PT  - JOURNAL ARTICLE
AU  - Roberto I. Melendez
AU  - Jompobe Vuthiganon
AU  - Peter W. Kalivas
TI  - Regulation of Extracellular Glutamate in the Prefrontal Cortex: Focus on the Cystine Glutamate Exchanger and Group I Metabotropic Glutamate Receptors
AID  - 10.1124/jpet.104.081521
DP  - 2005 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 139--147
VI  - 314
IP  - 1
4099  - http://jpet.aspetjournals.org/content/314/1/139.short
4100  - http://jpet.aspetjournals.org/content/314/1/139.full
SO  - J Pharmacol Exp Ther2005 Jul 01; 314
AB  - Microdialysis was used to determine the in vivo processes contributing to extracellular glutamate levels in the prefrontal cortex of rats. Reverse dialysis of a variety of compounds proved unable to decrease basal levels of extracellular glutamate, including Na+ and Ca2+ channel blockers, cystine/glutamate exchange (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document}) antagonists, and group I (mGluR1/5) and group II (mGluR2/3) metabotropic glutamate receptor (mGluR) agonists or antagonists. In contrast, extracellular glutamate was elevated by blocking Na+-dependent glutamate uptake (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{X}_{\mathrm{AG}}^{-}\) \end{document}) with dl-threo-β-benzyloxyaspartate (TBOA) and stimulating group I mGluRs with (R,S)-3,5-dihydroxy-phenylglycine (DHPG). The accumulation of extracellular glutamate produced by blocking \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{X}_{\mathrm{AG}}^{-}\) \end{document} was completely reversed by inhibiting system \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document} with 4-carboxyphenylglycine (CPG), but not by Na+ and Ca2+ channel blockers. Because CPG also inhibits group I mGluRs, two additional group I antagonists were examined, LY367385 [(+)-2-methyl-4-carboxyphenylglycine] and (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA). Whereas LY367385 also reduced TBOA-induced increases in extracellular glutamate, AIDA did not. In contrast, all three group I antagonists reversed the increase in extracellular glutamate elicited by stimulating mGluR1/5. In vitro evaluation revealed that similar to CPG, LY367385 inhibited \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document} and that stimulating or inhibiting mGluR1/5 did not directly affect [3H]glutamate uptake via \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document} or \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{X}_{\mathrm{AG}}^{-}\) \end{document}. These experiments reveal that although inhibiting \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document} cannot reduce basal extracellular glutamate in the prefrontal cortex, the accumulation of extracellular glutamate after blockade of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{X}_{\mathrm{AG}}^{-}\) \end{document} arises predominately from \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document}. The accumulation of glutamate elicited by mGluR1/5 stimulation does not seem to result from modulating \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{X}_{\mathrm{AG}}^{-},{\\ }\mathrm{x}_{\mathrm{c}}^{-}\) \end{document}, or synaptic glutamate release. The American Society for Pharmacology and Experimental Therapeutics