Session Information
Date: Wednesday, June 7, 2017
Session Title: Neuropharmacology
Session Time: 1:15pm-2:45pm
Location: Exhibit Hall C
Objective: To investigate the effect of metabotropic glutamate receptor 2 (mGluR2) activation on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced psychosis-like behaviours (PLBs) and dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson’s disease (PD)
Background: Psychosis and dyskinesia undermine the quality of life of as many as 50-95% of patients with advanced PD. Available therapies are few, their efficacy is partial and they may elicit important side effects. Serotonergic 2A receptor (5-HT2AR) blockade is a validated approach to alleviate both psychosis and dyskinesia, but the effectiveness of this approach is also limited. 5-HT2AR forms a functional hetero-complex with mGluR2 involved in psychotic symptoms of schizophrenia and hallucinogenic effects of psychotomimetic drugs. We hypothesised that mGluR2 activation is a new and effective approach to reduce both L-DOPA-induced dyskinesia and psychosis in PD.
Methods: Six common marmosets were rendered parkinsonian by MPTP administration. Dyskinesia and PLBs were induced by chronic administration of L-DOPA. The potent and highly-selective mGluR2 positive allosteric modulator (PAM) LY-487,379 (vehicle, 0.1, 1 and 10 mg/kg) was then administered in combination with L-DOPA and its effects on each of dyskinesia, PLBs and parkinsonism were assessed.
Results: LY-487,379 1 and 10 mg/kg significantly alleviated PLBs (by 35% and 42%, respectively, both P < 0.05), when compared to vehicle. LY-487,379 1 and 10 mg/kg also significantly reduced the severity of dyskinesia (by 46% and 53%, respectively, both P < 0.05). LY-487,379 also significantly improved the quality of on-time, by reducing the duration of on-time with disabling PLBs/dyskinesia. Importantly, LY-487,379 did not hinder with L-DOPA anti-parkinsonian action.
Conclusions: Selective mGluR2 activation stands as a new and promising approach to alleviate both PD psychosis and dyskinesia without negative impact on parkinsonian symptoms.
To cite this abstract in AMA style:
L. Sid-Otmane, S. Nuara, A. Hamadjida, N. Veyres, C. Rouillard, M. Panisset, J. Gourdon, P. Huot. The highly-selective metabotropic glutamate receptor 2 positive allosteric modulator LY-487,379 alleviates psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset [abstract]. Mov Disord. 2017; 32 (suppl 2). https://www.mdsabstracts.org/abstract/the-highly-selective-metabotropic-glutamate-receptor-2-positive-allosteric-modulator-ly-487379-alleviates-psychosis-like-behaviours-and-dyskinesia-in-the-mptp-lesioned-marmoset/. Accessed May 11, 2025.« Back to 2017 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-highly-selective-metabotropic-glutamate-receptor-2-positive-allosteric-modulator-ly-487379-alleviates-psychosis-like-behaviours-and-dyskinesia-in-the-mptp-lesioned-marmoset/