title: Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism.
abstract: 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.
authors.affiliation: Institut de Biologie du Développement de Marseille Luminy, UMR 6216 CNRS-Université de la Méditerranée, Marseille, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Beurrier
authors.forename: Sebastien
authors.initials: S
authors.lastname: Lopez
authors.forename: Delphine
authors.initials: D
authors.lastname: Révy
authors.forename: Chelliah
authors.initials: C
authors.lastname: Selvam
authors.forename: Cyril
authors.initials: C
authors.lastname: Goudet
authors.forename: Morgane
authors.initials: M
authors.lastname: Lhérondel
authors.forename: Paolo
authors.initials: P
authors.lastname: Gubellini
authors.forename: Lydia
authors.initials: L
authors.lastname: Kerkerian-LeGoff
authors.forename: Francine
authors.initials: F
authors.lastname: Acher
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pin
authors.forename: Marianne
authors.initials: M
authors.lastname: Amalric
mesh_terms: D000613:Aminobutyrates / Q000627:therapeutic use*; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001519:Behavior / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D002460:Cell Line; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D005917:Globus Pallidus / Q000187:drug effects / Q000503:physiopathology; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D010721:Phosphinic Acids / Q000627:therapeutic use*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000613:Aminobutyrates; D000978:Antiparkinson Agents; C555637:LSP1 2111; D010721:Phosphinic Acids; D018094:Receptors, Metabotropic Glutamate; D006220:Haloperidol; C108823:metabotropic glutamate receptor 4