Suppression of Harmaline Tremor by Activation of an Extrasynaptic GABA A Receptor: Implications for Essential Tremor

Tremor and Other Hyperkinetic Movements

article

Adrian Handforth¹  Pournima A. Kadam²  Hovsep P. Kosoyan²  Pirooz Eslami² 

[1] Veterans Affairs Greater Los Angeles Healthcare System;Research Service, Veterans Affairs Greater Los Angeles Healthcare System

关键词: Harmaline;    GABA;    cerebellum;    essential tremor;   

DOI  :  10.5334/tohm.407

学科分类：社会科学、人文和艺术（综合）

来源: Ubiquity Press

【 摘 要 】

Background: Metabolic imaging has revealed excessive cerebellar activity in essential tremor patients. Golgi cells control cerebellar activity by releasing gammaaminobutyric acid (GABA) onto synaptic and extrasynaptic receptors on cerebellar granule cells. We postulated that the extrasynaptic GABA A receptor-specific agonist THIP (gaboxadol; 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) would suppress tremor in the harmaline model of essential tremor and, since cerebellar extrasynaptic receptors contain α6 and  δ subunits, would fail to do so in mice lacking either subunit. Methods: Digitally measured motion power, expressed as 10–16 Hz power (the tremor bandwidth) divided by background 8–32 Hz motion power, was accessed during pre-harmaline baseline, pre-THIP harmaline exposure, and after THIP administration (0, 2, or 3 mg/kg). These low doses were chosen as they did not impair performance on the straight wire test, a sensitive test for psychomotor impairment. Littermate  δ wild-type and knockout ( Gabrd +/+ , Gabrd –/– ) and littermate α6 wild-type and knockout ( Gabraδ +/+ , Gabraδ –/– ) mice were tested. Results: Gabrd +/+ mice displayed tremor reduction at 3 mg/kg THIP but not 2 mg/kg, and Gabraδ +/+ mice showed tremor reduction at 2 and 3 mg/kg. Their respective subunit knockout littermates displayed no tremor reduction compared with vehicle controls at either dose. Discussion: The loss of anti-tremor efficacy with deletion of either  δ or α6 GABA A receptor subunits indicates that extrasynaptic receptors containing both subunits, most likely located on cerebellar granule cells where they are highly expressed, mediate tremor suppression by THIP. A medication designed to activate only these receptors may display a favorable profile for treating essential tremor.

【 授权许可】

CC BY