A Role for GABAA Receptor β3 Subunits in Mediating Harmaline Tremor Suppression by Alcohol: Implications for Essential Tremor Therapy

Background: Essential tremor patients may find that low alcohol amounts suppress tremor. A candidate mechanism is modulation of alpha 6 beta 38 extra -synaptic GABA A receptors, that in vitro respond to non -intoxicating alcohol levels. We previously found that lowdose alcohol reduces harmaline tremor in wild -type mice, but not in littermates lacking 8 or alpha 6 subunits. Here we addressed whether low -dose alcohol requires the beta 3 subunit for tremor suppression. Methods: We tested whether low -dose alcohol suppresses tremor in cre-negative mice with intact beta 3 exon 3 flanked by loxP, and in littermates in which this region was excised by cre expressed under the alpha 6 subunit promotor. Tremor in the harmaline model was measured as a percentage of motion power in the tremor bandwidth divided by overall motion power. Results: Alcohol, 0.500 and 0.575 g/kg, reduced harmaline tremor compared to vehicletreated controls in floxed beta 3 cre- mice, but had no effect on tremor in floxed beta 3 cre+ littermates that have beta 3 knocked out. This was not due to potential interference of alpha 6 expression by the insertion of the cre gene into the alpha 6 gene since non-floxed beta 3 cre+ and cre- littermates exhibited similar tremor suppression by alcohol. Discussion: As alpha 6 beta 38 GABA A receptors are sensitive to low -dose alcohol, and cerebellar granule cells express beta 3 and are the predominant brain site for alpha 6 and 8 expression together, our overall findings suggest alcohol acts to suppress tremor by modulating alpha 6 beta 38 GABA A receptors on these cells. Novel drugs that target this receptor may potentially be effective and well -tolerated for essential tremor. Highlights We previously found with the harmaline essential tremor model that GABA A receptors containing alpha 6 and 8 subunits mediate tremor suppression by alcohol. We now show that beta 3 subunits in alpha 6-expressing cells, likely cerebellar granule cells, are also required, indicating that alcohol suppresses tremor by modulating alpha 6 beta 38 extra -synaptic GABA A receptors.