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Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism

Corinne Beurrier^*,1, Sebastien Lopez^,1, Delphine Révy^*,1, Chelliah Selvam, Cyril Goudet, Morgane Lhérondel, Paolo Gubellini^*, Lydia Kerkerian-LeGoff^*, Francine Acher, Jean-Philippe Pin and Marianne Amalric^,2

^* Institut de Biologie du Développement de Marseille Luminy, UMR 6216 CNRS-Université de la Méditerranée, Marseille, France;

Laboratoire de Neurobiologie de la Cognition, UMR 6155 CNRS-Université de Provence, Marseille, France;

Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS-Université Paris Descartes, Paris, France; and

Institut de Génomique Fonctionnelle, UMR 5203 CNRS, INSERM U661, Université de Montpellier I & II, Montpellier, France

² Correspondence: Laboratoire de Neurobiologie de la Cognition, UMR 6155 CNRS-Université de Provence, Case C, 3 Pl. Victor Hugo, 13331 Marseille cedex 3, France. E-mail: marianne.amalric{at}univ-provence.fr

Developing nondopaminergic palliative treatments for Parkinson’s disease represents a major challenge to avoid the debilitating side effects produced by L-DOPA therapy. Increasing interest is addressed to the selective targeting of group III metabotropic glutamate (mGlu) receptors that inhibit transmitter release at presumably overactive synapses in the basal ganglia. Here we characterize the functional action of a new orthosteric group III mGlu agonist, LSP1-2111, with a preferential affinity for mGlu4 receptor. In mouse brain slices, LSP1-2111 inhibits striatopallidal GABAergic transmission by selectively activating the mGlu4 receptor but has no effect at a synapse modulated solely by the mGlu7 and mGlu8 receptors. Intrapallidal LSP1-2111 infusion reverses the akinesia produced by nigrostriatal dopamine depletion in a reaction time task, whereas an mGlu8-receptor agonist has no effect. Finally, systemic administration of LSP1-2111 counteracts haloperidol-induced catalepsy, opening promising perspectives for the development of antiparkinsonian therapeutic strategies focused on orthosteric mGlu4-receptor agonists.—Beurrier, C., Lopez, S., Révy, D., Selvam, C., Goudet, C., Lhérondel, M., Gubellini, P., Kerkerian-LeGoff, L., Acher, F., Pin, J.-P., Amalric, M. Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism.

Key Words: orthosteric ligands • 6-hydroxydopamine • GABA-A receptor • globus pallidus • mice • rats