The Anticonvulsant Gabapentin (Neurontin) Does Not Act through γ-Aminobutyric Acid-B Receptors

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Abstract
The actions of the anticonvulsant gabapentin [1-(aminomethyl)cyclohexaneacetic acid, Neurontin] have been somewhat enigmatic until recently, when it was claimed to be a γ-aminobutyric acid-B (GABAB) receptor agonist acting exclusively at a heterodimeric complex containing the GABAB(1a) splice variant (Mol Pharmacol2001;59:144–152). In this study, we have investigated the effects of gabapentin on recombinant GABAB(1a)and GABAB(1b) receptors coexpressed with GABAB(2) in five different functional recombinant assays, its ability to inhibit [3H]GABA binding in a GABAB receptor-selective binding assay using rat synaptic membranes, and its ability to inhibit transient lower esophageal sphincter relaxations in Labrador retriever dogs. Up to a concentration of 1 mM, gabapentin displayed no agonistic effects on either the GABAB(1a,2) or the GABAB(1b,2) heterodimer, when these were expressed in Xenopus laevis oocytes or mammalian cells and assayed by means of electrophysiology, calcium mobilization, inositol phosphate, and fluorometry assays. Gabapentin did not displace [3H]GABA from GABABreceptor sites in rat synaptic membranes. Finally, in contrast to the classic GABAB receptor agonist baclofen, gabapentin was unable to inhibit transient lower esophageal sphincter relaxations in dogs. Because of high levels of GABAB(1a) in the canine nodose ganglion, this finding indirectly supports the inactivity of gabapentin on the GABAB(1a,2) heterodimer demonstrated in various in vitro assays. In light of these results, we find it highly questionable that gabapentin is a GABAB receptor agonist. Hence, the anticonvulsive effects of the compound have to arise from GABAB receptor-independent mechanisms. This also implies that the first GABAB receptor splice variant-selective ligand remains to be discovered.