Effects of intrastriatal injections of glutamate receptor antagonists on the severity of paroxysmal dystonia in the dtsz mutant.
Imbalances of the glutamatergic system are implicated in the pathophysiology of various basal ganglia disorders, but few is known about their role in dystonia, a common neurological syndrome in which involuntary muscle co-contractions lead to twisting movements and abnormal postures. Previous systemic administrations of glutamate receptor antagonists in dtsz hamsters, an animal model of primary paroxysmal dystonia, exerted antidystonic effects and electrophysiological experiments pointed to an enhanced corticostriatal glutamatergic activity. In order to examine the pathophysiological relevance of these findings, we performed striatal microinjections of the alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor antagonist 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX) and the N-methyl-D-aspartate (NMDA) receptor antagonists D(-)-2-amino-5-phosphopentanoic acid (AP-5), (R)-(+)-3-amino-1-hydroxypyrrolidin-2-one (HA-966) and dizocilpine (MK-801). The striatal application of NBQX reduced the severity and increased the latency to onset of dystonia significantly only at a dosage of 0.08 microg per hemisphere, lower (0.03 microg) and higher dosages (0.16 microg and 0.32 microg) failed to exert comparable effects on the severity. None of the striatal injected NMDA receptor antagonists influenced the severity of the dystonic attacks in the mutant hamster. The combined application of NBQX (0.08 microg) with AP-5 (1.0 microg) failed to exert synergistic antidystonic effects, but the beneficial effect on the severity of dystonia of the single application of NBQX was reproduced. Therefore, corticostriatal glutamatergic overactivity mediated by AMPA receptors, but not by NMDA receptors, is possibly important for the manifestation of dystonic attacks in the dtsz hamster mutant.
Sander
Svenja Esther
SE
Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universität Berlin, Koserstr. 20, 14195 Berlin, Germany. sander.svenja@vetmed.fu-berlin.de
Richter
Angelika
A
D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008845:Microinjections; D009068:Movement / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009154:Mutation; D011187:Posture; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012720:Severity of Illness Index; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D011760:Pyrrolidinones; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D016291:Dizocilpine Maleate; C056639:2-amino-5-phosphopentanoic acid; C001369:1-hydroxy-3-amino-2-pyrrolidone; D014633:Valine