It has previously been found that the sensitivity of hippocampal slices to adenosine depends on magnesium ions. The addition of 2-amino-5-phosphonopentanoic acid (2AP5) in magnesium-free medium, thus blocking receptors for N-methyl-D-aspartate (NMDA) did not modify this dependence. Here it is shown that if 2AP5 is present before the removal of magnesium ions the sensitivity to adenosine is maintained. The channel blocker MK-801 also restores adenosine responsiveness. Superfusing slices with NMDA itself directly suppresses adenosine responses and can reverse adenosine inhibition of synaptic potentials. Increasing neuronal excitability non-selectively with 8.5 mM potassium in the presence of 2AP5 has little effect on adenosine sensitivity, while removing the 2AP5 causes a loss of sensitivity. The results indicate that activation of NMDA receptor-coupled channels causes a reduction of adenosine sensitivity. This sequence of events may be viewed as a positive feedback and may be of fundamental importance in phenomena such as long-term potentiation, seizure generation and kindling.