Gabapentin increases expression of δ subunit-containing GABAA receptors

Background: Gabapentin is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GAB(A)). Its anticonvulsant, analgesic and anxiolytic properties suggest that it increases GABAergic inhibition; however, the molecular basis for these effects is unknownas gabapentin does not directlymodify GABA type A (GABA(A)) receptor function, nor does itmodify synaptic inhibition. Here, we postulated that gabapentin increases expression of delta subunit-containing GABAA (dGABA(A)) receptors that generate a tonic inhibitory conductance inmultiple brain regions including the cerebellum and hippocampus. Methods: Cell-surface biotinylation, Western blotting, electrophysiologic recordings, behavioral assays, highperformance liquid chromatography and gas chromatography-mass spectrometry studies were performed using mouse models. Findings: Gabapentin enhanced expression of dGABA(A) receptors and increased a tonic inhibitory conductance in neurons. This increased expression likely contributes to GABAergic effects as gabapentin caused ataxia and anxiolysis in wild-type mice but not d subunit null-mutant mice. In contrast, the antinociceptive properties of gabapentin were observed in both genotypes. Levels of GABA(A) receptor agonists and neurosteroids in the brain were not altered by gabapentin. Interpretation: These results provide compelling evidence to account for the GABAergic properties of gabapentin. Since reduced expression of dGABAA receptor occurs in several disorders, gabapentin may have much broader therapeutic applications than is currently recognized.