Search for Novel Therapies for Essential Tremor Based on Positive Modulation of Α6-Containing GABAA Receptors.

Background: Prior work using GABA A receptor subunit knockouts and the harmaline model has indicated that low-dose alcohol, gaboxadol, and ganaxolone suppress tremor via a6 ss d GABA A receptors. This suggests that drugs specifically enhancing the action of a6 ss d or alpha 6 ss gamma 2 GABA A receptors, both predominantly expressed on cerebellar granule cells, would be effective against tremor. We thus examined three drugs described by in vitro studies as selective a6 ss d (ketamine) or a6 ss gamma 2 (Compound 6, flumazenil) receptor modulators. Methods: In the first step of evaluation, the maximal dose was sought at which 6/6 mice pass straight wire testing, a sensitive test for psychomotor impairment. Only non-impairing doses were used to evaluate for anti-tremor efficacy in the harmaline model, which was assessed in wildtype and alpha 6 subunit knockout littermates. Results: Ketamine, in maximally tolerated doses of 2.0 and 3.5 mg/kg had minimal effect on harmaline tremor in both genotypes. Compound 6, at well-tolerated doses of 1-10 mg/kg, effectively suppressed tremor in both genotypes. Flumazenil suppressed tremor in wildtype mice at doses (0.015-0.05 mg/kg) far lower than those causing straight wire impairment, and did not suppress tremor in a6 knockout mice. Discussion: Modulators of a6 ss d and a6 ss gamma 2 GABA A receptors warrant attention for novel therapies as they are anticipated to be effective and well-tolerated. Ketamine likely failed to attain a6 ss d-active levels. Compound 6 is an attractive candidate, but further study is needed to clarify its mechanism of action. The flumazenil results provide proof of principle that targeting a6 ss gamma 2 receptors represents a worthy strategy for developing essential tremor therapies. HIGHLIGHTS We tested for harmaline tremor suppression drugs previously described as in vitro a6 ss d or a6 ss gamma 2 GABA A receptor-selective modulators. Well-tolerated flumazenil doses suppressed tremor in alpha 6-wildtype but not alpha 6-knockout mice. Compound 6 and ketamine failed to display this profile, likely from off-target effects. Selective a6 modulators hold promise as tremor therapy.