Role of striatal NMDA receptor subunits in a model of paroxysmal dystonia.

Dystonia is a movement disorder in which abnormal plasticity in the basal ganglia has been hypothesized to play a critical role. In a model of paroxysmal dystonia, the dt(sz) mutant hamster, previous studies indicated striatal dysfunctions, including an increased long-term potentiation (LTP). Beneficial effects were exerted by subunit-unspecific antagonists at NMDA receptors, which blocked LTP. NR2B subtype selective antagonists aggravated dystonia after systemic treatment in dt(sz) hamsters, suggesting that beneficial effects involved the NR2A receptor subtype. In the present study, NVP-AAM077, an antagonist with preferential activity on NR2A-containing NMDA receptors, exerted significant antidystonic effects in mutant hamsters after systemic administration (20 and 30mg/kg i.p.) and delayed the onset of a dystonic episode after intrastriatal injections (0.12 and 0.24μg). As shown by present electrophysiological examinations in corticostriatal slices of dt(sz) hamsters and non-dystonic control hamsters, NVP-AAM077 (50nM) completely blocked LTP in dt(sz) slices, but did not exert significant effects on LTP in non-dystonic controls. In contrast, the NR2B antagonist Ro 25-6981 (1-10μmol) reduced LTP to a lower extent in dt(sz) mutant hamsters than in control animals. By using quantitative RT-PCR, the NR2A/NR2B ratio was found to be increased in the striatum, but not in the cortex of mutant hamsters in comparison to non-dystonic controls. These data indicate that NR2A-mediated activation may be involved in the pathophysiology of paroxysmal dystonia. Since significant antidystonic effects were observed after systemic administration of NVP-AAM077 already at well tolerated doses, antagonists with preferential activity on NR2A-containing NMDA receptors could be interesting candidates for the treatment of dystonia.