CHARACTERIZATION OF GLUTAMATE, ASPARTATE, AND GABA RELEASE FROM ISCHEMIC RAT CEREBRAL-CORTEX

The purpose of this study was to evaluate potential mechanisms of isch emia-evoked amino acid transmitter release. Changes in extracellular l evels of transmitter amino acids and lactic acid dehydrogenase (LDH) i n rat cerebral cortex during and following four-vessel occlusion elici ted global cerebral ischemia were examined using a cortical cup techni que. Ischemia-evoked release of glutamate, aspartate and gamma-aminobu tyric acid (GABA) was compared in control vs. drug-treated animals. Te trodotoxin and antagonists of glutamate receptors (DNQX, MK-801, and A P-3) depressed the initial rate of increase in extracellular glutamate and aspartate without altering the total amount of these amino acids collected in the cortical superfusates. Cobalt, a calcium channel anta gonist, failed to alter efflux. Acidic amino acid transport inhibitors (dihydrokainate, L-trans-PDC) depressed the rate of onset of,glutamat e and aspartate release and dihydrokainate depressed total release by 44%. PD 81723, an allosteric enhancer at the A(1) adenosine receptor, depressed glutamate efflux, as did L-NAME, an inhibitor of nitric oxid e synthase. Extracellular increases in GABA levels were depressed by t etrodotoxin and L-trans-PDC. The GABA transport inhibitor, nipecotic a cid, increased the initial rate of onset of GABA release. Increases in LDH levels in the extracellular fluid became apparent during the peri od of ischemia and continued to increase during the subsequent 90 min of reperfusion. These results suggest that ischemia evokes a release o f neurotransmitter amino acids that is only partially dependent upon C a2+ influx activation or the reversal of amino acid transporters. Nons elective mechanisms, resulting from the disruption of plasma membrane integrity, may contribute significantly to the total ischemia-evoked r elease of excitatory amino acids.