Neurology Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.
Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.
Tremor Other Hyperkinet Mov (N Y). 2023 May 18;13:18. doi: 10.5334/tohm.760. eCollection 2023.
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 δ-subunit-containing GABA receptors are sensitive to low alcohol levels, we wondered whether these receptors mediate alcohol's anti-tremor effect and, moreover, whether the δ-associated GABA receptor α6 subunit, found abundantly in the cerebellum, is required.
We tested the hypotheses that low-dose alcohol will suppress harmaline-induced tremor in wild-type mice, but not in littermates lacking GABA receptor δ subunits, nor in littermates lacking α6 subunits. As the neurosteroid ganaxolone also activates extra-synaptic GABA 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.
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 δ or the α6 GABA receptor subunit.
As cerebellar granule cells are the predominant brain site intensely expressing GABA receptors containing both α6 and δ subunits, these findings suggest that this is where alcohol acts to suppress tremor. It is anticipated that medications designed specifically to target α6βδ-containing GABA receptors may be effective and well-tolerated for treating essential tremor.
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.
长期以来，人们一直想知道为什么特发性震颤通常对非致醉剂量的酒精有反应。血流成像和高密度脑电图表明，酒精作用于小脑内的震颤。由于突触外 δ 亚基 GABA 受体对低酒精水平敏感，我们想知道这些受体是否介导酒精的抗震颤作用，此外，是否需要在小脑中大量存在的 δ 相关 GABA 受体 α6 亚基。
我们测试了以下假设：低剂量酒精将抑制野生型小鼠中海洛因诱导的震颤，但不能抑制缺乏 GABA 受体 δ 亚基的同窝仔鼠，也不能抑制缺乏 α6 亚基的同窝仔鼠。由于神经甾体 ganaxolone 也激活突触外 GABA 受体，我们同样评估了这种化合物。利用海洛因诱导的特发性震颤小鼠模型产生震颤，以震颤带宽（9-16 Hz）内运动功率与 0.25-32 Hz 背景运动功率之比的百分比表示。
乙醇 0.500 和 0.575 g/kg 和 ganaxolone 7 和 10 mg/kg，这些剂量在敏感的运动任务中不会损害表现，与野生型小鼠中的载体处理对照相比，降低了海洛因引起的震颤，但未能抑制缺乏 δ 或 α6 GABA 受体亚基的同窝仔鼠的震颤。
由于小脑颗粒细胞是强烈表达包含 α6 和 δ 亚基的 GABA 受体的主要脑区，这些发现表明这是酒精发挥作用以抑制震颤的部位。预计专门针对包含 α6βδ 的 GABA 受体的药物可能对治疗特发性震颤有效且耐受良好。
酒精如何暂时缓解特发性震颤？这项使用小鼠模型的研究发现，酒精发挥作用需要两种特定类型的 GABA 受体亚基。由于这两种亚基的受体主要存在于小脑，这项工作表明酒精在小脑内发挥作用以抑制震颤。
