Regulation of extracellular glutamate in the prefrontal cortex: Focus on the cystine glutamate exchanger and group I metabotropic glutamate receptors

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