Avchalumov, Yosef, Sander, Svenja, Porath, Katrin, Hamann, Melanie, Richter, Franziska, Kirschstein, Timo, Köhling, Rüdiger and Richter, Angelika (2014) Role of striatal NMDA receptor subunits in a model of paroxysmal dystonia. Experimental Neurology, 261. pp. 677-684. ISSN 00144886

Abstract

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 dtsz mutant hamster, previous studies indicated striatal dysfunctions, including an increased long-term potentiation (LTP). Beneficial effects were exerted by antagonists at NMDA receptors containing both NR1/NR2A and NR1/NR2B, which blocked LTP. NR2B subtype selective antagonists aggravated dystonia after systemic treatment in dtsz 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 30 mg/kg i.p.) and delayed the onset of a dystonic episode after intrastriatal injections (0.12 and 0.24 μg). As shown by present electrophysiological examinations in corticostriatal slices of dtsz hamsters and non-dystonic control hamsters, NVP-AAM077 (50 nM) completely blocked LTP in dtsz slices, but did not exert significant effects on LTP in non-dystonic controls. In contrast, the NR2B antagonist Ro 25-6981 (1-10 μmol) reduced LTP to a lower extent in dtsz 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 is 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.

Item Type:	Article
Keywords:	basal ganglia, dyskinesia, glutamate, movement disorders, striatum, NVP-AAM077
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/20477