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Additive effects of mGluR2 positive allosteric modulation, mGluR2 orthosteric stimulation and 5-HT2AR antagonism on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset

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Abstract

Purpose

Antagonising serotonin (5-HT) type 2A receptors (5-HT2AR) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson’s disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR2), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT2AR antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT2AR antagonism with concurrent mGluR2 orthosteric stimulation and mGluR2 positive allosteric modulation.

Methods

Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered l-3,4-dihydroxyphenylalanine (l-DOPA) in combination with vehicle or the 5-HT2AR antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR2 orthosteric agonist (OA) LY-354,740, the mGluR2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated.

Results

EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on l-DOPA anti-parkinsonian action were observed.

Conclusion

Our results suggest that combining 5-HT2AR antagonism with mGluR2 activation results in greater reduction of l-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR2 OA and a mGluR2 PAM are combined with a 5-HT2AR antagonist than when a mGluR2 OA or a mGluR2 PAM are added to a 5-HT2AR antagonist.

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Data are included as a supplemental Prism file.

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Funding

PH has had research support from Parkinson Canada, Parkinson Québec, Fonds de Recherche Québec – Santé, the Weston Brain Institute, the Michael J Fox Foundation for Parkinson’s Research, the Natural Sciences and Engineering Research Council of Canada and Healthy Brains for Healthy Lives. PH has received payments from Neurodiem.

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Authors and Affiliations

  1. Comparative Medicine & Animal Resource Centre, McGill University, Montreal, QC, Canada

    Stephen G Nuara & Jim C Gourdon

  2. Talon Pharmaceuticals, Mississauga, ON, Canada

    Shawn Maddaford

  3. Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, H3A 2B4, Canada

    Philippe Huot

  4. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Philippe Huot

  5. Department of Neuroscience, Division of Neurology, Movement Disorder Clinic, McGill University Health Centre, Montreal, QC, Canada

    Philippe Huot

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  1. Stephen G Nuara
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  2. Jim C Gourdon
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  4. Philippe Huot
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Contributions

SGN, JCG, PH conceived and designed research. SN, JC, PH conducted experiments and analysed data. SM and PH wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Philippe Huot.

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Experiments were approved by McGill University and the Montreal Neurological Institute-Hospital (The Neuro) Animal Care Committees, which are in accordance with the regulations defined by the Canadian Council on Animal Care.

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Nuara, S.G., Gourdon, J.C., Maddaford, S. et al. Additive effects of mGluR2 positive allosteric modulation, mGluR2 orthosteric stimulation and 5-HT2AR antagonism on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset. Naunyn-Schmiedeberg's Arch Pharmacol 394, 2381–2388 (2021). https://doi.org/10.1007/s00210-021-02162-7

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