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NEUROPHARMACOLOGY

Regulation of Extracellular Glutamate in the Prefrontal Cortex: Focus on the Cystine Glutamate Exchanger and Group I Metabotropic Glutamate Receptors

Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina

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 () 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 () with DL-threo--benzyloxyaspartate (TBOA) and stimulating group I mGluRs with (R,S)-3,5-dihydroxy-phenylglycine (DHPG). The accumulation of extracellular glutamate produced by blocking was completely reversed by inhibiting system 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 and that stimulating or inhibiting mGluR1/5 did not directly affect [³H]glutamate uptake via or . These experiments reveal that although inhibiting cannot reduce basal extracellular glutamate in the prefrontal cortex, the accumulation of extracellular glutamate after blockade of arises predominately from . The accumulation of glutamate elicited by mGluR1/5 stimulation does not seem to result from modulating , or synaptic glutamate release.

Address correspondence to: Dr. Roberto I. Melendez, Department of Neurosciences, Medical University of South Carolina 173 Ashley Ave., Suite 403 BSB, Charleston, SC 29425. E-mail: melendez{at}musc.edu

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