The effect of the stable adenosine analogue, 2-chloro-adenosine (CADO), on the currents elicited by iontophoretic application of N-methyl-D-aspartate (NMDA) to pyramidal cells acutely dissociated from the CA1 area of the rat hippocampus was studied using the patch-clamp technique in the whole-cell configuration. CADO (3-300 nM) reversibly inhibited NMDA receptor-mediated currents (maximal effect: 54.2 +/- 6.6% decrease, EC50 = 10.3 nM). This effect was prevented by the adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (50 nM). CADO (100 nM inhibited the conductance induced by iontophoretic application of NMDA, without changing its reversal potential, in both the absence and the presence of Mg2+ (30 microM). Adenosine may contribute to the regulation of the NMDA receptor function, particularly under conditions, like hypoxia and ischaemia, leading to excessive NMDA receptor activation.