Exposure of rat hippocampal slices to hypoxic conditions for 15 min produced a rapid, profound, but completely reversible depression of evoked synaptic potentials. The specific A1 adenosine receptor antagonist 8-cyclopentyltheophylline (8-CPT) significantly reduced hypoxia-induced synaptic depression in a concentration-dependent manner. It is concluded that adenosine, which is neuroprotective when exogenously applied during severe hypoxia because of its ability to depress synaptic transmission, may have an important and exploitable endogenous role in the protection of sensitive neurons.