Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism.
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
Corinne
C
Institut de Biologie du Développement de Marseille Luminy, UMR 6216 CNRS-Université de la Méditerranée, Marseille, France.
Lopez
Sebastien
S
Révy
Delphine
D
Selvam
Chelliah
C
Goudet
Cyril
C
Lhérondel
Morgane
M
Gubellini
Paolo
P
Kerkerian-LeGoff
Lydia
L
Acher
Francine
F
Pin
Jean-Philippe
JP
Amalric
Marianne
M
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
D000613:Aminobutyrates; D000978:Antiparkinson Agents; C555637:LSP1 2111; D010721:Phosphinic Acids; D018094:Receptors, Metabotropic Glutamate; D006220:Haloperidol; C108823:metabotropic glutamate receptor 4