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

Abstract

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-β-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.