The results of several previous studies have suggested that pretreatment with adenosine can block the induction of long-term potentiation (LTP), although other studies have found no effect of adenosine on the induction of LTP. The interaction of adenosine with the induction of LTP in the rat hippocampal slice was investigated. Inhibition of synaptic responses by adenosine either prior to or immediately after high-frequency or theta-burst stimulation did not affect LTP measured after washout of the adenosine. The only conditions under which adenosine blocked the development of LTP was when it was given 3-5 minutes prior to the stimulation train. To understand how it was possible to induce LTP, during the period 1-3 minutes following adenosine when synaptic responses were virtually eliminated, evoked responses during the 100 Hz stimulation train were recorded. Although synaptic responses to low-frequency stimulation were virtually eliminated by adenosine, they reappeared during high-frequency stimulation. These results suggest that although adenosine can depress synaptic responses, an increase in neurotransmission during a high-frequency train can partially overcome this effect of adenosine, and the hypothesis that adenosine can selectively block LTP is not supported.