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.
Melendez
Roberto I
RI
Department of Neurosciences, Medical University of South Carolina, 173 Ashley Ave., Suite 403 BSB, Charleston, SC 29425, USA. melendez@musc.edu
Vuthiganon
Jompobe
J
Kalivas
Peter W
PW
D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
D018094:Receptors, Metabotropic Glutamate; C120673:benzyloxyaspartate; C104077:metabotropic glutamate receptor type 1; D001224:Aspartic Acid; D018698:Glutamic Acid; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol