Gabapentin is a drug with anticonvulsant and analgesic properties causing the reduction of neurotransmitter release. We show that one of the mechanisms implicated in this effect of gabapentin is the reduction of the axon excitability measured as an amplitude change of the presynaptic fibre volley (FV) in the CA1 area of rat hippocampal slices. Interestingly, we found that gabapentin-induced depression of FV is mimicked and occluded by NMDA receptor (NMDA-R) antagonists, indicating that these receptors are located presynaptically and are activated by ambient levels of glutamate. Conversely, NMDA application (20 µm, 10 min) elicits a reversible FV potentiation which is reduced by gabapentin. Both NMDA- and gabapentin-induced FV changes are partially explained by modifications in the firing threshold of individual fibres. Increasing [K+]o does not mimic or occlude (at a concentration of 6.5 mm) the effect of NMDA on FV amplitude, which makes it unlikely that a rise in [K+]o induced by NMDA receptor activation could indirectly participate in the potentiation of the FV. The NMDA-induced FV potentiation is independent of extracellular calcium presence but is completely inhibited in a low-Na+ solution (50% reduction) or under NMDA channel block (high Mg2+ or MK 801). These findings suggest that sodium entry through presynaptic NMDA-R channels facilitates axon excitability. The interaction of gabapentin with this newly described mechanism might contribute to its therapeutic benefits.