Evidence for striatal dopaminergic overactivity in paroxysmal dystonia indicated by microinjections in a genetic rodent model.
Mutant dystonic hamsters (dt(sz)), a model of primary paroxysmal dystonia, display attacks of generalized dystonia in response to mild stress in an age-dependent manner. Recent studies in dystonic hamsters have revealed decreased densities of dopamine D(1) and D(2) in the dorsal striatum. This finding has been interpreted as a down-regulation in response to enhanced dopamine release because systemic treatments with neuroleptics reduced the severity of dystonia while levodopa exerted prodystonic effects. Therefore, in the present study we investigated the effects of amphetamine as well as of selective D(1) or D(2) receptor agonists and antagonists on the severity of dystonia after systemic administrations and after microinjections into the dorsal striatum. Amphetamine and the dopamine D(2) agonist quinpirole increased the severity of dystonia after systemic and striatal injections, while the dopamine D(1) agonist SKF 38393 exerted only moderate prodystonic effects after systemic administration of a high dose but not after striatal injections. These results suggest that a predominant overstimulation of D(2) receptors is pathogenetically involved in the dystonic syndrome. Combined systemic or striatal administrations of the D(1) and D(2) receptor agonists did not reveal synergistic prodystonic effects at the examined doses. The selective D(1) antagonist SCH 23390 as well as the D(2) antagonist raclopride tended to decrease the severity of dystonia after systemic administration but failed to exert significant effects after striatal injection. The coadministration of ineffective doses of the antagonists SCH 23390 and raclopride, however, exerted an enormous antidystonic efficacy after both systemic and striatal injections. Since striatal injections of compounds which enhance dopaminergic activity aggravated dystonia, while coinjections of dopamine D1 and D2 receptor antagonists reduced the severity of dystonia, the present findings clearly support the hypothesis that striatal dopaminergic overactivity plays a crucial role for the manifestation of dystonic attacks in the hamster model of paroxysmal dystonia.
Rehders
J H
JH
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Bünteweg 17, D-30559, Hannover, Germany.
Löscher
W
W
Richter
A
A
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000008:administration & dosage / Q000494:pharmacology*; D000375:Aging; D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004421:Dystonia / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D007839:Functional Laterality; D008297:Male; D008845:Microinjections; D019257:Quinpirole / Q000008:administration & dosage / Q000494:pharmacology; D020891:Raclopride / Q000008:administration & dosage / Q000494:pharmacology*; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D020891:Raclopride; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000661:Amphetamine