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The Journal of Neuroscience, June 20, 2007, 27(25):6701-6711; doi:10.1523/JNEUROSCI.0299-07.2007

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Neurobiology of Disease
Targeting Group III Metabotropic Glutamate Receptors Produces Complex Behavioral Effects in Rodent Models of Parkinson's Disease

Sebastien Lopez,¹ Nathalie Turle-Lorenzo,¹ Francine Acher,² Elvira De Leonibus,³ Andrea Mele,³ and Marianne Amalric¹

¹Laboratoire de Neurobiologie de la Cognition, Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 6155, 13331 Marseille, France, ²Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601-CNRS, Université René Descartes-Paris V, 75270 Paris Cedex 06, France, and ³Dipartimento di Genetica e Biologia Molecolare C. Darwin, Università degli Studi di Roma La Sapienza, 00185 Rome, Italy

Correspondence should be addressed to Marianne Amalric, Laboratoire de Neurobiologie de la Cognition, Unité Mixte de Recherche 6155 Centre National de la Recherche Scientifique, Université de Provence, Case C, 3 Place Victor Hugo, 13331 Marseille Cedex 3, France. Email: mamalric{at}up.univ-mrs.fr

Drugs activating group III metabotropic glutamate receptors (mGluRs) represent therapeutic alternatives to L-DOPA (L-3,4-dihydroxyphenylalanine) for the treatment of Parkinson's disease (PD). Their presynaptic location at GABAergic and glutamatergic synapses within basal ganglia nuclei provide a critical target to reduce abnormal activities associated with PD. The effects of selective group III mGluR agonists (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) infused into the globus pallidus (GP) or the substantia nigra pars reticulata (SNr) were thus studied in rat models of PD. Bilateral infusions of ACPT-I (1, 2.5, and 5 nmol/µl) into the GP fully reverse the severe akinetic deficits produced by 6-hydroxydopamine nigrostriatal dopamine lesions in a reaction-time task without affecting the performance of controls. Similar results were observed after L-AP4 (1 nmol) or picrotoxin, a GABA_A receptor antagonist, infused into the GP. In addition, intrapallidal ACPT-I counteracts haloperidol-induced catalepsy. This effect is reversed by concomitant administration of a selective group III receptor antagonist (RS)--cyclopropyl-4-phosphonophenylglycine. In contrast, ACPT-I (0.05, 0.1, and 0.25 nmol) infusions into the SNr enhance the lesion-induced akinetic deficits in control and lesioned rats and do not reverse haloperidol-induced catalepsy. L-AP4 (0.05 nmol) and picrotoxin in the SNr produce the same effects. Together, these results show that activation of group III mGluRs in the GP provides benefits in parkinsonian rats, presumably by modulating GABAergic neurotransmission. The opposite effects produced by group III mGluR activation in the SNr, also observed with a selective mGluR8 agonist, support the use of subtype-selective group III mGluR agonists as a potential antiparkinsonian strategy.

Key words: metabotropic glutamate receptor; 6-hydroxydopamine; Parkinson's disease; GABA_A receptor; substantia nigra; globus pallidus

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Received Sept. 28, 2006; revised May 11, 2007; accepted May 11, 2007.

Correspondence should be addressed to Marianne Amalric, Laboratoire de Neurobiologie de la Cognition, Unité Mixte de Recherche 6155 Centre National de la Recherche Scientifique, Université de Provence, Case C, 3 Place Victor Hugo, 13331 Marseille Cedex 3, France. Email: mamalric{at}up.univ-mrs.fr

This article has been cited by other articles:

				C. Beurrier, S. Lopez, D. Revy, C. Selvam, C. Goudet, M. Lherondel, P. Gubellini, L. Kerkerian-LeGoff, F. Acher, J.-P. Pin, et al. Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism FASEB J, October 1, 2009; 23(10): 3619 - 3628. [Abstract] [Full Text] [PDF]

				C. M. Niswender, K. A. Johnson, C. D. Weaver, C. K. Jones, Z. Xiang, Q. Luo, A. L. Rodriguez, J. E. Marlo, T. de Paulis, A. D. Thompson, et al. Discovery, Characterization, and Antiparkinsonian Effect of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4 Mol. Pharmacol., November 1, 2008; 74(5): 1345 - 1358. [Abstract] [Full Text] [PDF]

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