Functional characterization of a novel adenosine A 2B 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.
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