Effects of adenosine A1 and A2A receptor activation on the evoked release of glutamate from rat cerebrocortical synaptosomes

Abstract

The effects of adenosine A_2A and A₁ receptor activation on the release of glutamate were studied in rat cerebral cortex synaptosomes exposed in superfusion to adenosine receptor ligands. Adenosine (0.1 μM) produced a significant potentiation of the Ca²⁺‐dependent K⁺(15 mM)‐evoked [³H]‐D‐aspartate overflow (20.4±3.5%), which was blocked by A_2A blocker SCH58261 (0.1 μM). At higher concentrations (10 – 1000 μM) adenosine inhibited in a DPCPX‐sensitive manner the Ca²⁺‐dependent K⁺‐evoked [³H]‐D‐aspartate overflow. The inhibitory effect of adenosine at 1000 μM was significantly increased by SCH58261. This inhibition was antagonized by 1 μM 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 Ca²⁺‐dependent K⁺‐evoked overflow of [³H]‐D‐aspartate (EC₅₀ ≃ 1 pM). The effect of 0.01 nM CGS 21680 was totally sensitive to the A_2A receptor antagonist SCH58261 (IC₅₀ ≃5 nM). The A₁ receptor agonist CCPA inhibited the Ca²⁺‐dependent K⁺‐evoked [³H]‐D‐aspartate overflow (EC₅₀ ≃ 20 nM). The effect of 100 nM CCPA was abolished by 100 nM of the A₁ receptor antagonist DPCPX. The K⁺(15 mM)‐evoked overflow of endogenous glutamate was enhanced by CGS 21680 (0.01 nM) and inhibited by CCPA (0.1 μM). The effect of CGS 21680 was abolished by SCH58261 (0.1 μM) and that of CCPA by DPCPX (0.1 μM). It is concluded that adenosine and adenosine receptor agonists modulate glutamate release by activating inhibitory A₁ 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