The α2β3γ2 GABA_A receptor preferring agonist NS11394 aggravates dystonia in the phenotypic dt^sz model

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• 作者：Christine Sprö ; te ; Franziska Richter ; Anne Bauer ; Julia Gerstenberger ; Angelika Richter ; ^{angelika.richter@vetmed.uni-leipzig.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：GABA ; gamma-aminobutyric acid ; GABAA receptor ; gamma-aminobutyric acid type A receptor
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：791
• 期：Complete
• 页码：655-658
• 全文大小：439 K

文摘

Dystonia is a movement disorder, characterized by involuntary muscle contractions resulting in abnormal movements and/or postures. Antidystonic effects of benzodiazepines in patients with different types of dystonia could be replicated in the dt^sz mutant hamster, a phenotypic model of paroxysmal dystonia. Compounds with preferred binding at specific subunits of the gamma aminobutyric acid type A (GABA_A) receptor may provide a more beneficial spectrum of effects in comparison with benzodiazepines. We therefore examined the effects of the α1β3γ2 GABA_A receptor preferring compound zolpidem (2.0–10.0 mg/kg i.p.) and of the α2β3γ2 GABA_A receptor preferring compound NS11394 (3.0–30 mg/kg i.p.) on the severity of dystonia in the dt^sz mutant in comparison with the benzodiazepine clonazepam (0.5–1.0 mg/kg i.p.). As expected, clonazepam exerted pronounced antidystonic effects. While zolpidem showed moderate beneficial effects, NS11394 significantly increased the severity of dystonia. The present results indicate for the first time that positive GABA_A receptor modulators show contrary effects on dystonia dependent on their preference for alpha-subunits. The potential link between alterations in GABA_A receptor subunits and GABAergic disinhibition in dystonia deserves further attention in research on the pathophysiology and therapeutic targets.