Functional characterization of a novel adenosine A2B receptor agonist on short-term plasticity and synaptic inhibition during oxygen and glucose deprivation in the rat CA1 hippocampus

Adenosine is an endogenous neuromodulator exerting its biological functions via four receptor subtypes, A(1), A(2A), A(2B), and A(3). A(2B) receptors (A(2B)Rs) are expressed at hippocampal level where they are known to inhibit paired pulse facilitation (PPF), whose reduction reflects an increase in presynaptic glutamate release. The effect of A(2B)Rs on PPF is known to be sensitive not only to A(2B)R blockade but also to the A(1)R antagonist DPCPX, indicating that it involves A(1)R activation. In this study we provide the first functional characterization of the newly synthesized non-nucleoside like A(2B)R agonist P453, belonging to the amino-3,5-dicyanopyridine series. By extracellular electrophysiological recordings, we demonstrated that P453 mimicked the effect of the prototypical A(2B)R agonist BAY60-6583 in decreasing PPF at Schaffer collateral-CA1 synapses in rat acute hippocampal slices. This effect was prevented by two different A(2B)R antagonists, PSB603 and MRS1754, and by the A(1)R antagonist DPCPX. We also investigated the functional role of A(2B)R during a 2 min of oxygen and glucose deprivation (OGD) insult, known to produce a reversible fEPSP inhibition due to adenosine A(1)R activation. We found that P453 and BAY60-6583 significantly delayed the onset of fEPSP reduction induced by OGD and the effect was blocked by PSB603. We conclude that P453 is a functional A(2B)R agonist whose activation decreases PPF by increasing glutamate release at presynaptic terminals and delays A(1)R-mediated fEPSP inhibition during a 2-minute OGD insult.