Adenosine A2A receptors control the extracellular levels of adenosine through modulation of nucleoside transporters activity in the rat hippocampus

Adenosine, a neuromodulator of the CNS, activates inhibitory-A(1) receptors and facilitatory-A(2A) receptors; its synaptic levels are controlled by the activity of bi-directional equilibrative nucleoside transporters. To study the relationship between the extracellular formation/inactivation of adenosine and the activation of adenosine receptors, we investigated how A(1) and A(2A) receptor activation modifies adenosine transport in hippocampal synaptosomes. The A(2A) receptor agonist, CGS 21680 (30 nM), facilitated adenosine uptake through a PKC-dependent mechanism, but A1 receptor activation had no effect. CGS 21680 (30 nM) also increased depolarization-induced release of adenosine. Both effects were prevented by A2A receptor blockade. A2A receptor-mediated enhancement of adenosine transport system is important for formatting adenosine neuromodulation according to the stimulation frequency, as: (1) A(1) receptor antagonist, DPCPX (250 nM), facilitated the evoked release of [H-3] acetylcholine under low-frequency stimulation (2 Hz) from CA3 hippocampal slices, but had no effect under high-frequency stimulation (50 Hz); (2) either nucleoside transporter or A(2A) receptor blockade revealed the facilitatory effect of DPCPX (250 nM) on [H-3] acetylcholine evoked-release triggered by high-frequency stimulation. These results indicate that A(2A) receptor activation facilitates the activity of nucleoside transporters, which have a preponderant role in modulating the extracellular adenosine levels available to activate A(1) receptors.