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 (GABA_B) receptor agonist acting exclusively at a heterodimeric complex containing the GABA_B(1a) splice variant (Mol Pharmacol2001;59:144–152). In this study, we have investigated the effects of gabapentin on recombinant GABA_B(1a)and GABA_B(1b) receptors coexpressed with GABA_B(2) in five different functional recombinant assays, its ability to inhibit [³H]GABA binding in a GABA_B 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 GABA_B(1a,2) or the GABA_B(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 GABA_Breceptor sites in rat synaptic membranes. Finally, in contrast to the classic GABA_B receptor agonist baclofen, gabapentin was unable to inhibit transient lower esophageal sphincter relaxations in dogs. Because of high levels of GABA_B(1a) in the canine nodose ganglion, this finding indirectly supports the inactivity of gabapentin on the GABA_B(1a,2) heterodimer demonstrated in various in vitro assays. In light of these results, we find it highly questionable that gabapentin is a GABA_B receptor agonist. Hence, the anticonvulsive effects of the compound have to arise from GABA_B receptor-independent mechanisms. This also implies that the first GABA_B receptor splice variant-selective ligand remains to be discovered.