Effects of adenosine A₁ and A_2A receptor activation on the evoked release of glutamate from rat cerebrocortical synaptosomes

Abstract

The effects of adenosine A 2A and A 1 receptor activation on the release of glutamate were studied in rat cerebral cortex synaptosomes exposed in superfusion to adenosine receptor ligands. Adenosine (0.1 μ M ) produced a significant potentiation of the Ca 2+ ‐dependent K + (15 m M )‐evoked [ 3 H]‐ D ‐aspartate overflow (20.4±3.5%), which was blocked by A 2A blocker SCH58261 (0.1 μ M ). At higher concentrations (10 – 1000 μ M ) adenosine inhibited in a DPCPX‐sensitive manner the Ca 2+ ‐dependent K + ‐evoked [ 3 H]‐ D ‐aspartate overflow. The inhibitory effect of adenosine at 1000 μ M was significantly increased by SCH58261. This inhibition was antagonized by 1 μ M DPCPX. Adenosine did not produce any effect on basal release. The A 2A receptor agonist CGS 21680 was ineffective on basal release, but stimulated the Ca 2+ ‐dependent K + ‐evoked overflow of [ 3 H]‐ D ‐aspartate (EC 50 ≃ 1 p M ). The effect of 0.01 n M CGS 21680 was totally sensitive to the A 2A receptor antagonist SCH58261 (IC 50 ≃5 n M ). The A 1 receptor agonist CCPA inhibited the Ca 2+ ‐dependent K + ‐evoked [ 3 H]‐ D ‐aspartate overflow (EC 50 ≃ 20 n M ). The effect of 100 n M CCPA was abolished by 100 n M of the A 1 receptor antagonist DPCPX. The K + (15 m M )‐evoked overflow of endogenous glutamate was enhanced by CGS 21680 (0.01 n M ) and inhibited by CCPA (0.1 μ M ). The effect of CGS 21680 was abolished by SCH58261 (0.1 μ M ) and that of CCPA by DPCPX (0.1 μ M ). It is concluded that adenosine and adenosine receptor agonists modulate glutamate release by activating inhibitory A 1 and excitatory A 2A receptors present on glutamatergic terminals of the rat cerebral cortex. British Journal of Pharmacology (2002) 136 , 434–440; doi: 10.1038/sj.bjp.0704712