DESCRIPTION (provided by applicant): Essential tremor affects 0.5-0.9% of the general population and about 4.5% of those above age 65. Medications for tremor are re-purposed drugs found empirically rather than through laboratory research. As such they lack potency and specificity, and are often not well tolerated. In our program we seek to identify molecular targets to which anti-tremor drugs could be designed, offering greater on-target specificity and potency. A clue is that patients often report that as little as 1-2 glasses of wine can suppress tremor. Brain mapping studies in essential tremor indicate that hyper-oscillatory activity within circuits of the cerebellum underlies tremor. When patients are given low doses of alcohol, not only does the tremor diminish, but excessive activity in the cerebellar cortex also diminishes. We postulate that low-dose alcohol works on tremor by activating GABAA receptors that contain alpha6, beta3 and delta subunits, found only in the cerebellar cortex. If we can show that this receptor can mediate tremor suppression, it could represent an important target for anti-tremor therapy. The GABAA receptor is a pentamer made of alpha, beta, and either gamma or delta subunits. Delta GABAA receptors exert tonic inhibition, and are much more sensitive to GABA. Studies with receptors expressed in cells, and with brain slices, have shown that THIP, muscimol and neurosteroids such as ganaxolone selectively activate delta GABAA receptors rather than gamma GABAA receptors. In addition, ethanol in the range of 1-2 glasses of wine has been found to activate those delta GABAA receptors that use beta3 subunits. We hypothesize that activation of delta GABAA receptors by THIP, muscimol, ganaxolone, and low-dose alcohol will suppress tremor in the harmaline model of essential tremor in wild-type but not littermate delta knockout mice. In addition, the tremor-suppressing effect of alcohol in wild-type mice should be reversed by the alcohol antagonist Ro15-4513, providing further evidence that alcohol is suppressing tremor via a GABAA receptor. We use the harmaline tremor model, which has many similarities to tremor of essential tremor. Motion power is digitally analyzed to provide measures of motion in the tremor bandwidth as a ratio of overall motion power. Our pilot data indicate that THIP, muscimol, ganaxolone, and low-dose alcohol all suppress harmaline tremor in wild-type but not in delta knockout mice. The effect of low-dose alcohol was blocked by Ro15-4513. We propose to replicate these findings (Aim 1). The delta subunit is associated with either alpha 4 or with alpha 6 in GABAA receptors. The alpha4- delta receptors mediate sedation and motor impairment when activated, whereas no behavior has previously been found associated with alpha6-delta receptor activation. Our pilot experiments showed that THIP and low-dose alcohol suppress harmaline tremor in wild-type but not in alpha6 knockout mice, indicating the alpha6-d...