The novel selective and silent 5-HT1A receptor antagonist (+)-WAY-100135 aggravates dystonic movements in a mutant hamster model.
Several clinical and experimental findings suggest that abnormal serotonin (5-HT) function may be involved in movement disorders such as dystonia, and it was proposed that selective 5-HT1A receptor antagonists may be of benefit in treating such disorders. In the present study, the novel, highly selective and silent 5-HT1A receptor antagonist (+)-WAY-100135 (N-tert-butyl-3(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylprop ionamide) was tested in an inbred line of Syrian hamsters with generalized dystonia, i.e. a frequent movement disorder in humans. In order to demonstrate that WAY-100135 acts as a 5-HT1A receptor antagonist in the hamster, the drug was shown to antagonize the behavioural syndrome induced by 8-hydroxy-2-(di-n-propylamino)tetralin. When administered at 5-HT1A receptor antagonistic doses in dystonic hamsters, (+)-WAY-100135 dramatically aggravated the dystonic attacks. The data thus suggest that, in contrast to previous theoretical proposals, 5-HT1A receptor antagonists provide no novel therapeutic approach to involuntary movement disorders such as dystonia.
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
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Löscher
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Richter
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D006224:Cricetinae; D004421:Dystonia / Q000503:physiopathology*; D005260:Female; D008297:Male; D008647:Mesocricetus; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D012702:Serotonin Antagonists
D010879:Piperazines; D012702:Serotonin Antagonists; C081293:WAY 100135; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin