Alcohol and Ganaxolone Suppress Tremor via Extra-Synaptic GABA <sub>A</sub> Receptors in the Harmaline Model of Essential Tremor

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Abstract

Background:

A long-standing question is why essential tremor often responds to non-intoxicating amounts of alcohol. Blood flow imaging and high-density electroencephalography have indicated that alcohol acts on tremor within the cerebellum. As extra-synaptic δ-subunit-containing GABA _A receptors are sensitive to low alcohol levels, we wondered whether these receptors mediate alcohol’s anti-tremor effect and, moreover, whether the δ-associated GABA _A receptor α6 subunit, found abundantly in the cerebellum, is required.

Methods:

We tested the hypotheses that low-dose alcohol will suppress harmaline-induced tremor in wild-type mice, but not in littermates lacking GABA _A receptor δ subunits, nor in littermates lacking α6 subunits. As the neurosteroid ganaxolone also activates extra-synaptic GABA _A receptors, we similarly assessed this compound. The harmaline mouse model of essential tremor was utilized to generate tremor, measured as a percentage of motion power in the tremor bandwidth (9–16 Hz) divided by background motion power at 0.25–32 Hz.

Results:

Ethanol, 0.500 and 0.575 g/kg, and ganaxolone, 7 and 10 mg/kg, doses that do not impair performance in a sensitive psychomotor task, reduced harmaline tremor compared to vehicle-treated controls in wild-type mice but failed to suppress tremor in littermates lacking the δ or the α6 GABA _A receptor subunit.

Discussion:

As cerebellar granule cells are the predominant brain site intensely expressing GABA _A receptors containing both α6 and δ subunits, these findings suggest that this is where alcohol acts to suppress tremor. It is anticipated that medications designed specifically to target α6βδ-containing GABA _A receptors may be effective and well-tolerated for treating essential tremor.

Highlights:

How does alcohol temporarily ameliorate essential tremor? This study with a mouse model found that two specific kinds of GABA receptor subunits were needed for alcohol to work. As receptors with both these subunits are found mainly in cerebellum, this work suggests this is where alcohol acts to suppress tremor.

Related collections

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Author and article information

Contributors

Adrian Handforth

Ram P. Singh

Journal

Journal ID (nlm-ta): Tremor Other Hyperkinet Mov (N Y)

Journal ID (iso-abbrev): Tremor Other Hyperkinet Mov (N Y)

Journal ID (issn): 2160-8288

Title: Tremor and Other Hyperkinetic Movements

Publisher: Ubiquity Press

ISSN (Electronic): 2160-8288

Publication date (Electronic, pub): 18 May 2023

Publication date (Electronic, collection): 2023

Volume: 13

Electronic Location Identifier: 18

Affiliations

[1 ]Neurology Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America

[2 ]Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America

Author notes

CORRESPONDING AUTHORS: Adrian Handforth, M.D. Neurology Service (W127), VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, California 90073, USA Charles.Handforth@ 123456va.gov ; Ram P. Singh, Ph.D. Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America Ram.Singh@ 123456va.gov

Article

DOI: 10.5334/tohm.760

PMC ID: 10198231

PubMed ID: 37214542

SO-VID: 21371795-ee75-461a-8302-ab86c9287720

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 February 2023

Date accepted : 06 May 2023

Funding

Funded by: International Essential Tremor Foundation, doi open-funder-registry10.13039/open_funder_registry10.13039/100008447;

Funded by: Veterans Affairs;

Supported by International Essential Tremor Foundation and by Veterans Affairs. Adrian Handforth served on the Medical Advisory Board of the International Essential Tremor Foundation. A Handforth and H Kosoyan have received salary support from Veterans Affairs. Aside from these grants and salary support, none of the authors have received funds from the following sources: stock ownership in medically related fields, intellectual property rights, consultancies, expert testimony, advisory boards, employment, partnerships, contracts, honoraria, royalties, or grants.