Search for Novel Therapies for Essential Tremor Based on Positive Modulation of α6-Containing GABA(A) 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 α6βδ GABA(A) receptors. This suggests that drugs specifically enhancing the action of α6βδ or α6βγ2 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 α6βδ (ketamine) or α6βγ2 (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 α6 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 α6 knockout mice. DISCUSSION: Modulators of α6βδ and α6βγ2 GABA(A) receptors warrant attention for novel therapies as they are anticipated to be effective and well-tolerated. Ketamine likely failed to attain α6βδ-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 α6βγ2 receptors represents a worthy strategy for developing essential tremor therapies. HIGHLIGHTS: We tested for harmaline tremor suppression drugs previously described as in vitro α6βδ or α6βγ2 GABA(A) receptor-selective modulators. Well-tolerated flumazenil doses suppressed tremor in α6-wildtype but not α6-knockout mice. Compound 6 and ketamine failed to display this profile, likely from off-target effects. Selective α6 modulators hold promise as tremor therapy.