Acute effects of neurosteroids in a rodent model of primary paroxysmal dystonia.
The pathophysiology of various types of dyskinesias, including dystonias, is poorly understood. Clinical and epidemiological studies in humans revealed that the severity of dyskinesias and the frequency of paroxysmal forms of the disease are altered by factors such as the onset of puberty, pregnancy, cyclical changes and stress, indicating an underlying hormonal component. The dystonic phenotype in the dt(sz) hamster, a genetic animal model of paroxysmal dystonia, has been suggested to be based on a deficit of striatal gamma-aminobutyric acid (GABA)ergic interneurons and changes in the GABA(A) receptor complex. In this animal model, hormonal influences seem to be also involved in the pathophysiology, but an influence of peripheral sex hormones has already been excluded. Possibly, neurosteroids as endogenous regulators of the GABA(A) receptor may be critically involved in the pathophysiology of dystonia in this animal model. Therefore, in the present study, the effects of the neurosteroids allopregnanolone acetate and allotetrahydrodeoxycorticosterone (THDOC), representing positive modulators of the GABA(A) receptor, as well as of the negative GABA(A) receptor modulators pregnenolone sulfate and dehydroepiandrosterone (DHEA), on severity of dystonia were examined in dt(sz) hamsters after acute intraperitoneal injections. Allopregnanolone acetate and THDOC exerted a moderate reduction of dystonia, whereas pregnenolone sulfate and DHEA had no significant effects. Although the effects of allopregnanolone acetate and THDOC were moderate and short-lasting, the present results suggest that changes in neurosteroid levels might be involved in the initiation of dystonic episodes. Future studies have to include measurements of brain neurosteroid levels as well as of chronic neurosteroid administrations to clarify the pathophysiological role and therapeutic potential of neurosteroids in dystonia.
Hamann
Melanie
M
Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universität Berlin, Koserstrasse 20, 14195 Berlin, Germany. Hamann.Melanie@vetmed.fu-berlin.de
Richter
Franziska
F
Richter
Angelika
A
D000818:Animals; D030801:Animals, Genetically Modified; D006224:Cricetinae; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000494:pharmacology*; D003900:Desoxycorticosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D005260:Female; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007274:Injections, Intraperitoneal; D008297:Male; D008647:Mesocricetus; D011280:Pregnanolone / Q000008:administration & dosage / Q000494:pharmacology*; D011284:Pregnenolone / Q000008:administration & dosage / Q000494:pharmacology*
D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; C018370:pregnenolone sulfate; D003900:Desoxycorticosterone; D003687:Dehydroepiandrosterone; C009413:tetrahydrodeoxycorticosterone; D011284:Pregnenolone; D011280:Pregnanolone