Gabapentin increases expression of δ subunit-containing GABA A receptors

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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 unknown as gabapentin does not directly modify GABA type A (GABA A ) receptor function, nor does it modify synaptic inhibition. Here, we postulated that gabapentin increases expression of δ subunit-containing GABA A (δGABA A ) receptors that generate a tonic inhibitory conductance in multiple brain regions including the cerebellum and hippocampus. Methods: Cell-surface biotinylation, Western blotting, electrophysiologic recordings, behavioral assays, high-performance liquid chromatography and gas chromatography-mass spectrometry studies were performed using mouse models. Findings: Gabapentin enhanced expression of δGABA 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 δ 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 δGABA A receptor occurs in several disorders, gabapentin may have much broader therapeutic applications than is currently recognized. Fund: Supported by a Foundation Grant (FDN-154312) from the Canadian Institutes of Health Research (to B.A.O.); a NSERC Discovery Grant (RGPIN-2016-05538), a Canada Research Chair in Sensory Plasticity and Reconsolidation, and funding from the University of Toronto Centre for the Study of Pain (to R.P.B.).

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Yu, J., Wang, D. S., Bonin, R. P., Penna, A., Alavian-Ghavanini, A., Zurek, A. A., … Orser, B. A. (2019). Gabapentin increases expression of δ subunit-containing GABA A receptors. EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.03.008

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