In previous work we found that a brief period of hypoxia occurring within 1-2 min of high-frequency stimulation disrupts the development of long-term potentiation (LTP) in the CA1 field of rat hippocampal slices. We now report that extracellular application of adenosine if applied within 1 min but not 5 min after high-frequency stimulation similarly prevents LTP. Adenosine was ineffective if DPCPX (1,3-dipropyl-8-cyclopentyl-xanthine), a selective antagonist of adenosine A1 receptors, was present. The post-stimulation application mode excludes the possibility that adenosine interferes with NMDA receptor activation and its role in initiating LTP. It suggests instead that changes in intracellular control systems linked to adenosine receptors can during a brief vulnerable period interrupt the biochemical processes leading to the expression of long-term potentiation.