Paradoxical aggravation of paroxysmal dystonia during chronic treatment with phenobarbital in a genetic rodent model.
Recent studies in mutant hamsters (dt(sz)), an animal model of primary paroxysmal dystonia, indicated that altered function of the gamma-aminobutyric acid (GABA)ergic system plays a critical role in the pathogenesis of dystonia. In the present study, dt(sz) hamsters were chronically treated with phenobarbital, which has been found to exert antidystonic effects in mutant hamsters after acute administration. In untreated dt(sz) hamsters, the severity of dystonia follows an age-dependent time course with a maximum between the 30th and 40th day of life, followed by a continuous decline of severity until complete remission occurs at the age of about 70 days. In contrast to acute effects, chronic treatment with phenobarbital via drinking water starting at an age of 21 days (i.e., after weaning) worsened dystonia and retarded the spontaneous remission. The unexpected prodystonic effect was more marked after administration of higher doses and when chronic treatment with phenobarbital started at an age of 1 day (neonatal administration via breast milk). After withdrawal of phenobarbital at the age of 70 days, the severity rapidly declined in all treated groups. When phenobarbital was readministered 1 week later, the hamsters again exhibited severe dystonia. The mechanism of these unexpected findings is unknown. Tentatively, activity-dependent GABA-mediated excitation caused by chronic treatment with phenobarbital may be important for the prodystonic effects under pathological conditions in dt(sz) hamsters.
Richter
A
A
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Bünteweg 17, D-30559, Hannover, Germany. arichter@pharma.tiho-hannover.de
Löscher
W
W
D000375:Aging; D000818:Animals; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D008297:Male; D009154:Mutation; D010634:Phenobarbital / Q000493:pharmacokinetics / Q000494:pharmacology*; D012720:Severity of Illness Index; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D010634:Phenobarbital