Antiparkinsonian activity of Ro 25-6981, a NR2B subunit specific NMDA receptor antagonist, in animal models of Parkinson’s disease Peter-Andreas Lo ¨schmann, a,1 Carmen De Groote, a,1 Lance Smith, b Ullrich Wu ¨llner, c Gu ¨nther Fischer, d John A. Kemp, d Peter Jenner, b and Thomas Klockgether c, * a Department of Neurology, University of Tu ¨bingen, Tu ¨bingen, Germany b Neurodegenerative Disease Research Centre, Biomedical Science Division, King’s College, London, UK c Department of Neurology, University of Bonn, Bonn, Germany d Hoffmann-La Roche Ltd., Preclinical Research, Basel, Switzerland Received 17 September 2003; revised 9 December 2003; accepted 22 January 2004 Abstract N-methyl-D-aspartate (NMDA) receptor antagonists have antiakinetic and antidyskinetic effects in animals models of Parkinson’s disease (PD). However, non-selective inhibition of NMDA receptors throughout the central nervous system may result in undesired effects such as ataxia and psychosis. We therefore studied Ro 25-6981, an activity-dependent antagonist of NMDA receptors containing the NR2B subunit which are predominantly expressed in the striatum. Ro 25-6981 induced contraversive rotations in 6-hydroxydopamine (6-OHDA)-lesioned rats without stimulating locomotion in normal rats and reversed parkinsonian symptoms in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-treated common marmosets. Due to the small number of marmosets, there were no significant differences between Ro 25-6981 and vehicle though there was a significant trend toward differences, as shown by the Page test. Furthermore, Ro 25-6981 potentiated the action of levodopa in both species and attenuated the maximal levodopa response in 6-OHDA-lesioned rats chronically treated with levodopa without reducing the overall response. Ro 25-6981 also potentiated the action of the dopamine receptor agonists apomorphine, A68930 and quinpirole in 6-OHDA-lesioned rats. The present observations suggest a therapeutic potential of NR2B-selective NMDA receptor antagonists in the management of PD. D 2004 Elsevier Inc. All rights reserved. Keywords: NMDA receptors; Parkinson’s disease, 6-OHDA; MPTP, Ro 25-6981 Introduction Depletion of striatal dopamine in Parkinson’s disease (PD) results in overactivity of the striatal pathway to the external pallidum, disinhibition of the subthalamic nucleus and excessive glutamatergic excitation of the basal ganglia output nuclei (Albin et al., 1989). Consequently, glutamate receptor antagonists, in particular N-methyl-D-aspartate (NMDA) antagonists have been shown to potentiate the actions of levodopa and dopamine receptor agonists in animal models of PD suggesting that such compounds might be beneficial for treating PD (Klockgether and Turski, 1990). In addition, the antiparkinsonian action of amanta- dine is at least partly due to non-competitive NMDA receptor antagonism (Kornhuber et al., 1991). NMDA receptors have been also implicated in the development and maintenance of levodopa-induced dyski- nesias and motor fluctuations. Experimental evidence in rodents and primates revealed that intermittent administra- tion of levodopa increases the sensitivity of striatal NMDA receptors resulting in a shortened and abnormally enhanced response to levodopa. NMDA receptor antagonists prevent and reverse levodopa-induced dyskinesias in experimental animals (Papa et al., 1995). Furthermore, amantadine ameli- orates dyskinesias in levodopa-treated PD patients without worsening parkinsonian symptoms (Verhagen et al., 1998). Non-selective inhibition of NMDA receptors throughout the central nervous system resulting in undesired effects such as ataxia and psychosis limits the therapeutic benefit of 0014-4886/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2004.01.018 * Corresponding author. Department of Neurology, University of Bonn, Sigmund-Freud Street 25, D-53105 Bonn, Germany. Fax: +49-228-287- 5024. E-mail address: klockgether@uni-bonn.de (T. Klockgether). 1 Both authors equally contributed to the study. www.elsevier.com/locate/yexnr Experimental Neurology 187 (2004) 86 – 93