Effects of striatal injections of GABA(A) receptor agonists and antagonists in a genetic animal model of paroxysmal dystonia.
The underlying mechanisms of idiopathic dystonias are poorly understood. The dystonic phenotype in the dt(sz) mutant hamster, a model of paroxysmal dystonia, has been suggested to be based on a deficit of gamma-aminobutyric acid (GABA)ergic interneurons and changes of the GABA(A)-benzodiazepine receptor complex in the striatum. In order to confirm and extend previous observations, the effects of compounds which bind to different sites of the GABA(A) receptor on the severity of dystonia were determined after striatal microinjections in comparison to systemic treatments in dt(sz) mutants. The GABA(A) receptor agonist (muscimol) and the benzodiazepine (flurazepam) reduced the severity of dystonia after striatal and systemic injections. The antidystonic effects of the barbiturate phenobarbital were less marked both after striatal and intraperitoneal administration of drugs. Intrastriatal injections of GABA delayed the onset of dystonic attacks. Striatal and systemic treatments with the GABA(A) receptor antagonist, bicuculline, and with pentylenetetrazole, which reduces GABAergic function, accelerated the onset of dystonia at subconvulsant doses. The benzodiazepine receptor antagonists flumazenil aggravated dystonia after systemic and intrastriatal injections. In all, the present data substantiate the relevance of striatal GABAergic disinhibition in the pathogenesis of paroxysmal dystonia in dt(sz) mutants.
Hamann
Melanie
M
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany.
Richter
Angelika
A
D000818:Animals; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology; D001665:Binding Sites; D003342:Corpus Striatum / Q000187:drug effects* / Q000503:physiopathology; D006224:Cricetinae; D004421:Dystonia / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D005479:Flurazepam / Q000494:pharmacology; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007274:Injections, Intraperitoneal; D008297:Male; D008647:Mesocricetus; D008845:Microinjections; D009118:Muscimol / Q000008:administration & dosage / Q000494:pharmacology; D010433:Pentylenetetrazole / Q000008:administration & dosage / Q000494:pharmacology; D010634:Phenobarbital / Q000008:administration & dosage / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D009118:Muscimol; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D005479:Flurazepam; D010433:Pentylenetetrazole; D001640:Bicuculline; D010634:Phenobarbital