There is substantial evidence for an interaction between adenosine A1 and muscarinic M1/M3 receptors in some tissues, either at the level of the receptors themselves or at the associated transduction system. We have now addressed the question of whether there is a similar interaction between A1 and presynaptic M2 receptors in the hippocampus. The effects of cyclopentyladenosine (CPA) were studied alone or in combination with the M2 receptor agonist oxotremorine-M. The ability of both to depress synaptic transmission presynaptically at the concentrations used was confirmed using paired-pulse inhibition. When combined at a range of concentrations, the effects of the two agents were less than additive, suggesting that they are acting by a common transduction system. The results indicate that the modulatory, antagonistic effects of A1 adenosine receptors are exerted not only on postjunctional M1/M3 receptors but also at M2 presynaptic receptors.