The mGlu2/3 antagonist LY-341,495 reverses the anti-dyskinetic and anti-psychotic effects of the mGlu2 activators LY-487,379 and LY-354,740 in the MPTP-lesioned marmoset

Stephen G Nuara; Adjia Hamadjida; Jim C Gourdon; Philippe Huot

doi:10.1007/s00702-020-02196-w

The mGlu_2/3 antagonist LY-341,495 reverses the anti-dyskinetic and anti-psychotic effects of the mGlu₂ activators LY-487,379 and LY-354,740 in the MPTP-lesioned marmoset

J Neural Transm (Vienna). 2020 Jul;127(7):1013-1021. doi: 10.1007/s00702-020-02196-w. Epub 2020 Apr 24.

Authors

Stephen G Nuara¹, Adjia Hamadjida^{2

3}, Jim C Gourdon¹, Philippe Huot^{4

5

6}

Affiliations

¹ Comparative Medicine and Animal Resource Centre, McGill University, Montreal, QC, Canada.
² Neurodegenerative Disease Group, Montreal Neurological Institute, 3801 University St, Montreal, QC, H3A 2B4, Canada.
³ École Normale supérieure de Bertoua, Université de Ngaoundéré, Ngaoundéré, Cameroon.
⁴ Neurodegenerative Disease Group, Montreal Neurological Institute, 3801 University St, Montreal, QC, H3A 2B4, Canada. philippe.huot@mcgill.ca.
⁵ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada. philippe.huot@mcgill.ca.
⁶ Movement Disorder Clinic, Division of Neurology, Department of Neurosciences, McGill University Health Centre, Montreal, QC, Canada. philippe.huot@mcgill.ca.

PMID: 32333122
DOI: 10.1007/s00702-020-02196-w

Abstract

We have recently shown that activation of metabotropic glutamate 2 (mGlu₂) receptors through positive allosteric modulation and orthosteric stimulation is a novel approach to reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and dopaminergic psychosis in Parkinson's disease (PD). We have obtained these benefits with the mGlu₂-positive allosteric modulator (PAM) LY-487,379 and the mGlu_2/3 orthosteric agonist (OA) LY-354,740 in experiments conducted in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to pharmacologically characterise the anti-dyskinetic and anti-psychotic effects of LY-487,379 and LY-354,740, by assessing whether their benefits would be reversed by the mGlu_2/3 orthosteric antagonist LY-341,495. Six MPTP-lesioned marmosets exhibiting stable dyskinesia and psychosis-like behaviours (PLBs) entered the experiments. In the first series of experiments, animals were injected L-DOPA in combination with either vehicle, LY-487,379 (10 mg/kg), LY-341,495 (1 mg/kg) or LY-487,379/LY-341,495. In the second series of experiments, marmosets were injected L-DOPA in combination with either vehicle, LY-354,740 (1 mg/kg), LY-341,495 (1 mg/kg) or LY-354,740/LY-341495. As we previously demonstrated, both LY-487,379 and LY-354,740 alleviated dyskinesia (by 44% and 47%, both P < 0.001) and PLBs (by 44% and 39%, P < 0.01 and P < 0.001) when compared to vehicle treatment. When LY-487,379 and LY-354,740 were administered concurrently with LY-341,495, the anti-dyskinetic and anti-psychotic benefits were abolished. When administered with L-DOPA in the absence of LY-487,379 and LY-354,740, LY-341,495 did not worsen dyskinesia or PLBs and did not hamper L-DOPA anti-parkinsonian action. Our results indicate that the anti-dyskinetic and anti-psychotic effects of mGlu₂-positive allosteric modulation and mGlu_2/3 orthosteric stimulation are reversed by mGlu_2/3 orthosteric blockade.

Keywords: Dyskinesia; LY-341,495; LY-354,740; LY-487,379; MPTP-lesioned marmoset; Parkinson’s disease; Psychosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Animals
Antiparkinson Agents / pharmacology
Behavior, Animal
Callithrix*
Dyskinesia, Drug-Induced*
Levodopa

Substances

Antiparkinson Agents
Levodopa
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine