Effects of pharmacological manipulation of GABAergic neurotransmission in a new mutant hamster model of paroxysmal dystonia.
Attacks of sustained dystonic postures of limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage) in an inbred line of Syrian hamsters. The severity of the dystonic syndrome in these mutant hamsters (gene symbol dtsz) is age-dependent, with a peak at about 30-40 days of age. A scoring system for grading type and severity of the dystonic attacks can be used to study the activity of drugs against dystonic movements with individual pre- and post-drug vehicle trials as control. In the present experiments, the effects of drugs which alter GABAergic functions in the brain were studied in dystonic hamsters. Anticonvulsants, i.e. valproate, diazepam and phenobarbital, which augment GABAergic neurotransmission, decreased the severity of dystonic attacks in the mutant hamsters, while administration of subconvulsive doses of pentylenetetrazol or the inverse benzodiazepine receptor agonist FG 7142 increased the severity of the syndrome. Anticonvulsants, i.e. phenytoin and carbamazepine, which are not thought to act via effects on GABAergic neurotransmission, exerted no antidystonic effects, but even worsened the attack in several animals. In contrast, the GABA-elevating drug, aminooxyacetic acid, produced a marked antidystonic effect in the hamsters. Similarly, the GABAB receptor agonist, baclofen, significant decreased the severity of the dystonic attack. The data indicate that dystonic movements in dtsz mutant hamsters can be attenuated by drugs which facilitate GABAergic functions, but worsened by drugs which impair GABAergic neurotransmission. These data thus seem to suggest that the dystonic syndrome in dtsz mutant hamsters is under GABAergic influence. The data show furthermore that dystonic hamsters are a suitable model to detect antidystonic effects of drugs.
Fredow
G
G
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, F.R.G.
Löscher
W
W
D000818:Animals; D001418:Baclofen / Q000494:pharmacology / Q000627:therapeutic use; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use; D006224:Cricetinae; D003975:Diazepam / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004421:Dystonia / Q000188:drug therapy / Q000503:physiopathology*; D008647:Mesocricetus / Q000235:genetics*; D009154:Mutation; D010433:Pentylenetetrazole / Q000494:pharmacology* / Q000627:therapeutic use; D010634:Phenobarbital / Q000494:pharmacology / Q000627:therapeutic use; D010672:Phenytoin / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D010672:Phenytoin; D001418:Baclofen; D003975:Diazepam; D010433:Pentylenetetrazole; D010634:Phenobarbital