Gabapentin inhibits presynaptic Ca2+ influx and synaptic transmission in rat hippocampus and neocortex

Swammerdam Institute for Life Sciences, Neurobiology Section, University of Amsterdam, P.O. Box 94084, NL-1090 GB, Amsterdam, The Netherlands.
European Journal of Pharmacology (Impact Factor: 2.53). 09/2002; 449(3):221-28. DOI: 10.1016/S0014-2999(02)02044-7
Source: PubMed


Gabapentin is a widely used drug with anticonvulsant, antinociceptive and anxiolytic properties. Although it has been previously shown that Gabapentin binds with high affinity to the alpha(2)delta subunit of voltage-operated Ca(2+) channels (VOCC), little is known about the functional consequences of this interaction. Here, we investigated the effect of Gabapentin on VOCCs and synaptic transmission in rat hippocampus and neocortex using whole-cell patch clamp and confocal imaging techniques. Gabapentin (100-300 microM) did not affect the peak amplitude or voltage-dependency of VOCC currents recorded from either dissociated or in situ neocortical and hippocampal pyramidal cells. In contrast, Gabapentin inhibited K(+)-evoked increases in [Ca(2+)] in a subset of synaptosomes isolated from rat hippocampus and neocortex in a dose-dependent manner, with an apparent half-maximal inhibitory effect at approximately 100 nM. In hippocampal slices, Gabapentin (300 microM) inhibited the amplitude of evoked excitatory- and inhibitory postsynaptic currents recorded from CA1 pyramidal cells by 30-40%. Taken together, the results suggest that Gabapentin selectively inhibits Ca(2+) influx by inhibiting VOCCs in a subset of excitatory and inhibitory presynaptic terminals, thereby attenuating synaptic transmission.

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Available from: Johannes A van Hooft
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    • "However, it is widely accepted that the mechanism of action of these agents involves a modulation of calcium conductance, but the precise mechanism for this remains to be elucidated. The modulation of calcium currents by gabapentin has been demonstrated in several studies of isolated neurones (Stefani et al., 1998; Sutton et al., 2002; van Hooft et al., 2002), although other studies have struggled to demonstrate such an effect (Schlicker et al., 1985). More recently, it has been proposed that gabapentin may exert an action through binding to the α 2 δ subunit within the cytosol, rather than at the cell surface, and that this interaction can over time reduce the trafficking of α 1 /α 2 δ complexes to functional sites within the cell membrane (Hendrich et al., 2008; Mich and Horne, 2008). "
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    • "A series of studies in other laboratories have shown that gabapentin effects involve GABA B receptors, at least in part (Xiong and Stringer, 1997; Stringer and Lorenzo, 1999; Parker et al., 2004). Gabapentin acts as an agonist at GABA B receptors coupled to VOCC in mouse cultured neurons (Bertrand et al., 2001; van Hooft et al., 2002). Neverthless, despite this compelling evidence, conventional binding studies failed to demonstrate a direct interaction between gabapentin and GABA B receptors (Lanneau et al., 2001; Jensen et al., 2002). "
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