Neurobiology of Aging 29 (2008) 1040–1051 mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP monkeys Pershia Samadi a,b , Laurent Gr´ egoire a , Marc Morissette a , Fr´ ederic Calon a,b , Abdallah Hadj Tahar c , Mehdi Dridi a,b , Nancy Belanger c , Leonard T. Meltzer d , Paul J. B´ edard c,e , Th´ er` ese Di Paolo a,b,∗ a Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre, Quebec, Canada b Faculty of Pharmacy, Laval University, Quebec, Canada c Neuroscience Research Centre, Laval University Medical Centre, Quebec, Canada d Pfizer Global Research and Development, Ann Arbor Laboratories, Michigan, USA e Faculty of Medicine, Laval University, Quebec, Canada Received 20 September 2006; received in revised form 17 January 2007; accepted 5 February 2007 Available online 13 March 2007 Abstract Modulation of excessive glutamatergic transmission within the basal ganglia is considered as an alternative approach to reduce l-Dopa- induced dyskinesias (LIDs) in Parkinson’s disease (PD). In this study receptor binding autoradiography of [ 3 H]MPEP, a metabotropic glutamate receptor 5 (mGluR5) selective radioligand, was used to investigate possible changes in mGluR5 in the basal ganglia of l-Dopa-treated 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys having developed LIDs compared to animals in which LIDs was prevented by adjunct treatments. LIDs were associated with an increase of mGluR5 specific binding in the posterior putamen and pallidum (+41% and +56%) compared to controls. By contrast, prevention of dyskinesias was associated with an important decrease of mGluR5 specific binding in these areas (-37% and -48%) compared with dyskinetic animals. Moreover, an upregulation (+34%) of mGluR5 receptor binding was seen in the anterior caudate nucleus of saline treated MPTP monkeys. This study is the first to provide evidence that enhanced mGluR5 specific binding in the posterior putamen and pallidum may contribute to the pathogenesis of LIDs in PD. © 2007 Elsevier Inc. All rights reserved. Keywords: Basal ganglia; Parkinson’s disease; Dyskinesias; mGluR5; NMDA antagonist; Cabergoline 1. Introduction In Parkinson’s disease (PD) the death of dopaminergic neurons in the substantia nigra pars compacta (SNc) leads to striatal dopamine loss, which is responsible for the major parkinsonian syndromes (Sealfon and Olanow, 2000). l- Dopa, a dopamine precursor, is still the most effective drug for treating motor symptoms in PD (Mercuri and Bernardi, 2005). Unfortunately, this therapy is often associated with ∗ Corresponding author at: Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre, CHUL, 2705 Laurier Blvd, Quebec, Canada G1V 4G2. Tel.: +1 418 654 2296; fax: +1 418 654 2761. E-mail address: theresedipaolo@crchul.ulaval.ca (T. Di Paolo). the development of involuntary movements termed l-Dopa- induced dyskinesias (LIDs). Although the mechanism of these involuntary movements is not well understood it is par- alleled by changes in neurotransmitter systems, intracellular signaling pathways and aberrant form of plasticity (Calon et al., 2000). Recent data on the development of motor dysfunctions in PD and related l-Dopa therapy suggest a critical involvement of enhanced glutamatergic transmission in the basal ganglia nuclei (Calabresi et al., 2000; Calon et al., 2003). In fact, phar- macological treatments that reduce NMDA receptors activity may limit the extent of nigro-striatal damage (Sonsalla et al., 1998), improve motor symptoms of PD (Chase and Oh, 2000) and prevent or reduce LIDs (Blanchet et al., 1999; Hadj Tahar et al., 2004; Papa and Chase, 1996) in animal models 0197-4580/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2007.02.005