Sensitivity to selective adenosine A 1 and A 2A receptor antagonists of the release of glutamate induced by ischemia in rat cerebrocortical slices

Abstract

Adenosine released during cerebral ischemia is considered to act as a neuroprotectant, possibly through the inhibition of glutamate release. The involvement of A 1 and A 2A receptors in the control of the rise of extracellular glutamate during ischemia was investigated by monitoring the effects of selective A 1 and A 2A receptor antagonists on ischemia-evoked glutamate release in rat cerebrocortical slices. Slices were superfused with oxygen- and glucose-deprived medium and [ 3H] d-aspartate or endogenous glutamate was measured in the superfusate fractions. Withdrawal of Ca 2+ ions or addition of tetrodotoxin more than halved the ischemia-evoked efflux of [ 3H] d-aspartate or glutamate, compatible with a vesicular-like release. The glutamate transporter inhibitor dl-TBOA prevented the ischemia-evoked efflux of [ 3H] d-aspartate by about 40%, indicating a carrier-mediated efflux. The ischemia-evoked efflux of [ 3H] d-aspartate or glutamate was increased by the A 1 receptor antagonist DPCPX. The A 2A antagonist SCH 58261 decreased [ 3H] d-aspartate or endogenous glutamate efflux (50 and 55% maximal inhibitions; EC 50: 14.9 and 7.6 nM, respectively); the drug was effective also if added during ischemia. No effect of either the A 1 or the A 2A receptor antagonist was found on the ischemia-evoked efflux of [ 3H] d-aspartate in Ca 2+-free medium. Our data suggest that adenosine released during cerebral ischemia can activate inhibitory A 1 and stimulatory A 2A receptors that down- or up-regulate the vesicular-like component of glutamate release.