Effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits

Schmitt, A., Zink, M., Muller, B., May, B., Herb, A., Jatzko, A., Braus, D. F., Henn, F. A. (February 2003) Effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits. Neurochemical Research, 28 (2). pp. 235-41. ISSN 0364-3190

Abstract

Postmortem studies in schizophrenic patients revealed alterations in NMDA receptor binding and gene expression of specific subunits. Because most of the patients had been treated with antipsychotics over long periods, medication effects might have influenced those findings. We treated animals with haloperidol and clozapine in clinical doses to investigate the effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits. Rats were treated with either haloperidol (1.5 mg/kg/day) or clozapine (45 mg/kg/day) given in drinking water over a period of 6 months. Quantitative receptor autoradiography with [3H]-MK-801 was used to examine NMDA receptor binding. In situ hybridization was performed for additional gene expression studies of the NR1, NR2A, NR2B, NR2C, and NR2D subunits. [3H]-MK-801 binding was found to be increased after haloperidol treatment in the striatum and nucleus accumbens. Clozapine was shown to up-regulate NMDA receptor binding only in the nucleus accumbens. There were no alterations in gene expression of NMDA subunits in any of the three regions. However, the NR2A subunit was down-regulated in the hippocampus and prefrontal cortex by both drugs, whereas only clozapine induced a down-regulation of NR1 in the dorsolateral prefrontal cortex. NR2B, 2C, and 2D subunits did not differ between treatment groups and controls. Both altered NMDA receptor binding and subunit expression strengthen a hyperglutamatergic function after haloperidol treatment and may contribute to some of our postmortem findings in antipsychotically treated schizophrenic patients. Because the effects seen in different brain areas clearly vary between haloperidol and clozapine, they may also be responsible for some of the differences in efficacy and side effects.

Item Type:	Paper
Uncontrolled Keywords:	Animals Antipsychotic Agents/administration & dosage/ pharmacology Autoradiography Clozapine/administration & dosage/ pharmacology Gene Expression/ drug effects Haloperidol/administration & dosage/ pharmacology Male Protein Binding Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate/genetics/ metabolism
Subjects:	diseases & disorders > mental disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:	Henn, Fritz A.
Communities:	CSHL labs > Henn lab
Depositing User:	Matt Covey
Date:	February 2003
Date Deposited:	01 Jul 2013 16:32
Last Modified:	01 Jul 2013 16:32
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/27891

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