Presynaptic NMDA autoreceptors facilitate axon excitability: a new molecular target for the anticonvulsant gabapentin

Abstract

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 microM, 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 Mg(2+) 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.

Pregabalin Reduces the Release of Synaptic Vesicles from Cultured Hippocampal Neurons

“…Alternatively, several studies have shown that presynaptic NMDA receptors can alter synaptic action of glutamate synapses, and our findings might be explained by a requirement for activation of presynaptic NMDA receptors (MacDermott et al, 1999). The idea that presynaptic NMDA receptors are involved is supported by a recent study suggesting that gabapentin, which is closely related to pregabalin, reduces presynaptic sodium-channel activation via an NMDA-dependent mechanism (Suarez et al, 2005). However, additional experiments are required to further characterize the NMDA dependence of pregabalin action that our study has suggested.…”

“…Both positive and negative interactions between gabapentin and NMDA receptor responses have been reported in the literature (Shimoyama et al, 2000;Gu and Huang, 2002;Suarez et al, 2005), despite the fact that neither gabapentin nor pregabalin interacts with NMDA, phencyclidine, or strychnine-insensitive glycine binding sites of NMDA receptors (Piechan et al, 2004). We tested the effects of NMDA receptor blockade on the action of pregabalin in our system.…”

The Role of Granulocyte-Colony Stimulating Factor (G-CSF) in the Healthy Brain: A Characterization of G-CSF-Deficient Mice

“…It is well established that NMDA receptors are a molecular detector of the coincidence of both the presynaptic release of glutamate and a postsynaptic depolarization at the origin of LTP induction (Sourdet and Debanne, 1999). Presynaptic NMDA receptors have recently been suggested to potentiate the afferent field volley evoked by Schaffer axon stimulation (Suárez et al, 2005). However, other presynaptic mechanisms such as involvement of kainate receptors (Schmitz et al, 2001) or transient outward potassium current could also modify presynaptic excitability (Gu et al, 2004).…”

Mechanisms of the Antinociceptive Action of Gabapentin

“…The depressant effect of gabapentin was occluded by NMDA-receptor antagonists, and the enhancing effect of NMDA was blocked by lowering extracellualr Na + concentration, but not affected by increasing K + concentrations. Therefore, they suggested that the effect of gabapentin might be mediated via a decrease of Na + influx through presynaptic NMDA receptors (90).…”

“…Suarez et al (90) reported that gabapentin depressed, but NMDA enhanced, the presynaptic fiber volley (the presynaptic terminal action potentials recorded extracellularly) in the CA1 region of rat hippocampal slices. The depressant effect of gabapentin was occluded by NMDA-receptor antagonists, and the enhancing effect of NMDA was blocked by lowering extracellualr Na + concentration, but not affected by increasing K + concentrations.…”