The α2β3γ2 GABAAreceptor preferring agonist NS11394 aggravates dystonia in the phenotypic dtszmodel.
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 dtszmutant hamster, a phenotypic model of paroxysmal dystonia. Compounds with preferred binding at specific subunits of the gamma aminobutyric acid type A (GABAA) receptor may provide a more beneficial spectrum of effects in comparison with benzodiazepines. We therefore examined the effects of the α1β3γ2 GABAAreceptor preferring compound zolpidem (2.0-10.0mg/kg i.p.) and of the α2β3γ2 GABAAreceptor preferring compound NS11394 (3.0-30mg/kg i.p.) on the severity of dystonia in the dtszmutant in comparison with the benzodiazepine clonazepam (0.5-1.0mg/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 GABAAreceptor modulators show contrary effects on dystonia dependent on their preference for alpha-subunits. The potential link between alterations in GABAAreceptor subunits and GABAergic disinhibition in dystonia deserves further attention in research on the pathophysiology and therapeutic targets.
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, 04103 Leipzig, Germany.
Christine
C
Spröte
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, 04103 Leipzig, Germany.
Franziska
F
Richter
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, 04103 Leipzig, Germany.
Anne
A
Bauer
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, 04103 Leipzig, Germany.
Julia
J
Gerstenberger
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, 04103 Leipzig, Germany. Electronic address: angelika.richter@vetmed.uni-leipzig.de.
Angelika
A
Richter
D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D058785:GABA-A Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D010641:Phenotype; D021122:Protein Subunits / Q000819:agonists* / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D013379:Substrate Specificity
C533864:3'-(5-(1-hydroxy-1-methylethyl)benzoimidazol-1-yl)biphenyl-2-carbonitrile; D001562:Benzimidazoles; D058785:GABA-A Receptor Agonists; D021122:Protein Subunits; D011963:Receptors, GABA-A
Dyskinesia; Dystonia; GABA; Movement disorders; Subunits