A Role for GABA <subscript>A</subscript> Receptor β3 Subunits in Mediating Harmaline Tremor Suppression by Alcohol: Implications for Essential Tremor Therapy.
In: Tremor and other hyperkinetic movements (New York, N.Y.), Jg. 14 (2024-04-26), S. 20
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Zugriff:
Background: Essential tremor patients may find that low alcohol amounts suppress tremor. A candidate mechanism is modulation of α6β3δ extra-synaptic GABA A 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 δ or α6 subunits. Here we addressed whether low-dose alcohol requires the β3 subunit for tremor suppression.
Methods: We tested whether low-dose alcohol suppresses tremor in cre-negative 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 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 vehicle-treated controls in floxed β3 cre- mice, but had no effect on tremor in floxed β3 cre+ littermates that have β3 knocked out. This was not due to potential interference of α6 expression by the insertion of the cre gene into the α6 gene since non-floxed β3 cre+ and cre- littermates exhibited similar tremor suppression by alcohol.
Discussion: As α6β3δ GABA A receptors are sensitive to low-dose alcohol, and cerebellar granule cells express β3 and are the predominant brain site for α6 and δ expression together, our overall findings suggest alcohol acts to suppress tremor by modulating α6β3δ 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 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 GABA A receptors.
Competing Interests: The authors have no competing interests to declare.
(Copyright: © 2024 The Author(s).)
| Titel: |
A Role for GABA <subscript>A</subscript> Receptor β3 Subunits in Mediating Harmaline Tremor Suppression by Alcohol: Implications for Essential Tremor Therapy.
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| Autor/in / Beteiligte Person: | Handforth, A ; Singh, RP ; Kosoyan, HP ; Kadam, PA |
| Zeitschrift: | Tremor and other hyperkinetic movements (New York, N.Y.), Jg. 14 (2024-04-26), S. 20 |
| Veröffentlichung: | 2020- : East London Works, UK : Ubiquity Press ; <i>Original Publication</i>: New York : Center for Digital Research and Scholarship, 2024 |
| Medientyp: | academicJournal |
| ISSN: | 2160-8288 (electronic) |
| DOI: | 10.5334/tohm.834 |
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