GABA-A Alpha 2/3 but Not Alpha 1 Receptor Subunit Ligand Inhibits Harmaline and Pimozide-Induced Tremor in Rats

Abstract

Treatment of tremors, such as in essential tremor (ET) and Parkinson’s disease (PD) is mostly ineffective. Exact tremor pathomechanisms are unknown and relevant animal models are missing. GABA-A receptor is a target for tremorolytic medications, but current non-selective drugs produce side effects and have safety liabilities. The aim of this study was a search for GABA-A subunit-specific tremorolytics using different tremor-generating mechanisms. Two selective positive allosteric modulators (PAMs) were tested. Zolpidem, targeting GABA-A α1, was not effective in models of harmaline-induced ET, pimozide- or tetrabenazine-induced tremulous jaw movements (TJMs), while the novel GABA-A α2/3 selective MP-III-024 significantly reduced both the harmaline-induced ET tremor and pimozide-induced TJMs. While zolpidem decreased the locomotor activity of the rats, MP-III-024 produced small increases. These results provide important new clues into tremor suppression mechanisms initiated by the enhancement of GABA-driven inhibition in pathways controlled by α2/3 but not α1 containing GABA-A receptors. Tremor suppression by MP-III-024 provides a compelling reason to consider selective PAMs targeting α2/3-containing GABA-A receptors as novel therapeutic drug targets for ET and PD-associated tremor. The possibility of the improved tolerability and safety of this mechanism over non-selective GABA potentiation provides an additional rationale to further pursue the selective α2/3 hypothesis.

Phenols and GABAA receptors: from structure and molecular mechanisms action to neuropsychiatric sequelae

“…This finding is similar to the essential tremors observed in patients. In contrast, results from recent studies provide important new clues into tremor suppression mechanisms initiated by the enhancement of GABA-driven inhibition in pathways controlled by the α2/3 GABA A R subunits but not the α1 subunit ( Kosmowska et al, 2023 ). In addition, GABA A R α6 subunit-selective drugs were found to cause a substantial reduction in tremors and restoration of physical wellbeing in a mouse model ( Huang et al, 2021 ).…”

Bibliometric Analysis on GABA-A Receptors Research Based on CiteSpace and VOSviewer

“…10 Genetic studies have documented the relationship between GABA-A receptor subunit genes and epilepsy, 11 eating disorder, 12 autism, 13 and bipolar disorders. 14 Besides, there is also interest in GABA-A receptors as potential targets for Parkinson disease and other neurological dysfunctions, 15 essential tremor, 16 ischemic stroke, 17 pain management. 18 Even some of the World's major insecticides.…”