Abstract

Gabapentin (GBP; Neurontin) and pregabalin (PGB; Lyrica, S-(+)-3-isobutylgaba) are used clinically to treat several disorders associated with excessive or inappropriate excitability, including epilepsy; pain from diabetic neuropathy, postherpetic neuralgia, and fibromyalgia; and generalized anxiety disorder. The molecular basis for these drugs' therapeutic effects are believed to involve the interaction with the auxiliary α₂δ subunit of voltage-sensitive Ca²⁺ channel (VSCC) translating into a modulation of pathological neurotransmitter release. Glutamate as the primary excitatory neurotransmitter in the mammalian central nervous system contributes, under conditions of excessive glutamate release, to neurological and psychiatric disorders. This study used enzyme-based microelectrode arrays to directly measure extracellular glutamate release in rat neocortical slices and determine the modulation of this release by GBP and PGB. Both drugs attenuated K⁺-evoked glutamate release without affecting basal glutamate levels. PGB (0.1–100 μM) exhibited concentration-dependent inhibition of K⁺-evoked glutamate release with an IC₅₀ value of 5.3 μM. R-(−)-3-Isobutylgaba, the enantiomer of PGB, did not significantly reduce K⁺-evoked glutamate release. The decrease of K⁺-evoked glutamate release by PGB was blocked by the l-amino acid l-isoleucine, a potential endogenous ligand of the α₂δ subunit. In neocortical slices from transgenic mice having a point mutation (i.e., R217A) of the α₂δ-1 (subtype) subunit of VSCC, PGB did not affect K⁺-evoked glutamate release yet inhibited this release in wild-type mice. The results show that GBP and PGB attenuated stimulus-evoked glutamate release in rodent neocortical slices and that the α₂δ-1 subunit of VSCC appears to mediate this effect.