| Summary: | Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A<sub>1</sub> and A<sub>2A</sub> receptors (A<sub>1</sub>R, A<sub>2A</sub>R), respectively. Supramaximal activation of A<sub>1</sub>R can block hippocampal synaptic transmission, and the tonic engagement of A<sub>1</sub>R-mediated inhibition is increased with increased frequency of nerve stimulation. This is compatible with an activity-dependent increase in extracellular adenosine in hippocampal excitatory synapses, which can reach levels sufficient to block synaptic transmission. We now report that A<sub>2A</sub>R activation decreases A<sub>1</sub>R-medated inhibition of synaptic transmission, with particular relevance during high-frequency-induced long-term potentiation (LTP). Thus, whereas the A<sub>1</sub>R antagonist DPCPX (50 nM) was devoid of effects on LTP magnitude, the addition of an A<sub>2A</sub>R antagonist SCH58261 (50 nM) allowed a facilitatory effect of DPCPX on LTP to be revealed. Additionally, the activation of A<sub>2A</sub>R with CGS21680 (30 nM) decreased the potency of the A<sub>1</sub>R agonist CPA (6–60 nM) to inhibit hippocampal synaptic transmission in a manner prevented by SCH58261. These observations show that A<sub>2A</sub>R play a key role in dampening A<sub>1</sub>R during high-frequency induction of hippocampal LTP. This provides a new framework for understanding how the powerful adenosine A<sub>1</sub>R-mediated inhibition of excitatory transmission can be controlled to allow the implementation of hippocampal LTP.
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