Functional characterization of a novel adenosine A 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, A, A, and A. A receptors (ARs) 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 ARs on PPF is known to be sensitive not only to AR blockade but also to the AR antagonist DPCPX, indicating that it involves AR activation. In this study we provide the first functional characterization of the newly synthesized non-nucleoside like AR agonist P453, belonging to the amino-3,5-dicyanopyridine series. By extracellular electrophysiological recordings, we demonstrated that P453 mimicked the effect of the prototypical AR agonist BAY60-6583 in decreasing PPF at Schaffer collateral-CA1 synapses in rat acute hippocampal slices. This effect was prevented by two different AR antagonists, PSB603 and MRS1754, and by the AR antagonist DPCPX. We also investigated the functional role of AR during a 2 min of oxygen and glucose deprivation (OGD) insult, known to produce a reversible fEPSP inhibition due to adenosine AR 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 AR agonist whose activation decreases PPF by increasing glutamate release at presynaptic terminals and delays AR-mediated fEPSP inhibition during a 2-minute OGD insult.