Blockade of adenosine A2 receptors has been shown to significantly reduce the level of tetanus-induced long-term potentiation in area CA1 of rat hippocampus [Kessey K. et al. (1997) Brain Res. 756, 184-190; Sekino Y. et al. (1991) Biochem. biophys. Res. Commun. 181, 1010-1014]. In the present study, the effects of A2 receptor activation and blockade on the modulation of normal synaptic transmission and tetanus-induced long-term potentiation were examined at the Schaffer-CA1 synapse in rat hippocampal slices. A2 receptor activation reversibly enhanced synaptic transmission evoked by low-frequency test pulses as measured by the dendritic field excitatory postsynaptic potential. In the presence of A1 receptor blockade, A2 activation further enhanced the excitatory postsynaptic potential, while A2 receptor blockade resulted in a reversible decrease of the excitatory postsynaptic potential. The A2a receptor agonist, CGS21680, had no effect on the excitatory postsynaptic potential, suggesting that tonic activation of A2b receptors contributes to synaptic transmission under normal physiological conditions. Furthermore, we investigated the contribution of A2 receptors to the level of tetanus-induced long-term potentiation. Under control conditions, a single tetanus potentiated the excitatory postsynaptic potential by 63.5% relative to baseline 30 min post-tetanus. In contrast, tetanus-induced long-term potentiation during A2 blockade was 21.3%. A2 receptor activation increased the level of tetanus-induced long-term potentiation to 90.2%. Because A2 receptors are known to stimulate cyclic-AMP accumulation, the possible involvement of cyclic-AMP was examined. Forskolin, a direct adenylate cyclase activator, and 8-bromo-cyclic-AMP, a membrane-permeable analog of cyclic-AMP, were able to reconstitute tetanus-induced long-term potentiation during A2 receptor blockade; however, the inactive analog 1,9-dideoxyforskolin had no effect, indicating that the effects of A2 activation on synaptic transmission were mediated largely through the regulation of intracellular cyclic-AMP. Because A1 receptors exert an opposing effect on synaptic transmission relative to A2 receptors, these results suggest that the stoichiometry of A1 versus A2 receptor activation appears to play an important role in the modulation of normal synaptic transmission and long-term potentiation in the CA1 region of the hippocampus.