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 α6β3δ extra-synaptic GABAA receptors, that in vitro respond to non-intoxicating alcohol levels. We previously found that low-dose alcohol reduces harmaline tremor in wild-t...

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Bibliographic Details
Published in:Tremor and other hyperkinetic movements (New York, N.Y.) N.Y.), 2024, Vol.14 (1), p.20-20
Main Authors: Handforth, Adrian, Singh, Ram P., Kosoyan, Hovsep P., Kadam, Pournima A.
Format: Article
Language:English
Subjects:
Alcohol
Brain research
Hyperactivity
Hypotheses
Laboratory animals
Tremor (Muscular contraction)
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Summary:Background: Essential tremor patients may find that low alcohol amounts suppress tremor. A candidate mechanism is modulation of α6β3δ extra-synaptic GABAA receptors, that in vitro respond to non-intoxicating alcohol levels. We previously found that low-dose alcohol reduces harmaline tremor in wild-type mice, but not in littermates lacking the δ or α6 subunit. Here we addressed another prediction: the requirement of low-dose alcohol tremor suppression for the β3 subunit.Methods: We tested whether low-dose alcohol suppresses tremor in cre-null mice with intact β3 exon 3 flanked by loxP, and in littermates in which this region was excised by cre expressed under the α6 subunit promotor. Tremor in the harmaline tremor model was measured as a percentage of motion power in the tremor bandwidth divided by background motion power.Results: Alcohol, 0.500 and 0.575 g/kg, reduced harmaline tremor compared to vehicle-treated controls in cre-null loxPβ3-homozygotes, but had no effect on tremor in cre-heterozygous loxPβ3-homozygous littermates that have β3 knocked out. This was not due to potential interference of α6 expression by cre-recombinase insertion into the α6 gene since loxPβ3-null mice that were cre-null or cre-heterozygous littermates exhibited similar tremor suppression by alcohol.Discussion: As α6β3δ GABAA receptors are sensitive to low-dose alcohol, and cerebellar granule cells express β3 and are the predominant brain site for combined α6 and δ expression, our overall findings suggest alcohol acts to suppress tremor by modulating α6β3δ GABAA receptors on these cells. Novel drugs that target this receptor may be effective and well-tolerated for essential tremor.HighlightsWe previously found with the harmaline essential tremor model that GABAA receptors containing α6 and δ subunits mediate tremor suppression by alcohol. We now show that β3 subunits in α6-expressing cells, likely cerebellar granule cells, are also required, indicating that alcohol suppresses tremor by modulating α6β3δ extra-synaptic GABAA receptors.
ISSN:2160-8288
2160-8288
DOI:10.5334/tohm.834