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

FASEB J. 2009 Oct;23(10):3619-28. doi: 10.1096/fj.09-131789. Epub 2009 Jun 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobutyrates / therapeutic use*
  • Animals
  • Antiparkinson Agents / therapeutic use*
  • Behavior / drug effects
  • Catalepsy / chemically induced
  • Catalepsy / drug therapy
  • Cell Line
  • Disease Models, Animal
  • Electrophysiological Phenomena
  • Globus Pallidus / drug effects
  • Globus Pallidus / physiopathology
  • Haloperidol / pharmacology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / physiopathology*
  • Phosphinic Acids / therapeutic use*
  • Rats
  • Receptors, Metabotropic Glutamate / agonists*
  • Synaptic Transmission / drug effects


  • Aminobutyrates
  • Antiparkinson Agents
  • LSP1 2111
  • Phosphinic Acids
  • Receptors, Metabotropic Glutamate
  • Haloperidol
  • metabotropic glutamate receptor 4