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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

  • Neurology and Preclinical Neurological Studies - Original Article
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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 mGlu2/3 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 mGlu2/3 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 mGlu2/3 orthosteric stimulation are reversed by mGlu2/3 orthosteric blockade.

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References

  • Conde-Ceide S, Martinez-Viturro CM, Alcazar J, Garcia-Barrantes PM, Lavreysen H, Mackie C, Vinson PN, Rook JM, Bridges TM, Daniels JS, Megens A, Langlois X, Drinkenburg WH, Ahnaou A, Niswender CM, Jones CK, Macdonald GJ, Steckler T, Conn PJ, Stauffer SR, Bartolome-Nebreda JM, Lindsley CW (2015) Discovery of VU0409551/JNJ-46778212: an mGlu5 positive allosteric modulator clinical candidate targeting schizophrenia. ACS Med Chem Lett 6(6):716–720. https://doi.org/10.1021/acsmedchemlett.5b00181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R, Ballard C (2014) Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383(9916):533–540. https://doi.org/10.1016/S0140-6736(13)62106-6

    Article  CAS  PubMed  Google Scholar 

  • Di Menna L, Joffe ME, Iacovelli L, Orlando R, Lindsley CW, Mairesse J, Gressèns P, Cannella M, Caraci F, Copani A (2018) Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system. Neuropharmacology 128:301–313

    Article  Google Scholar 

  • Fox SH, Visanji N, Reyes G, Huot P, Gomez-Ramirez J, Johnston T, Brotchie JM (2010) Neuropsychiatric behaviors in the MPTP marmoset model of Parkinson's disease. Can J Neurol Sci 37(1):86–95

    Article  Google Scholar 

  • Fox SH, Visanji NP, Johnston TH, Gomez-Ramirez J, Voon V, Brotchie JM (2006) Dopamine receptor agonists and levodopa and inducing psychosis-like behavior in the MPTP primate model of Parkinson disease. Arch Neurol 63(9):1343–1344. https://doi.org/10.1001/archneur.63.9.1343

    Article  PubMed  Google Scholar 

  • Frouni I, Hamadjida A, Kwan C, Bédard D, Nafade V, Gaudette F, Nuara SG, Gourdon JC, Beaudry F, Huot P (2019) Activation of mGlu2/3 receptors, a novel therapeutic approach to alleviate dyskinesia and psychosis in experimental parkinsonism. Neuropharmacology 158:107725

    Article  CAS  Google Scholar 

  • Gaudette F, Hamadjida A, Bedard D, Nuara SG, Beaudry F, Huot P (2017) Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method to quantify LY-354,740 in rat and marmoset plasma. J Chromatogr B Anal Technol Biomed Life Sci 1061–1062:392–398. https://doi.org/10.1016/j.jchromb.2017.07.007

    Article  CAS  Google Scholar 

  • Gaudette F, Hamadjida A, Bedard D, Nuara SG, Gourdon JC, Michaud V, Beaudry F, Huot P (2018) Development of a selective and sensitive high-performance liquid chromatography-tandem mass spectrometry assay to support pharmacokinetic studies of LY-487,379 in rat and marmoset. J Chromatogr B Anal Technol Biomed Life Sci 1093–1094:1–7. https://doi.org/10.1016/j.jchromb.2018.06.036

    Article  CAS  Google Scholar 

  • Hamadjida A, Nuara SG, Bedard D, Frouni I, Kwan C, Gourdon JC, Huot P (2018a) Nefazodone reduces dyskinesia, but not psychosis-like behaviours, in the parkinsonian marmoset. Naunyn Schmiedebergs Arch Pharmacol 391(12):1339–1345. https://doi.org/10.1007/s00210-018-1549-6

    Article  CAS  PubMed  Google Scholar 

  • Hamadjida A, Nuara SG, Bedard D, Gaudette F, Beaudry F, Gourdon JC, Huot P (2018b) The highly selective 5-HT2A antagonist EMD-281,014 reduces dyskinesia and psychosis in the l-DOPA-treated parkinsonian marmoset. Neuropharmacology 139:61–67. https://doi.org/10.1016/j.neuropharm.2018.06.038

    Article  CAS  PubMed  Google Scholar 

  • Hamadjida A, Nuara SG, Gourdon JC, Huot P (2018c) The effect of mianserin on the severity of psychosis and dyskinesia in the parkinsonian marmoset. Prog Neuropsychopharmacol Biol Psychiatry 81:367–371. https://doi.org/10.1016/j.pnpbp.2017.09.001

    Article  CAS  PubMed  Google Scholar 

  • Hamadjida A, Nuara SG, Gourdon JC, Huot P (2018d) Trazodone alleviates both dyskinesia and psychosis in the parkinsonian marmoset model of Parkinson's disease. J Neural Transm (Vienna) 125(9):1355–1360. https://doi.org/10.1007/s00702-017-1830-8

    Article  CAS  Google Scholar 

  • Hamadjida A, Nuara SG, Veyres N, Frouni I, Kwan C, Sid-Otmane L, Harraka MJ, Gourdon JC, Huot P (2017) The effect of mirtazapine on dopaminergic psychosis and dyskinesia in the parkinsonian marmoset. Psychopharmacology 234(6):905–911. https://doi.org/10.1007/s00213-017-4530-z

    Article  CAS  PubMed  Google Scholar 

  • Hauser RA, Pahwa R, Tanner CM, Oertel W, Isaacson SH, Johnson R, Felt L, Stempien MJ (2017) ADS-5102 (Amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson's Disease (EASE LID 2 Study): interim results of an open-label safety study. J Parkinsons Dis 7(3):511–522. https://doi.org/10.3233/JPD-171134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hely MA, Morris JG, Reid WG, Trafficante R (2005) Sydney multicenter study of Parkinson's disease: non-l-Dopa-responsive problems dominate at 15 years. Mov Disord 20(2):190–199. https://doi.org/10.1002/mds.20324

    Article  PubMed  Google Scholar 

  • Huot P, Johnston TH, Gandy MN, Reyes MG, Fox SH, Piggott MJ, Brotchie JM (2012a) The monoamine re-uptake inhibitor UWA-101 improves motor fluctuations in the MPTP-lesioned common marmoset. PLoS ONE 7(9):e45587. https://doi.org/10.1371/journal.pone.0045587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huot P, Johnston TH, Koprich JB, Fox SH, Brotchie JM (2012b) l-DOPA pharmacokinetics in the MPTP-lesioned macaque model of Parkinson's disease. Neuropharmacology 63(5):829–836. https://doi.org/10.1016/j.neuropharm.2012.06.012

    Article  CAS  PubMed  Google Scholar 

  • Huot P, Johnston TH, Lewis KD, Koprich JB, Reyes MG, Fox SH, Piggott MJ, Brotchie JM (2011) Characterization of 3,4-methylenedioxymethamphetamine (MDMA) enantiomers in vitro and in the MPTP-lesioned primate: R-MDMA reduces severity of dyskinesia, whereas S-MDMA extends duration of ON-time. J Neurosci 31(19):7190–7198. https://doi.org/10.1523/JNEUROSCI.1171-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huot P, Johnston TH, Lewis KD, Koprich JB, Reyes MG, Fox SH, Piggott MJ, Brotchie JM (2014) UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances l-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset. Neuropharmacology 82:76–87. https://doi.org/10.1016/j.neuropharm.2014.01.012

    Article  CAS  PubMed  Google Scholar 

  • Johnston TH, Fox SH, McIldowie MJ, Piggott MJ, Brotchie JM (2010) Reduction of l-DOPA-induced dyskinesia by the selective metabotropic glutamate receptor 5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease. J Pharmacol Exp Ther 333(3):865–873. https://doi.org/10.1124/jpet.110.166629

    Article  CAS  PubMed  Google Scholar 

  • Kingston AE, Ornstein PL, Wright RA, Johnson BG, Mayne NG, Burnett JP, Belagaje R, Wu S, Schoepp DD (1998) LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology 37(1):1–12. https://doi.org/10.1016/s0028-3908(97)00191-3

    Article  CAS  PubMed  Google Scholar 

  • Kwan C, Frouni I, Bedard D, Nuara SG, Gourdon JC, Hamadjida A, Huot P (2019) 5-HT2A blockade for dyskinesia and psychosis in Parkinson's disease: is there a limit to the efficacy of this approach? A study in the MPTP-lesioned marmoset and a literature mini-review. Exp Brain Res 237(2):435–442. https://doi.org/10.1007/s00221-018-5434-9

    Article  CAS  PubMed  Google Scholar 

  • Li ML, Yang SS, Xing B, Ferguson BR, Gulchina Y, Li YC, Li F, Hu XQ, Gao WJ (2015) LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment. Exp Neurol 273:190–201. https://doi.org/10.1016/j.expneurol.2015.08.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizuno Y, Kanazawa I, Kuno S, Yanagisawa N, Yamamoto M, Kondo T (2007) Placebo-controlled, double-blind dose-finding study of entacapone in fluctuating parkinsonian patients. Mov Disord 22(1):75–80. https://doi.org/10.1002/mds.21218

    Article  PubMed  Google Scholar 

  • Monn JA, Valli MJ, Massey SM, Wright RA, Salhoff CR, Johnson BG, Howe T, Alt CA, Rhodes GA, Robey RL, Griffey KR, Tizzano JP, Kallman MJ, Helton DR, Schoepp DD (1997) Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties. J Med Chem 40(4):528–537. https://doi.org/10.1021/jm9606756

    Article  CAS  PubMed  Google Scholar 

  • Okamura N, Hashimoto K, Shimizu E, Koike K, Ohgake S, Koizumi H, Kumakiri C, Komatsu N, Iyo M (2003) Protective effect of LY379268, a selective group II metabotropic glutamate receptor agonist, on dizocilpine-induced neuropathological changes in rat retrosplenial cortex. Brain Res 992(1):114–119. https://doi.org/10.1016/j.brainres.2003.08.045

    Article  CAS  PubMed  Google Scholar 

  • Pahwa R, Hauser RA (2017) ADS-5102 (Amantadine) extended release for levodopa-induced dyskinesia. JAMA Neurol 74(12):1507–1508. https://doi.org/10.1001/jamaneurol.2017.3205

    Article  PubMed  Google Scholar 

  • Pahwa R, Tanner CM, Hauser RA, Isaacson SH, Nausieda PA, Truong DD, Agarwal P, Hull KL, Lyons KE, Johnson R, Stempien MJ (2017) ADS-5102 (Amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson Disease (EASE LID Study): a randomized clinical trial. JAMA Neurol 74(8):941–949. https://doi.org/10.1001/jamaneurol.2017.0943

    Article  PubMed  PubMed Central  Google Scholar 

  • Pinkerton AB, Cube RV, Hutchinson JH, James JK, Gardner MF, Schaffhauser H, Rowe BA, Daggett LP, Vernier JM (2004) Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 2: 4-thiopyridyl acetophenones as non-tetrazole containing mGlu2 receptor potentiators. Bioorg Med Chem Lett 14(23):5867–5872. https://doi.org/10.1016/j.bmcl.2004.09.028

    Article  CAS  PubMed  Google Scholar 

  • Postma JU, Van Tilburg W (1975) Visual hallucinations and delirium during treatment with amantadine (Symmetrel). J Am Geriatr Soc 23(5):212–215

    Article  CAS  Google Scholar 

  • Rook JM, Xiang Z, Lv X, Ghoshal A, Dickerson JW, Bridges TM, Johnson KA, Foster DJ, Gregory KJ, Vinson PN, Thompson AD, Byun N, Collier RL, Bubser M, Nedelcovych MT, Gould RW, Stauffer SR, Daniels JS, Niswender CM, Lavreysen H, Mackie C, Conde-Ceide S, Alcazar J, Bartolome-Nebreda JM, Macdonald GJ, Talpos JC, Steckler T, Jones CK, Lindsley CW, Conn PJ (2015) Biased mGlu5-positive allosteric modulators provide in vivo efficacy without potentiating mGlu5 modulation of NMDAR currents. Neuron 86(4):1029–1040. https://doi.org/10.1016/j.neuron.2015.03.063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schaffhauser H, Rowe BA, Morales S, Chavez-Noriega LE, Yin R, Jachec C, Rao SP, Bain G, Pinkerton AB, Vernier JM, Bristow LJ, Varney MA, Daggett LP (2003) Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2. Mol Pharmacol 64(4):798–810. https://doi.org/10.1124/mol.64.4.798

    Article  CAS  PubMed  Google Scholar 

  • Schoepp DD, Johnson BG, Wright RA, Salhoff CR, Mayne NG, Wu S, Cockerman SL, Burnett JP, Belegaje R, Bleakman D, Monn JA (1997) LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Neuropharmacology 36(1):1–11. https://doi.org/10.1016/s0028-3908(96)00160-8

    Article  CAS  PubMed  Google Scholar 

  • Sheffler DJ, Wenthur CJ, Bruner JA, Carrington SJ, Vinson PN, Gogi KK, Blobaum AL, Morrison RD, Vamos M, Cosford ND, Stauffer SR, Daniels JS, Niswender CM, Conn PJ, Lindsley CW (2012) Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM. Bioorg Med Chem Lett 22(12):3921–3925. https://doi.org/10.1016/j.bmcl.2012.04.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sid-Otmane L, Hamadjida A, Nuara SG, Bedard D, Gaudette F, Gourdon JC, Michaud V, Beaudry F, Panisset M, Huot P (2020) 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 873:172957. https://doi.org/10.1016/j.ejphar.2020.172957

    Article  CAS  PubMed  Google Scholar 

  • Tison F, Keywood C, Wakefield M, Durif F, Corvol JC, Eggert K, Lew M, Isaacson S, Bezard E, Poli SM (2016) A Phase 2A trial of the novel mGluR5-negative allosteric modulator dipraglurant for levodopa-induced dyskinesia in Parkinson's Disease. Mov Disord 31(9):1373–1380

    Article  CAS  Google Scholar 

  • Tizzano JP, Griffey KI, Schoepp DD (2002) The anxiolytic action of mGlu2/3 receptor agonist, LY354740, in the fear-potentiated startle model in rats is mechanistically distinct from diazepam. Pharmacol Biochem Behav 73(2):367–374. https://doi.org/10.1016/s0091-3057(02)00850-x

    Article  CAS  PubMed  Google Scholar 

  • Veyres N, Hamadjida A, Huot P (2018) Predictive value of parkinsonian primates in pharmacologic studies: a comparison between the macaque, marmoset, and squirrel monkey. J Pharmacol Exp Ther 365(2):379–397. https://doi.org/10.1124/jpet.117.247171

    Article  CAS  PubMed  Google Scholar 

  • Visanji NP, Gomez-Ramirez J, Johnston TH, Pires D, Voon V, Brotchie JM, Fox SH (2006) Pharmacological characterization of psychosis-like behavior in the MPTP-lesioned nonhuman primate model of Parkinson's disease. Mov Disord 21(11):1879–1891. https://doi.org/10.1002/mds.21073

    Article  PubMed  Google Scholar 

  • Wenthur CJ, Morrison R, Felts AS, Smith KA, Engers JL, Byers FW, Daniels JS, Emmitte KA, Conn PJ, Lindsley CW (2013) Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM). J Med Chem 56(12):5208–5212. https://doi.org/10.1021/jm400439t

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Qu FR, Nakatsuka A, Nomura T, Nagai M, Nomoto M (2003) Pharmacokinetics of l-Dopa in plasma and extracellular fluid of striatum in common marmosets. Brain Res 993(1–2):54–58

    Article  CAS  Google Scholar 

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Funding

PH has received research support from Parkinson Canada, Fonds de Recherche Québec–Santé, the Weston Brain Institute (Grant No. TR150146), the Michael J Fox Foundation for Parkinson’s Research, and the Natural Sciences and Engineering Research Council of Canada and Healthy Brains for Healthy Lives.

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Authors and Affiliations

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

    Stephen G. Nuara & Jim C. Gourdon

  2. Neurodegenerative Disease Group, Montreal Neurological Institute, 3801 University St, Montreal, QC, H3A 2B4, Canada

    Adjia Hamadjida & Philippe Huot

  3. École Normale supérieure de Bertoua, Université de Ngaoundéré, Ngaoundéré, Cameroon

    Adjia Hamadjida

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

    Philippe Huot

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

    Philippe Huot

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  1. Stephen G. Nuara
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AH, SGN, JCG, and PH conceived and designed research. AH and SN conducted experiments. PH analysed data. PH wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Philippe Huot.

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Experiments were approved by McGill University and the Montreal Neurological Institute 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., Hamadjida, A., Gourdon, J.C. et al. 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. J Neural Transm 127, 1013–1021 (2020). https://doi.org/10.1007/s00702-020-02196-w

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