Alterations in pharmacological sensitivity of GABAergic but not dopaminergic and glutamatergic systems during ontogenesis in dystonic mutant hamsters.
Attacks of sustained dystonia of the limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage) in mutant (gene symbol dtsz) Syrian golden hamsters. The severity of the dystonic syndrome in these mutant hamsters is age-dependent, with a peak at weaning (21 days of age) and a second peak at about 30-40 days of age. Spontaneous remission occurs at an age of about 70 days. The syndrome in hamsters is thus similar to transient paroxysmal dystonia in children. In the present experiments, it was examined whether dystonic hamsters exhibit age-dependent differences in susceptibility to drugs which affect GABA (gamma-aminobutyrate)ergic, glutamatergic or dopaminergic functions. After acute administration, the GABA-elevating drug aminooxyacetic acid was significantly less potent in attenuating the severity of dystonic attacks at 21 days than at 31 days of age. Similar but less marked age-dependent differences in antidystonic activity were found for phenobarbital and diazepam. In contrast to these GABAmimetic drugs, the NMDA receptor antagonist CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid) or the dopamine receptor antagonist haloperidol had about the same antidystonic potency at both 21 and 31 days of age. Chronic treatment of dystonic hamsters with aminooxyacetic acid, starting at 21 days of age, did not alter the time course or the severity of dystonia.(ABSTRACT TRUNCATED AT 250 WORDS)
Richter
A
A
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Löscher
W
W
D000375:Aging / Q000502:physiology*; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D006224:Cricetinae; D003975:Diazepam / Q000494:pharmacology; D018492:Dopamine Antagonists; D004421:Dystonia / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D008647:Mesocricetus; D009154:Mutation / Q000235:genetics; D010634:Phenobarbital / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000187:drug effects*; D017470:Receptors, Glutamate / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012075:Remission, Spontaneous; D012680:Sensitivity and Specificity
D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000625:Aminooxyacetic Acid; D003975:Diazepam; D010634:Phenobarbital