Abstract
Rationale
Positive allosteric modulation of metabotropic glutamate type 4 (mGlu4) receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia. ADX-88178 is a highly selective mGlu4 positive allosteric modulator (PAM) that previously enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat model of Parkinson’s disease (PD).
Objectives
We sought to explore the effects of ADX-88178 on psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. We also aimed to determine the effect of ADX-88178 on parkinsonism and dyskinesia.
Methods
Six MPTP-lesioned marmosets were administered L-DOPA chronically to induce stable PLBs and dyskinesias. They were then administered ADX-88178 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA/benserazide (15/3.75 mg/kg), both sub-cutaneously, in a randomised fashion. PLBs, parkinsonism and dyskinesia were then measured.
Results
ADX-88178 mildly worsened global PLBs at the dose of 1 mg/kg (by 13%, P = 0.020). L-DOPA alone conferred 158 min of on-time, while the duration of on-time was 212 min (34% increase, P = 0.011), after adding ADX-88178 1 mg/kg to L-DOPA. Accordingly, ADX-88178 1 mg/kg reduced global parkinsonian disability, by 38% (P = 0.0096). ADX-88178 1 mg/kg diminished peak dose dyskinesia by 34% (P = 0.015). Minimal effects were provided by lower doses.
Conclusions
Whereas these results provide additional evidence of the anti-parkinsonian and anti-dyskinetic effects of mGlu4 positive allosteric modulation as an adjunct to L-DOPA, they also suggest that ADX-88178 may exacerbate dopaminergic psychosis. Further studies are needed to evaluate this possible adverse effect of mGlu4 PAMs on PD psychosis.
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Data Availability
Data will be made available upon email request to the corresponding author.
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Funding
IF and CK have had scholarships from Parkinson Canada. CK has had a scholarship from Fonds de Recherche du Québec – Santé. 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, the Social Sciences and Humanities Research Council of Canada and Healthy Brains for Healthy Lives.
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JCG and PH conceived and designed research. IF, CK, DB, WJ and SCG conducted experiments and analysed data. PH wrote the manuscript. IF, CK, DB, WJ, SGN and JCG reviewed and commented on the manuscript.
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PH has received payments from Abbvie, adMare BioInnovations, ConSynance Therapeutics, Neurodiem, Sanford Burnham Prebys, Sunovion, ConSynance Therapeutics and Througline Strategy.
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Frouni, I., Kwan, C., Bédard, D. et al. Effect of the mGlu4 positive allosteric modulator ADX-88178 on parkinsonism, psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset. Psychopharmacology 240, 2093–2099 (2023). https://doi.org/10.1007/s00213-023-06428-1
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DOI: https://doi.org/10.1007/s00213-023-06428-1