Exposure of the submerged hippocampal slice to in vitro ischemic conditions (superfusion with hypoxic medium lacking glucose) resulted in a progression of changes in the orthodromically evoked response recorded from the CA1 pyramidal region. There was an early depression of the population spike with no change in the presynaptic fiber volley, followed by a transient return of the population spike and, finally, a complete loss of both the population spike and fiber volley. The adenosine A1 subtype-selective antagonists, 8-phenyltheophylline (8-PT) and 8-cyclopentyltheophylline (8-CPT), greatly attenuated the early depression of the population spike such that the initial loss of the population spike was associated with the loss of the fiber volley. This result suggests that the initial loss of synaptic function in the hippocampal slice during exposure to in vitro ischemic conditions is due to increased levels of the inhibitory neuromodulator, adenosine.