N-methyl-d-aspartate, kainate and quisqualate release endogenous adenosine from rat cortical slices

N-Methyl-d-aspartate, kainate, and quisqualate released endogenous adenosine from superfused slices of rat parietal cortex. N-Methyl-d-aspartate-evoked adenosine release was blocked by d,1-2-amino-5-phosphono-valeric acid and ( + )-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), indicating that it was receptor-mediated, although it did not show the expected potentiation in the absence of Mg²⁺. In contrast, N-methyl-d-aspartate-evoked release of [³H]noradrenaline from the same slices was markedly potentiated in Mg²⁺-free medium. Therefore, the lack of Mg²⁺ modulation of N-methyl-d-aspartate-evoked adenosine release was not due to depolarization-induced alleviation of the Mg²⁺ block in the slices. Kainate-evoked adenosine release was diminished by the non-specific excitatory amino acid antagonist, γ-d-glutamyl-glycine, and kainate- and quisqualate-evoked adenosine release was diminished by 6,7-dinitroquinoxaline-2,3-dione, indicating that these agonists release adenosine by acting at non-N-methyl-d-aspartate receptors. Tetrodotoxin decreased N-methyl-d-aspartate- and kainate-evoked adenosine release by 40% and 19% respectively, indicating that release was mediated in part by propagated action potentials in the slices. Total release of adenosine by N-methyl-d-aspartate, kainate or quisqualate was not diminished in the absence of Ca²⁺. A second exposure to kainate following restoration of Ca²⁺ to slices previously depolarized in the absence of Ca²⁺resulted in an amount of adenosine release equal to an initial release by slices in the presence of Ca²⁺, a result suggesting the presence of separate Ca²⁺-dependent and Ca²⁺-independent pools of adenosine. The present experiments demonstrate that activation of all three major subtypes of excitatory amino acid receptors in the cortex releases adenosine, possibly from separate Ca²⁺-dependent and -independent pools. Adenosine released from the cortex following excitatory amino acid stimulation may, by acting at inhibitory P₁ purinoceptors, diminish excitatory neurotransmission and protect against excitotoxicity.