Gabapentin increases expression of subunit-containing GABAA receptors

To determine whether GABA receptors are involved in gabapentin’s action the authors started by measuring levels of the GABA_A 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 GABA_A 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 GABA_A receptor-dependent inhibitory currents.

They next sought to test whether the GABA_A receptor δ subunit was required for known behavioural effects of gabapentin, such as ataxia, anxiolysis, and analgesia, by conducting behaviour assays with mice lacking GABA_A 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 GABA_A receptors, but its analgesic properties are δ subunit-independent. Since diminished GABA_A 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.

These results suggest that the ataxic and anxiolytic effects of gabapentin are dependent on the δ subunit of GABA_A receptors, but its analgesic properties are δ subunit-independent.