Gabapentin increases expression of δ subunit-containing GABAA receptors

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.).

In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties

“…The rapid anxiolytic actions of gabapentinoids are thought to involve increased GABA A R activity, reminiscent of diazepam but mediated by increased cell surface expression instead of direct activation of GABA A Rs ( Yu et al, 2019 ). Therefore, to begin to test whether the behavioral effects of LCGA-17 in the EPM involved enhanced GABAergic transmission, we co-treated the mice with LCGA-17 and the GABA A R antagonist bicuculline.…”

“…Notably, similar to PAMs of GABA A Rs, inhibitory ligands of α2δ such as pregabalin and gabapentin (gabapentinoids) are widely used as anxiolytics and anticonvulsants and also as antinociceptives ( Bandelow et al, 2008 ; Baldwin et al, 2011 ; Ahmed et al, 2019 ). Interestingly, recent evidence suggests that the anxiolytic (but not antinociceptive) effects of gabapentinoids involve enhanced GABAergic transmission ( Yu et al, 2019 ). Moreover, and consistent with their highly overlapping therapeutic indications, GABA A Rs, and VGCCs may also serve as shared targets of the prototypical antidepressant, fluoxetine ( Robinson et al, 2003 ; Ye et al, 2008 ; Normann et al, 2018 ).…”

Gabapentin Relieves Vertigo of Periodic Vestibulocerebellar Ataxia: 3 Cases and Possible Mechanism

“…Peak serum concentration (T max ) of gabapentin occurs 2 to 3 hours after ingestion, its half-life (t 1/2 ) being between 5 and 7 hours. [2][3][4] GABA is the most important inhibitory neurotransmitter in the central nervous system. In the cerebellum, it is used by Purkinje cells to provide inhibitory outflow to the cerebellar nuclei.…”

An enigmatic role of tonic inhibition in gabapentin therapy

“…Gabapentin binds with high affinity to the α 2 δ VDCCs [6], which is considered the primary target of the drug. Yu and colleagues published a study in this issue of EBioMedicine that uncovered the hitherto hidden GABAergic mechanism for gabapentin [10]. They identified δGABA-A receptors as targets of gabapentin for eliciting anxiolysis and motor side effects (Fig.…”

“…Yu and coworkers' paper addresses this issue: Using specific cell-surface biotinylation and immunoblot analysis, they demonstrated an enhanced abundance of δ-subunit protein expression after acute and long-term gabapentin treatment [10]. This approach allowed them to delineate the membrane levels δGABA-ARs from the total cellular levels.…”