Selective metabotropic glutamate receptor 2 positive allosteric modulation alleviates L-DOPA-induced psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset

Eur J Pharmacol. 2020 Apr 15;873:172957. doi: 10.1016/j.ejphar.2020.172957. Epub 2020 Jan 28.


Psychosis and dyskinesia significantly diminish the quality of life of patients with advanced Parkinson's disease (PD). Available treatment options are unfortunately few and their use is limited by adverse effects. We have recently shown that activation of metabotropic glutamate 2 and 3 (mGlu2/3) receptors produced significant relief of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced psychosis-like behaviours (PLBs) and dyskinesia in experimental models of PD. Here, using the highly-selective mGlu2 positive allosteric modulator (PAM) LY-487,379, we seek to determine the contribution of selective mGlu2 activation on both L-DOPA-induced PLBs and dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We first determined the pharmacokinetic (PK) profile of LY-487,379 in the common marmoset, following which we administered it (0.1, 1 and 10 mg/kg) or its vehicle to 6 MPTP-lesioned marmosets previously exposed to L-DOPA to elicit stable PLBs and dyskinesia. We found that LY-487,379 provided a ≈45% reduction of the global PLBs observed and reduced global dyskinesia score by ≈ 55%. Moreover, LY-487,379 enhanced the anti-parkinsonian effect of L-DOPA, by reducing global parkinsonian score by ≈ 15%. Our data suggest that selective mGlu2 positive allosteric modulation with LY-487,379 may represent a potential therapeutic approach to alleviate both L-DOPA-induced PLBs and dyskinesia in PD.

Keywords: Dyskinesia; LY-487,379; MPTP; Marmoset; Parkinson's disease; Psychosis.

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology
  • Antiparkinson Agents / therapeutic use
  • Antipsychotic Agents / therapeutic use*
  • Behavior, Animal / drug effects*
  • Callithrix
  • Dyskinesia, Drug-Induced / drug therapy*
  • Female
  • GABA Modulators / pharmacokinetics
  • GABA Modulators / therapeutic use*
  • Levodopa*
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / psychology
  • Male
  • Parkinson Disease / complications
  • Parkinson Disease / drug therapy
  • Parkinson Disease / psychology
  • Psychoses, Substance-Induced / drug therapy*
  • Psychoses, Substance-Induced / psychology
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use*
  • Receptors, Metabotropic Glutamate / drug effects*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / therapeutic use*


  • Antiparkinson Agents
  • Antipsychotic Agents
  • GABA Modulators
  • N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine
  • Pyridines
  • Receptors, Metabotropic Glutamate
  • Sulfonamides
  • metabotropic glutamate receptor 2
  • Levodopa