Vol. 61, Issue 6, 1377-1384, June 2002

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

Anders A. Jensen, Johannes Mosbacher, Susanne Elg, Kurt Lingenhoehl, Tania Lohmann, Tommy N. Johansen, Bjarke Abrahamsen, Jan P. Mattsson, Anders Lehmann, Bernhard Bettler,¹ and Hans Bräuner-Osborne

NeuroScience PharmaBiotec Research Centre, Department of Medicinal Chemistry, the Royal Danish School of Pharmacy, Copenhagen, Denmark (A.A.J., T.N.J., B.A., H.B.-O.); Novartis Pharma AG, Therapeutic Area Nervous System, Basel, Switzerland (J.M., K.L., T.L., B.B.); AstraZeneca R&D Mölndal, Cell Biology & Biochemistry (S.E., J.P.M.) and Gastrointestinal Biology, Integrative Pharmacology (A.L.), Mölndal, Sweden; and Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, USP, São Paulo, Brazil (T.L.)

The actions of the anticonvulsant gabapentin [1-(aminomethyl)cyclohexaneacetic acid, Neurontin] have been somewhat enigmatic until recently, when it was claimed to be a -aminobutyric acid-B (GABA_B) receptor agonist acting exclusively at a heterodimeric complex containing the GABA_B(1a) splice variant (Mol Pharmacol 2001;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_B receptor 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.