Posted on 27-05-2019

Gabapentin upregulates GABAA receptor δ subunit – a novel mechanism of action

Gabapentin (also known as Neurontin) is clinically prescribed for the treatment of seizures, pain, and anxiety. While gabapentin is known to modulate voltage-gated calcium channels, some studies have suggested the effects of gabapentin are also dependent on GABAergic inhibition. However, gabapentin neither binds GABA receptors nor increases GABA release, thus its precise mechanisms of action remain unclear and is what UTCSP scientists, Dr. Beverly Orser, Dr. Robert Bonin, and collaborators, aimed to uncover.

To determine whether GABA receptors are involved in gabapentin’s action the authors started by measuring levels of the GABAA receptor, as changes in cell surface expression of ion channels is a key way to modulating neuronal activity. In this study, they found that gabapentin treatment increased surface expression of the δ subunit of GABAA receptor in the cerebellum and hippocampus. The δ subunit is typically expressed outside of synapses and accordingly, neurons from mice pretreated with gabapentin displayed increased tonic GABAA receptor-dependent inhibitory currents.

They next sought to test whether the GABAA receptor δ subunit was required for known behavioural effects of gabapentin, such as ataxia, anxiolysis, and analgesia, by conducting behaviour assays with mice lacking GABAA receptor δ subunit expression (Gabrd-/-). Unlike wild type mice that exhibit reduced motor coordination (tested with Rotarod) and reduced anxiety behaviour (tested with elevated plus maze) following gabapentin administration, Gabrd-/- mice given gabapentin showed no change in these behaviours. However, gabapentin remained effective in reducing pain behaviour after formalin injection in Gabrd-/- mice, similar to wild type mice.

Together, these results suggest that the ataxic and anxiolytic effects of gabapentin are dependent on the δ subunit of GABAA receptors, but its analgesic properties are δ subunit-independent. Since diminished GABAA receptor δ subunit expression is observed in certain psychiatric disorders, such as depression, gabapentin’s ability to upregulate δ subunit expression may serve as a potential novel therapeutic for such conditions.

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Reference: Yu, J., Wang, D.S., Bonin, R.P., Penna, A., Alavian-Ghavanini, A., Zurek, A.A., Rauw, G., Baker, G.B., and Orser, B.A. (2019). Gabapentin increases expression of δ subunit-containing GABAA receptors. EBioMedicine 42, 203–213.