1993 Jun 25;156(1-2):39-42 PMID: 8414186
  48. Beta-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase.
    Neuron. 1996 Feb;16(2):415-21 PMID: 8789956
  49. Involvement of adenosine and glutamate receptors in the induction of c-fos in the striatum by haloperidol.
    Synapse. 1996 Jan;22(1):70-7 PMID: 8822480
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2000-06-01
Pages
4011-20
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC4203343
Subset
IM
Grants
NIDA NIH HHS · R01 DA007134-14 · United States
NIDA NIH HHS · DA07134 · United States
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2