| dc.description.abstract | Background: Gabapentin is a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). 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 (GABAA) receptor
function, nor does itmodify synaptic inhibition. Here,we postulated that gabapentin increases expression of δ
subunit-containing GABAA (δGABAA) 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 δGABAA 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 δ subunit null-mutant mice. In contrast, the antinociceptive properties of
gabapentin were observed in both genotypes. Levels of GABAA 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 δGABAA receptor occurs in several disorders, gabapentin may have much broader
therapeutic applications than is currently recognized. | |
