Coactivation of metabotropic glutamate receptors (mGluRs) and β-adrenergic receptors causes a synergistic increase in cAMP formation in the rat hippocampus. Increases in CAMP are known to have many actions in the hippocampus via activation of CAMP-dependent protein kinase. We now report that coactivation of mGIuRs and β-adrenergic receptors induces an acute depression of EPSCs at the Schaffer collateral-CAl synapse. Interestingly, this depression of EPSCs is dependent upon increases in CAMP levels but independent of protein kinase activity. A series of studies suggests that CAMP-mediated depression of EPSCs is dependent on metabolism of cAMP and release of adenosine or 5′-AMP into the extracellular space with resultant activation of presynaptic adenosine receptors. These studies suggest that cAMP can have local hormone-like effects in the hippocampal formation which are independent of cAMP-dependent protein kinase.