Adenosine A(2A) receptors regulate the extracellular accumulation of excitatory amino acids upon metabolic dysfunction in chick cultured retinal cells

The role of endogenous extracellular adenosine as a tonic modulator of the extracellular accumulation of excitatory amino acids (glutamate and asparta te) caused by metabolic inhibition was investigated in cultured retinal cel ls. The selective adenosine A(2A) receptor antagonist, 4-[2-[7-amino-2-(2-f uryl)(1,2,4)-triazin-5-ylamino]-ethyl]phenol (ZM241385) (50 nm), 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 A(2A) receptors by ZM241385 also increased (nearly two-fold) the ischemia-induced release o f glutamate and aspartate. Furthermore, another selective A(2A) receptor an tagonist, 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2-4-triazo lo[1,5-c]pyrimidine (SCH58261), also increased the release of aspartate and glutamate by about two-fold in cells submitted to glycolysis inhibition. I n contrast, the selective adenosine A(1) receptor antagonist, 1,3-dipropyl- 8-cyclopentylxanehine (DPCPX) (100 nM), did not significantly modify the ex tracellular accumulation of either glutamate or aspartate caused by inducer s of chemical ischemia or glycolytic inhibitors. Inhibition of glycolysis a lso increased (about three-fold) the extracellular accumulation of GABA, wh ich was virtually unchanged by ZM241385. Furthermore, the GABA(A) receptor antagonist, bicuculline (10 mu M), only increased (nearly two-fold) the iod oacetic acid-induced Ca2+-dependent release of glutamate, whereas the GABA( B) receptor antagonist, 3-aminopropyl(diethoxymethyl) phosphinic acid, CGP3 5348 (100 mu M), 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 th e activation of A(2A), but not A(1), adenosine receptors, and this effect i s independent of GABA(A) and GABA(B) functions in the cultured retinal cell s. (C) 2000 Academic Press.