Excitatory Transmitter Amino Acid Release from the Ischemic Rat Cerebral Cortex: Effects of Adenosine Receptor Agonists and Antagonists

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Abstract
The effects of selective adenosine receptor agonists [N6‐cyclopentyladenosine (CPA) and N‐ethylcarboxamidoadenosine (NECA)] and antagonists {8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX) and 9‐chloro‐2‐(2‐furanyl)‐5,6‐dihydro‐1,2,4‐triazolo[1,5‐c]quinazoline‐5‐imine (CGS‐15943A)} on aspartate and glutamate release from the ischemic rat cerebral cortex were studied with the cortical cup technique. Cerebral ischemia (for 20 min) was elicited by four‐vessel occlusion. Excitatory amino acid releases were compared from control ischemic rats and drug‐treated rats. Basal levels of aspartate and glutamate release were not greatly affected by pretreatment with the adenosine receptor agonists or antagonists. However, CPA (10−10M) and NECA (10−9M) significantly inhibited the ischemia‐evoked release of aspartate and glutamate into cortical superfusates. The ability to block ischemia‐evoked release of excitatory amino acids was not evident at higher concentrations of CPA (10−6M) or NECA (10−5M). The selective A1 receptor antagonist DPCPX also had no effect on release when administered at a low dosage (0.01 mg/kg, i.p.) but blocked the ischemia‐evoked release of aspartate and glutamate at a higher dosage (0.1 mg/kg). Evoked release was inhibited by the selective A2 receptor antagonist CGS‐15943A (0.1 mg/kg, i.p.). Thus, adenosine and its analogs may suppress ischemia‐evoked release of excitatory neurotransmitter amino acids via high‐affinity A1 receptors, whereas coactivation of lower‐affinity A2 receptors may block (or reverse) the A1‐mediated response.