Received for publication December 3, 2004.
Revised February 28, 2005.
Accepted for publication March 1, 2005.

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 Ca⁺² 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-b-benzyloxyaspartate (TBOA) and stimulating group I mGluRs with (RS)-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 Ca⁺² channel blockers. Because CPG also inhibits group I mGluRs, two additional group I antagonists were examined, LY367385 and RS-1-aminoindan-1,5-dicarboxylic acid (AIDA). While LY 367385 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, LY 367385 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 following blockade of X^-_AG arises predominately from x_c^-. The accumulation of glutamate elicited by mGluR1/5 stimulation does not appear to result from modulating X^-_AG, x_c^- or synaptic glutamate release.

Key words: glutamate exchange, glutamate pools, glutamate uptake, medial prefrontal cortex, microdialysis, non vesicular glutamate release

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