Alcohol and Ganaxolone Suppress Tremor via ExtraSynaptic GABA A Receptors in the Harmaline Model of Essential Tremor

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 d-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 d-associated GABA A receptor a6 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 d subunits, nor in littermates lacking a6 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 d or the a6 GABA A receptor subunit. Discussion: As cerebellar granule cells are the predominant brain site intensely expressing GABA A receptors containing both a6 and d subunits, these findings suggest that this is where alcohol acts to suppress tremor. It is anticipated that medications designed specifically to target a6 beta d-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.