Differential effects of long-term treatment with clozapine or haloperidol on GABAA receptor binding and GAD67 expression

Zink, M., Schmitt, A., May, B., Muller, B., Demirakca, T., Braus, D. F., Henn, F. A. (February 2004) Differential effects of long-term treatment with clozapine or haloperidol on GABAA receptor binding and GAD67 expression. Schizophr Res, 66 (2-3). pp. 151-7. ISSN 0920-9964 (Print)

URL: http://www.ncbi.nlm.nih.gov/pubmed/15061247
DOI: 10.1016/s0920-9964(03)00088-4

Abstract

One of the most consistent findings in postmortem studies of schizophrenia is increased GABAA receptor binding and reduced glutamic acid decarboxylase (GAD67) expression. Due to long-term antipsychotic treatment before death, these findings may reflect not only the consequences of schizophrenia but also medication effects. To differentiate between these options, we used an animal model and evaluated long-term effects of typical (haloperidol) and atypical (clozapine) antipsychotic drugs on the GABAergic system. A total of 33 adult male rats were treated in three cohorts over a period of 6 months. One cohort of 11 animals received clozapine (45 mg/kg/day), another one received haloperidol (1.5 mg/kg/day) and a third one received pH-adapted minimal concentrations of HCl in the drinking water. Receptor autoradiography of the GABAA receptor ([3H]-muscimol binding) and in situ hybridization in adjacent sections with 35S-labeled cRNA probes of the y-aminobutyric acid (GABA)-producing enzyme, GAD67, was performed. While haloperidol increased GABAA receptor binding in striatum and nucleus accumbens (NA), it suppressed GABAA receptor binding in temporal (TEMPC) and parietal (PARC) cortex. Clozapine induced GABAA receptor binding in infralimbic cortex (ILC) and similar like haloperidol in anterior cingulate cortex (ACC), two regions of the limbic cortex. In addition, either drug increased gene expression of GAD67. It is concluded that antipsychotic drugs differentially alter the GABAergic system, strongly suggesting that drug effects are partially responsible for the up-regulation of GABAA receptor binding in certain brain regions as observed in postmortem brains of schizophrenic patients. However, the reduced GAD67 expression seen in postmortem brains does not appear to reflect drug effects, since our animal model demonstrated increased gene expression.

Item Type: Paper
Uncontrolled Keywords: Animals Antipsychotic Agents/administration & dosage/ pharmacology/ therapeutic use Binding Sites Clozapine/administration & dosage/ pharmacology/ therapeutic use Disease Models, Animal Drug Administration Schedule Glutamate Decarboxylase/ genetics/ metabolism Haloperidol/administration & dosage/ pharmacology/ therapeutic use Isoenzymes/ genetics/ metabolism Limbic System/metabolism Male Parietal Lobe/metabolism RNA, Complementary/genetics Rats Rats, Sprague-Dawley Receptors, GABA-A/ metabolism Schizophrenia/ drug therapy/ metabolism Temporal Lobe/metabolism Up-Regulation/drug effects
Subjects: diseases & disorders
bioinformatics > genomics and proteomics > small molecules > GABA
diseases & disorders > mental disorders
diseases & disorders > mental disorders > schizophrenia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein receptor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > small molecules
CSHL Authors:
Communities: CSHL labs > Henn lab
Depositing User: Matt Covey
Date: 1 February 2004
Date Deposited: 04 Mar 2013 21:31
Last Modified: 04 Mar 2013 21:31
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27700

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