Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Neuropsychopharmacology (2009) 34, 729–738 & 2009 Nature Publishing Group All rights reserved 0893-133X/09 $32.00 www.neuropsychopharmacology.org Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson’s Disease Elvira De Leonibus1,2, Francesca Managò1,2, Francesco Giordani1,2, Francesco Petrosino3, Sebastien Lopez4, Alberto Oliverio1,2,5, Marianne Amalric4 and Andrea Mele*,1,2,5 1 Dipartimento di Genetica e Biologia Molecolare ‘C.Darwin’, Università degli Studi di Roma ‘La Sapienza’, Rome, Italy; 2Centro di Ricerca in Neurobiologia-D. Bovet, Università degli Studi di Roma ‘La Sapienza’, Rome, Italy; 3Dipartimento di Fisiologia Umana e Farmacologia, Università degli Studi di Roma ‘La Sapienza’, Rome, Italy; 4Laboratoire de Neurobiologie de la Cognition, Universités Aix-Marseille, CNRS UMR6155, Marseille, France; 5Istituto di Neuroscienze-CNR, CERC, Rome, Italy Visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson’s disease (PD), and they are frequently associated to motor symptoms in the early stages of the disease when dopamine loss is moderate and still restricted to the caudate– putamen. The metabotropic glutamate receptor 5 (mGluR5) antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has beneficial effects on motor symptoms in animal models of PD. However, the effects of MPEP on the cognitive deficits of the disease have never been investigated. Thus, the purpose of this study was to explore its therapeutic potentials by investigating its effects on the visuo-spatial deficits induced by 6-hydroxydopamine (6-OHDA) lesions of dorsal striatum in CD1 mice. The results demonstrated that systemic injections of MPEP (6, 12, and 24 mg/kg, i.p.) impair visuo-spatial discrimination in intact mice at high concentrations, whereas lower doses (1.5 and 3 mg/kg, i.p.) were void of effects. Nevertheless, when an ineffective dose (MPEP 3 mg/kg) was injected, either acutely or subchronically (8 days), it antagonized the visuo-spatial discrimination deficit induced by bilateral dopamine lesion of the striatum. Furthermore, the same treatment increased contralateral turning induced by L-DOPA in mice bearing unilateral 6-OHDA lesion. These results confirm the therapeutic potential of mGluR5 blockade on motor symptoms induced by reduced striatal dopamine function. Further, they demonstrate that mGluR5 blockade may also have beneficial effects on cognitive deficits induced by dopamine depletion. Neuropsychopharmacology (2009) 34, 729–738; doi:10.1038/npp.2008.129; published online 13 August 2008 Keywords: visuo-spatial discrimination; Parkinson’s disease; mGluR5 antagonist; mice; rotational behavior INTRODUCTION It is widely recognized that motor symptoms are accompanied by cognitive deficits in Parkinsonian patients even at the early stages of the disease, when dopamine (DA) depletion is restricted to the striatal complex (Owen et al, 1997; Pillon et al, 1997, 1998). On the basis of recent evidence, visuo-spatial memory impairments seem to be the most constantly reported cognitive deficit in Parkinson’s disease (PD) patients (Berger et al, 2004; Cools et al, 2002, 2007; Giraudo et al, 1997; Lewis et al, 2003; Owen et al, 1998; Pillon et al, 1997, 1998). Consistently, extensive DA lesions, obtained through either medial forebrain bundle or dorsal striatum 6-hydroxydopamine (6-OHDA) administrations, *Correspondence: Professor A Mele, Dipartimento di Genetica e Biologia Molecolare ‘C.Darwin’, Università degli Studi di Roma ‘La Sapienza’, P.le Aldo Moro, 5, Rome I00185, Italy, Tel: + 1 39 064 991 2244, Fax: + 39 064 440 812, E-mail: Received 15 April 2008; revised 16 June 2008; accepted 11 July 2008 have been found to impair memory in the spatial version of the Morris water maze in rats (Miyoshi et al, 2002; Mura and Feldon, 2003; Whishaw and Dunnett, 1985). Furthermore, it has been recently shown that partial bilateral DA depletion of the dorsal striatum impairs spatial discrimination in the object–place association task in mice, and that this effect is specific for spatial information (De Leonibus et al, 2007), thus providing an useful animal model of cognitive deficit in the early stages of PD. On the basis of current theories, which consider the imbalance between DA and glutamate in the basal ganglia (BG) one of the major consequence of PD-related pathogenic cascade (Breysse et al, 2003; Greenamyre and O’Brien, 1991; Klockgether et al, 1991), metabotropic glutamate receptors (mGluRs) have been suggested as suitable targets to modulate parkinsonian motor symptoms. Accordingly, mGluR5 blockade ameliorates motor abnormalities induced by lesions of the nigrostriatal dopaminergic system, or by dopaminergic receptor antagonists in animal models of PD (Breysse et al, 2002; Coccurello et al, 2004; Dekundy et al, mGluR5 and cognitive deficit in Parkinson’s disease E De Leonibus et al 730 2006; Domenici et al, 2005; Ossowska et al, 2001, 2002, 2005; Oueslati et al, 2005; Phillips et al, 2006; Popoli et al, 2001; Turle-Lorenzo et al, 2005). However, to our knowledge, none of the studies in the literature investigated the possible therapeutic potentials of mGluR5 antagonists in the treatment of the cognitive symptoms of the disease. It is worth noting in this regard, that experimental findings using pharmacological approaches or mGluR5 KO mice demonstrate an involvement of mGluR5 in neural plasticity, as well as in learning and memory processes (Ballard et al, 2005; Campbell et al, 2004; Gravius et al, 2005; Gubellini et al, 2003; Homayoun et al, 2004; Lu et al, 1997; ManahanVaughan and Braunewell, 2005; Simonyi et al, 2005), suggesting that mGluR5 blockade could impair learning and memory in intact animals. Nevertheless, glutamate overactivity as a consequence of striatal DA depletion, might have a causal role in the cognitive deficits of Parkinson’s patients; in addition to motor dysfunction. Thus, mGluR5 blockade might improve, rather than impair, spatial memory in DA lesioned animals. Therefore, the present study was undertaken to determine whether the beneficial effects of mGluR5 blockade apply to both motor and cognitive deficits observed in animal models of PD. For this purpose, we first tested the effects of systemic acute injection of different doses of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective mGluR5 antagonist, on naı̈ve mice in the object–place association task (LenckSantini et al, 2005; Roullet et al, 2001). Afterward, we selected a dose of MPEP (3 mg/kg) that was void of any effect on naı̈ve animals and that in previous studies was demonstrated to reverse motor deficits in an animal model of PD (Breysse et al, 2002) and tested its acute or subchronic (8 days) effects on the spatial deficit induced by bilateral dorsal striatal 6-OHDA lesions. Finally, we tested the effects of acute and subchronic (8 days) systemic injections of MPEP (3 mg/kg) on contralateral t (...truncated)