Adenosine A2AReceptors Regulate the Extracellular Accumulation of Excitatory Amino Acids upon Metabolic Dysfunction in Chick Cultured Retinal Cells

Abstract

The role of endogenous extracellular adenosine as a tonic modulator of the extracellular accumulation of excitatory amino acids (glutamate and aspartate) caused by metabolic inhibition was investigated in cultured retinal cells. The selective adenosine A2Areceptor antagonist, 4-[2-[7-amino-2-(2-furyl)(1,2,4)-triazin-5-ylamino]-ethyl]phenol (ZM241385) (50 n ), increased the release of glutamate (three- to four-fold) and of aspartate (nearly two-fold) upon iodoacetic acid-induced glycolysis inhibition, in the presence or in the absence of Ca2+. Blockade of tonic activation of A2Areceptors by ZM241385 also increased (nearly two-fold) the ischemia-induced release of glutamate and aspartate. Furthermore, another selective A2Areceptor antagonist, 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3- e ]-1,2,4-triazolo[1,5- c ]pyrimidine (SCH58261), also increased the release of aspartate and glutamate by about two-fold in cells submitted to glycolysis inhibition. In contrast, the selective adenosine A1receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (100 n ), did not significantly modify the extracellular accumulation of either glutamate or aspartate caused by inducers of chemical ischemia or glycolytic inhibitors. Inhibition of glycolysis also increased (about three-fold) the extracellular accumulation of GABA, which was virtually unchanged by ZM241385. Furthermore, the GABAAreceptor antagonist, bicuculline (10 [mu]), only increased (nearly two-fold) the iodoacetic acid-induced Ca2+-dependent release of glutamate, whereas the GABABreceptor antagonist, 3-aminopropyl(diethoxymethyl) phosphinic acid, CGP35348 (100 [mu]), was devoid of effects on the extracellular accumulation of glutamate and aspartate. These results show that endogenous extracellular adenosine, which rises under conditions of inhibited glycolysis, tonically inhibits the extracellular accumulation of excitatory amino acid through the activation of A2A, but not A1, adenosine receptors, and this effect is independent of GABAAand GABABfunctions in the cultured retinal cells.