Abstract
To test the hypothesis that clozapine-induced reduction of glutamate transporter-1 (GLT-1) expression is mediated by astrocytes, we studied the effects of clozapine on Glu transporters and Glu uptake in primary astrocyte cultures of the cerebral cortex. Astrocyte cultures treated for 48 h with clozapine exhibited a reduction in GLT-1 levels of about 50%, whereas glutamate-aspartate transporter (GLAST) levels remained unchanged. Glu uptake was also lowered, and this reduction was dose-dependent. Our findings indicate that clozapine reduces GLT-1 expression and function by a mechanism that directly involves astrocytes. A better understanding of the molecular events by which antipsychotics regulate Glu uptake can contribute to identify new targets for the treatment of schizophrenia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Transport System X-AG / drug effects
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Amino Acid Transport System X-AG / metabolism
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Animals
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Animals, Newborn
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Antipsychotic Agents / pharmacology
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Astrocytes / drug effects*
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Astrocytes / metabolism
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Cells, Cultured
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Cerebral Cortex / cytology*
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Cerebral Cortex / drug effects*
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Cerebral Cortex / metabolism
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Clozapine / pharmacology*
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Dose-Response Relationship, Drug
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Excitatory Amino Acid Transporter 1
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Excitatory Amino Acid Transporter 2 / drug effects*
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Excitatory Amino Acid Transporter 2 / metabolism
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Glutamate Plasma Membrane Transport Proteins
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Glutamic Acid / metabolism*
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Rats
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Rats, Sprague-Dawley
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Schizophrenia / drug therapy
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Schizophrenia / metabolism
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Schizophrenia / physiopathology
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Symporters / drug effects
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Symporters / metabolism
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
Substances
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Amino Acid Transport System X-AG
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Antipsychotic Agents
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Excitatory Amino Acid Transporter 1
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Excitatory Amino Acid Transporter 2
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Glutamate Plasma Membrane Transport Proteins
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Slc1a3 protein, rat
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Symporters
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Glutamic Acid
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Clozapine