Unravelling the role of cerebellar α6GABAA receptors in anti-tremor pharmacotherapies

Essential tremor (ET), characterized by action tremor, is one of the most prevalent movement disorders significantly impacting patients' well-being. However, its pathogenesis has not been fully elucidated, posing challenges for developing targeted pharmacological interventions. We previously found that ethanol significantly suppressed harmaline-induced action tremor in ICR mice at low-to-moderate doses that mimic social-drinking alcohol levels in humans. This effect was antagonized by intra-cerebellarly (i.cb.)-administered furosemide, an antagonist of the α6 subunit-containing GABA_A receptors (α6GABA_ARs), suggesting the involvement of cerebellar α6GABA_ARs. Here, we further demonstrated that the anti-tremor effect of the same dose of ethanol (1.2 g/kg, i.p.) was nullified in Gabra6-knockout ICR mice in a gene dose-dependent manner. This supports our proposal that cerebellar α6GABA_ARs are an underexplored anti-tremor target. We therefore further examined whether cerebellar α6GABA_ARs are involved in the anti-tremor effects of clinically-effective ET medications, using the same pharmacological approach in the harmaline model. Results showed that gabapentin (30 mg/kg, i.p.), topiramate (30 mg/kg, i.p.), propranolol (20 mg/kg, i.p.), diazepam (4 mg/kg, i.p.), zonisamide (20 mg/kg, i.p.), and oxcarbazepine (15 mg/kg, i.p.) significantly attenuated harmaline (20 mg/kg, s.c.)-induced action tremor in ICR mice. Interestingly, the anti-tremor effects of gabapentin and topiramate, but not those of other anti-tremor medications, were no longer evident in i.cb.-administered furosemide. Furosemide per se did not alter harmaline tremor. These results suggest that cerebellar α6GABA_ARs contribute, at least partly, to the anti-tremor effects of topiramate and gabapentin and that α6GABA_AR-selective positive modulators are a potential novel therapy for ET patients.