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

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 ␥-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 [ 3 H]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 [3 H]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 variantselective ligand remains to be discovered.␥-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system, where it exerts its effect through the ionotropic GABA A receptors and the metabotropic GABA B receptors. The GABA B receptors belong to the family C of the G-protein-coupled receptor superfamily (Möhler and Fritschy, 1999;Marshall et al., 2000). Two receptors, GABA B(1) and GABA B(2) , have recently been cloned, and several splice variants of both receptors have been iden-

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

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