2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Dystonia

The pathophysiology of idiopathic dystonias is still unknown, but it is regarded as a basal ganglia disorder. Previous experiments in the dt(sz) hamster, a model of primary paroxysmal dystonia, demonstrated reduced discharge rates and an abnormal pattern within the entopeduncular nucleus (EPN), a basal ganglia output structure. To clarify if this is based on abnormal gamma-aminobutyric acid(GABA)ergic or glutamatergic input, microinjections into the EPN were done in mutant hamsters in the present study. The GABA(A) receptor antagonists pentylenetetrazole and bicuculline exerted moderate antidystonic effects, while previous systemic administrations worsened dystonia in the dt(sz) mutant. GABA-potentiating drugs, i.e., the GABA(A) receptor agonist muscimol and the GABA transporter inhibitor 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxy-lic acid (NNC-711), which are known to improve dystonia after systemic treatment in mutant hamsters, did not exert significant effects after EPN injections, but NNC-711 tended to increase the severity at the highest dose (2.5 ng bilateral). The NMDA receptor antagonist D(-)-2-amino-5-phosphopentanoic acid (AP-5) retarded the onset of a dystonic attack. However, this effect was not dose dependent and the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol(f)quinoxaline (NBQX) alone or in combination with AP-5 and NNC-711, also failed to show any effects on dystonia. The present data do not provide clear evidence for an enhanced striatal GABAergic input or a reduced glutamatergic activation of the EPN via the subthalamic nucleus, i.e., more pronounced antidystonic effects of GABA(A) receptor antagonists and stronger prodystonic effects of GABAmimetics and glutamate receptor antagonists were expected. Nevertheless, previously found changes in entopeduncular activity probably play a critical pathophysiological role in dystonic hamsters.

Topics: Animals; Animals, Newborn; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Dystonia; Entopeduncular Nucleus; Excitatory Amino Acid Antagonists; GABA Agents; Microinjections; Muscimol; Nipecotic Acids; Oximes; Pentylenetetrazole; Quinoxalines; Reaction Time; Severity of Illness Index; Time Factors; Valine

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.

Topics: Animals; Basal Ganglia; Caudate Nucleus; Cricetinae; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Dystonia; Excitatory Amino Acid Antagonists; Microinjections; Movement; Muscle Contraction; Mutation; Posture; Putamen; Pyrrolidinones; Quinoxalines; Reaction Time; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Severity of Illness Index; Valine

The effects of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) were studied in an inbred line of Syrian golden hamsters with paroxysmal dystonia. The severity of dystonia in these mutant hamsters was significantly reduced by NBQX at doses of 10-20 mg/kg i.p. Coadministration of the transport inhibitor probenecid prolonged the antidystonic action of NBQX, indicating that NBQX may be rapidly eliminated by a process sensitive to probenecid. A similar potent and long-lasting antidystonic effect was obtained when NBQX was administered as an aqueous suspension rather than an aqueous solution, which may be explained by retarded absorption of NBQX after its injection as a suspension. The antidystonic activity of the AMPA antagonist NBQX may indicate that an overactivity of excitatory acidergic neurotransmission is involved in the pathophysiology of dystonia in genetically dystonic hamsters.

Topics: Animals; Cricetinae; Dystonia; Electric Stimulation; Excitatory Amino Acid Antagonists; Female; Injections, Intraperitoneal; Male; Mesocricetus; Probenecid; Quinoxalines; Receptors, AMPA; Solutions; Suspensions