Combined Fenobam and Amantadine Treatment Promotes Robust Antidyskinetic Effects in the 1-Methyl-4-Phenyl- 1,2,3,6-Tetrahydropyridine (MPTP)-Lesioned Primate Model of Parkinson’s Disease Wai Kin D. Ko, PhD, 1,2,3 Elsa Pioli, PhD, 1 Qin Li, PhD, 4 Steve McGuire, MS, 1 Audrey Dufour, PhD, 5 Todd B. Sherer, PhD, 5 Erwan Bezard, PhD, 1,2,3 * and Maurizio F. Facheris, MD 5 1 Motac Neuroscience Ltd, Manchester, United Kingdom 2 Universit e de Bordeaux, Institut des Maladies Neurod eg en eratives, UMR 5293, Bordeaux, France 3 CNRS, Institut des Maladies Neurod eg en eratives, UMR 5293, Bordeaux, France 4 Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China 5 The Michael J. Fox Foundation for Parkinson’s Research, New York, New York, USA ABSTRACT: Amantadine, an N-methyl-D- aspartate glutamate receptor antagonist, is currently the only pharmacological treatment for levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD), but causes adverse effects on the central nervous system at thera- peutic doses. Fenobam, a negative modulator of metab- otropic glutamate receptor subtype 5, has recently been reported to attenuate LID in MPTP-treated macaques. The aim of the current study was to investigate the treat- ment interactions of fenobam and amantadine on LID in the MPTP-treated macaque model of PD. The antidyski- netic and -parkinsonian effects were measured after administration of fenobam (10-30 mg/kg) and amanta- dine (10-30 mg/kg) alone and in combination. Fenobam (30 mg/kg) and amantadine (30 mg/kg) alone reduced LID, whereas lower doses of either drug did not cause any significant effects. A combined treatment of fenobam and amantadine at subthreshold doses (10 and 20 mg/ kg) significantly reduced LID without worsening PD dis- ability. These data suggest that a low-dose combination of fenobam and amantadine can be used for alleviating dyskinesia without causing adverse motor effects. Such combined therapies may offer a new therapeutic strategy for treatment of LID in PD patients. V C 2014 International Parkinson and Movement Disorder Society Key Words: dyskinesia; Parkinson; macaque; mGluR5 antagonist Long-term levodopa treatment in Parkinson’s disease (PD) often leads to debilitating side effects, such as L- dopa-induced dyskinesia (LID). 1 Although the under- lying cause of LID remains unknown, increased gluta- matergic transmission is a major contributing factor in expression of LID. 2-4 Amantadine, a noncompetitive N-methyl-D- aspartate (NMDA) glutamate receptor antagonist, 5-8 is the only pharmacological treatment used to manage LID in PD patients, reducing dyskinesia by up to 50% to 60%. 9,10 However, clinical utility of amantadine can be limited because of associated side effects, such as cognitive impairments, 11 and a varied duration of efficacy. 12-14 Group I metabotropic glutamate receptors, specifi- cally subtype 5 (mGluR5), are also implicated in the pathophysiology of LID. 15,16 Treatment with the ------------------------------------------------------------ *Correspondence to: Dr. Erwan Bezard, Univ. de Bordeaux, Institut des Maladies Neurod eg en eratives, UMR 5293, 146 rue Leo Saignat, 33076 Bordeaux, France; erwan.bezard@u-bordeaux2.fr Funding agencies: This study was supported by the Michael J. Fox Foundation. Relevant conflicts of interest/financial disclosures: E.B. has an equity stake in Motac Holding Ltd and receives consultancy payments from Motac Neuroscience Ltd. and has current grant support from Agence Nationale de la Recherche, China Science Fund, the Michael J. Fox Foundation (MJFF), FP7 from EU, France Parkinson, Fondation de France, and Cariplo Foundation. M.F.F., A.D., and T.S. are employees of the MJFF, a nonprofit organization. W.K.K., E.P., Q.L., and S.M. are employees of Motac Neuroscience Ltd. Full financial disclosures and author roles may be found in the online ver- sion of this article. Received: 23 September 2013; Revised: 21 January 2014; Accepted: 10 February 2014 Published online 7 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25859 RESEARCH ARTICLE 772 Movement Disorders, Vol. 29, No. 6, 2014