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Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/03/09/jpet.117.247171.DC1

1521-0103/365/2/379–397$35.00 https://doi.org/10.1124/jpet.117.247171 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 365:379–397, May 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics

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Predictive Value of Parkinsonian Primates in Pharmacologic Studies: A Comparison between the Macaque, Marmoset, and Squirrel Monkey s

Nicolas Veyres, Adjia Hamadjida, and Philippe Huot Centre de Recherche du Centre Hospitalier de l’Université de Montréal (N.V.),Montreal Neurological Institute (A.H.,P.H.), and Downloaded from Department of Neurology and Neurosurgery, McGill University (P.H.), Montreal, Quebec, Canada Received December 13, 2017; accepted March 6, 2018

ABSTRACT jpet.aspetjournals.org The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned predictive value of 87.5% and a false-positive rate of 38.1%, primate is the gold-standard animal model of Parkinson disease whereas the marmoset has a positive predictive value of 76.9% and (PD) and has been used to assess the effectiveness of experimental afalse-positiverateof15.6%.Forparkinsonism, the macaque has a on , , and . Three species positive predictive value of 68.2% and a false-positive rate of have been used in most studies—the macaque, marmoset, and 44.4%, whereas the marmoset has a positive predictive value of squirrel monkey—the last much less so than the first two species; 86.9% and a false-positive rate of 41.7%. No that alleviates however, the predictive value of each species at forecasting clinical psychosis in the clinic has shown at doing so in the

efficacy, or lack thereof, is poorly documented. Here, we have macaque, whereas the marmoset has 100% positive predictive at ASPET Journals on September 24, 2021 reviewed all the published literature detailing pharmacologic studies value. The small number of studies conducted in the squirrel that assessed the effects of experimental drugs on dyskinesia, monkey precluded us from calculating its predictive efficacy. We parkinsonism, and psychosis in each of these species and have hope our results will help in the design of pharmacologic exper- calculated their predictive value of success and failure at the clinical iments and will facilitate the drug discovery and development level. We found that, for dyskinesia, the macaque has a positive process in PD.

Introduction primate when it relates to the effect of drugs on parkinsonian disability or psychosis, nor did it look at differences Since its accidental discovery (Davis et al., 1979; Langston et al., between different primate species when it comes to predicting the 1983), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has clinical effectiveness of an experimental molecule. been used extensively to model Parkinson disease (PD) in a We have therefore conducted a thorough and unbiased breadth of nonhuman primates, enabling the investigation of review of the literature to compare the predictive effectiveness anatomic (Jan et al., 2000; Zeng et al., 2008), behavioral of different MPTP-lesioned primate species on the clinical (Pessiglione et al., 2004a,b), neurochemical (Soghomonian et al., effectiveness of potential antidyskinetic, antiparkinsonian 1994; Huot et al., 2008), and other aspects of the disease. The and agents. MPTP-lesioned primate has also been invaluable in the search for We believe this review comes at a critical time given that it effective antidyskinetic and antiparkinsonian agents. A review has recently been suggested that some primate species might article previously examined the translational predictive value of be more suited than others to conduct behavioral pharmaco- the MPTP-lesioned primate for the development of antidyskinetic logic research (Porras et al., 2012); also, there have been drugs, but it was published more than a decade ago (Fox et al., several failures of high-profile drugs in clinical trials (Cook 2006a), and many drugs have since been tested both in the et al., 2014; Bespalov et al., 2016), emphasizing the need to use primate and in clinical settings. This previous review did not the best animal model possible in preclinical settings to examine the translational predictive value of the MPTP-lesioned maximize chances of success when translating to the clinic.

P.H. holds research support from Parkinson Canada, Fonds de Recherche Québec – Santé, Natural Sciences and Engineering Research Council of Materials and Methods Canada, and the Weston Brain Institute. https://doi.org/10.1124/jpet.117.247171. Three nonhuman primate species have been used in most experiments s This article has supplemental material available at jpet.aspetjournals.org. to determine the antidyskinetic, antiparkinsonian, and antipsychotic

ABBREVIATIONS: L-DOPA, L-3,4-dihydroxyphenylalanine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson disease.

379 380 Veyres et al. Downloaded from Fig. 1. A total of 98 experimental drugs were tested in the MPTP-lesioned Fig. 2. A total of 44 drugs that are either clinically approved or that macaque, 97 in the MPTP-lesioned marmoset, and nine in the MPTP- underwent clinical testing in PD were tested in the MPTP-lesioned lesioned squirrel monkey. macaque, 38 in the MPTP-lesioned marmoset, and one in the MPTP- lesioned squirrel monkey. effect of experimental drugs: the macaque [both cynomolgus (Di Paolo et al., 1986) and rhesus (Burns et al., 1983), Macaca fascicularis and Macaca considered. A drug was considered to have antiparkinsonian benefit jpet.aspetjournals.org mulatta, respectively], the common marmoset (Jenner et al., 1984) if it alleviated parkinsonism as monotherapy or as an adjunct to (Callithrix jacchus), and the common squirrel monkey (Langston et al., L-DOPA. Impulse-control disorders (Weintraub et al., 2010) were not 1984) (Saimiri sciureus). For each of these three primate species, we have considered a psychotic manifestation. reviewed all the studies that reported their effect, or lack thereof, on Several studies, especially in the macaque, were performed that dyskinesia, parkinsonism, and psychosis. We then sought which of these administered drugs (e.g., ) to reduce the development of drugs tested in the nonhuman primate underwent clinical testing and dyskinesia and then conducted postmortem experiments; we have compared their preclinical and clinical effects and calculated different included these studies in our analysis, even if their primary endpoint at ASPET Journals on September 24, 2021 predictive values (see Endpoints). was not determination of pharmacologic efficacy. Studies reporting the Inclusion Criteria. The literature search spans from 1983, when effects of experimental drugs on rotational behavior in the hemi-MPTP- the first MPTP-lesioned nonhuman primate was engineered (Burns lesioned primate (e.g., Vermeulen et al., 1995) were not included. et al., 1983), until December 10, 2017. Studies published after this In some instances, conflicting results were obtained with some drugs date, either online or in print format, are not included. (e.g., studies encountered a therapeutic benefit), whereas others did not Only drugs whose preclinical and clinicalefficacy,orlackthereof,were reach similar conclusions; whenever this happened, we calculated the reported in peer-reviewed articles are included in this article. Results predictive values using “best result” (i.e., the one that showed a disseminated solely through abstracts or conference proceedings are therapeutic effect), weighing in the methods used in the studies (Gad, therefore not reported here. We are aware that not all studies conducted 2009), if applicable. For instance, in the case of preladenant, phase on parkinsonian primates have been published and that the results of 2 studies have found antiparkinsonian efficacy (Hauser et al., 2011; some clinical trials have not been disseminated through peer-reviewed Factor et al., 2013), whereas phase 3 studies did not (Hauser et al., 2015; journals; by choosing to include only studies and reports that were Stocchi et al., 2017); but in one instance, the active comparator, published in peer-reviewed journals, we may be introducing a selection (Hauser et al., 2015), was also ineffective, despite proven antiparkinso- bias in our analysis. For instance, although it has been studied in nian benefit in randomized-controlled trials (Parkinson Study Group, (NCT00034814, NCT00108667), the clinical effectiveness of 2005; Rascol et al., 2005), somewhat casting doubt on study conclusion. In will not be discussed here, as the results of the clinical trials where it was this case, we considered that preladenant exerted antiparkinsonian assessed were not published in peer-reviewed scientific journals. In benefit. addition, we have excluded L-3,4-dihydroxyphenylalanine (L-DOPA) and Endpoints. By comparing the outcomes of the primate studies on inhibitors of L-aromatic amino acid decarboxylase [e.g., dyskinesia, parkinsonism, and psychosis, we have calculated, for each (Rinne et al., 1975) and (Marsden et al., 1973)] from our species, the positive predictive value, the negative predictive value, analysis, as these were used in almost all studies cited here to reverse and the false-positive rate. parkinsonism and induce dyskinesia. Here, we define the positive predictive value of a species as the Research Methods. Literature review was conducted primarily percentage of cases for which a primate species has correctly predicted through the United States National Library of Medicine database, that an antidyskinetic or antiparkinsonian benefit would be achieved accessed via PubMed. The search engine Google was used to complete in the clinic. For the positive predictive value (eq. 1), the denominator the literature review and to access articles not indexed in the National was the number of drugs for which a therapeutic effect was achieved in Library of Medicine database. The following terms were used to perform the clinic, whereas the numerator was the number of these drugs that the literature search: abnormal involuntary movements, chorea, cyno- showed efficacy in the primate: molgus, dyskinesia, dyskinetic, dystonia, , hyperactivity, hyperkinesia, L-DOPA, levodopa, macaque, marmoset, monkey, MPTP, number of molecules that showed effect in the primate (1) nonhuman primate, PD, parkinsonian, parkinsonism, primate, psychosis, number of clinically 2 effective molecules rhesus, squirrel monkey, visual hallucinations. Definition of Efficacy. Throughout our literature search, a Here, we define the negative predictive value of a species as the reduction in dyskinesia/psychosis was considered to have occurred percentage of cases for which a primate species has correctly only if statistical significance was reached; trends were not predicted that a lack of antidyskinetic or antiparkinsonian benefit Predictive Value of Parkinsonian Primates in Drug Research 381

TABLE 1 Drugs tested in the MPTP-lesioned macaque The number (n) of studies reporting the effect of each drug is in brackets.

Drug Dyskinesia Parkinsonism Psychosis References 17-a-Estradiol [n = 1] ne ne na Gomez-Mancilla and Bedard (1992b) 17-b-Estradiol [n =2] √√na Gomez-Mancilla and Bedard (1992b), Bélanger et al. (2003a) (-)-3-(3-Hydroxyphenyl)-N-n- Ne √ na Gomez-Mancilla and Bedard (1991) propylpiperone [n =1] (+)-4-Propyl-9-hydroxynaphthoxazine Ne √ na Gomez-Mancilla and Bedard (1991, 1992a), Luquin et al. (1992, [n =7] 1993b), Blanchet et al. (1993, 1994), Belluzzi et al. (1994) (-)-OSU-6162 [n =1] √ ne na Hadj Tahar et al. (2001) 5-MDOT [n =1] √ de na Gomez-Mancilla and Bedard (1993) 8-OH-DPAT [n =1] √ ne na Munoz et al. (2008) A-77,636 [n =2] √ na Blanchet et al. (1993, 1996b) A-86,929 [n =1] √ na Grondin et al. (1997) ADL-5510 [n =1] √ na Koprich et al. (2011) AFQ-056 [n=1] √√na Grégoire et al. (2011) [n =7] √ de na Blanchet et al. (1998), Bibbiani et al. (2005b), Rylander et al. (2010), Bezard et al. (2013b), Grégoire et al. (2013), Ko et al. (2014b), Shen

et al. (2015) Downloaded from Anpirtoline [n =1] √ de na Bézard et al. (2013a) [n =8] ne √ na Filion et al. (1991), Luquin et al. (1993a), Akai et al. (1995), Blanchet et al. (1997), Doan et al. (1999), Silverdale et al. (2002), Bibbiani et al. (2003, 2005a) AQW-051 [n =1] √√na Di Paolo et al. (2014) [n =1] ne √ na Gomez-Mancilla et al. (1991) [n = 1] ne de na Gomez-Mancilla and Bedard (1993)

BP-897 [n =1] √ ne na Bézard et al. (2003) jpet.aspetjournals.org [n] =9 ne √ na Bédard et al. (1986), Falardeau et al. (1988), Gagnon et al. (1990, 1995), Rouillard et al. (1990), Gomez-Mancilla and Bedard (1991), Blanchet et al. (1993), Gomez-Mancilla et al. (1993), Belluzzi et al. (1994) Cabergoline [n = 20] ne √ na Grondin et al. (1996), Morissette et al. (1998, 1999, 2010), Calon et al. (1999, 2000, 2002), Goulet et al. (1999, 2000), Hadj Tahar et al. (2000b), Bélanger et al. (2003b), Samadi et al. (2008a,b,c, 2010), Ouattara et al. (2009, 2010, 2011), Riahi et al. (2011)

CE [ = 1] ne √ na Cao et al. (2007) at ASPET Journals on September 24, 2021 [n =1] √ de na Fidalgo et al. (2015) CI-1041 [n =14] √ ne na Hadj Tahar et al. (2004), Morissette et al. (2006a,b, 2010), Samadi et al. (2008a,b,c, 2010), Ouattara et al. (2009, 2010, 2011), Tamim et al. (2010), Riahi et al. (2011) [n =2] √√na Gomez-Mancilla et al. (1991), Gomez-Mancilla and Bedard (1993) [n =1] √ ne na Grondin et al. (1999b) CLR-151 [n =1] √ de √ Koprich et al. (2013) Co-101,244/PD-174,494 √ ne na Blanchet et al. (1999) [n =1] CP-94,253 [n = 1] ne ne na Munoz et al. (2008) CP-101,606 [n =1] ne √ na Steece-Collier et al. (2000) CX-516 [n = 1] de ne na Konitsiotis et al. (2000) CY-208,243 [n =8] ne √ na Gomez-Mancilla and Bedard (1991, 1992a), Gomez-Mancilla et al. (1992a, 1993), Blanchet et al. (1993), Gagnon et al. (1993, 1995), Luquin et al. (1993b) DHEA [n =2] ne √ na Bélanger et al. (2003a, 2006) Diazepam [n = 1] √ ne na Gomez-Mancilla and Bedard (1993) Dipraglurant [n =1] √ ne na Bezard et al. (2014) Docosahexaenoic acid [n =5] √ ne na Samadi et al. (2006), Mahmoudi et al. (2009), Tamim et al. (2010), Riahi et al. (2012), Grégoire et al. (2015) [n =3] √ de na Bezard et al. (2013b), Pinna et al. (2016), Ko et al. (2017) [n =1] ne √ na Huot et al. (2013) []n =1 ne √ na Gomez-Mancilla et al. (1992b) F-15,599 [n =1] √ ne na Huot et al. (2015b) Famotidine [n =1] √√na Johnston et al. (2010d) Fenobam [n =2] √√na Rylander et al. (2010), Ko et al. (2014b) Fipamezole [n =1] √√na Johnston et al. (2010c) GYKI-47,261 [n =1] √ ne na Bibbiani et al. (2005b) [n =2] √√na Bezard et al. (1999), Grondin et al. (2000) [n = 3] ne/de √ na Grondin et al. (1999a), Bibbiani et al. (2003, Ko et al. (2016) JL-18 [n =1] √ de na Hadj Tahar et al. (2000a) L-745,870 [n =1] √ ne na Huot et al. (2012b) L- [n =1] √ de na Ko et al. (2014a) [n =1] √ ne na Bezard et al. (2004) LY-235,959 [n =1] √ ne na Papa and Chase (1996) MDL-100,453 [n =1] √ ne na Blanchet et al. (1999) Meperidine [n =1] √ ne na Gomez-Mancilla and Bedard (1993) [n =1] √ de na Gomez-Mancilla and Bedard (1993) (continued) 382 Veyres et al.

TABLE 1—Continued

Drug Dyskinesia Parkinsonism Psychosis References MK-801 [n =1] √ de na Gomez-Mancilla and Bedard (1993) ML-218 [n = 1] ne ne na Galvan et al. (2016) [n =2] √√na Samadi et al. (2004), Yan et al. (2014) MPEP [n =7] √ de na Morin et al. (2010, 2013a,b, 2015a,b), Morissette et al. (2016) MTEP [n =2] √ de na Johnston et al. (2010b), Morin et al. (2010) [n =1] √ de na Bézard et al. (2003) [n =1] √ ne na Potts et al. (2015) [n = 2] ne ne na Gomez-Mancilla and Bedard (1993), Samadi et al. (2003) [n = 5] ne/de ne na Samadi et al. (2003, 2005a,c), Tamim et al. (2010), Koprich et al. (2011) NBQX [n =2] ne √ na Klockgether et al. (1991), Luquin et al. (1993b) NNC-01-112 [n =1] √ de na Grondin et al. (1999b) PAMQX [n =1] na √ na Papa et al. (2004) PD-128,907 [n =1] ne √ na Blanchet et al. (1997) Physostigmine [n =1] √ de na Gomez-Mancilla and Bedard (1993) [n =1] √ ne na Vanover et al. (2008) Pioglitazone [n =1] √ de na Huot et al. (2015a) PPI-1011 [n =1] √ ne na Grégoire et al. (2015)

Prazosin [n = 1] ne ne na Visanji et al. (2009b) Downloaded from Preladenant [n =3] ne √ na Hodgson et al. (2010), Pinna et al. (2016), Ko et al. (2017) [n = 1] ne ne na Gomez-Mancilla and Bedard (1992b) [n =1] √ de na Gomez-Mancilla and Bedard (1993) [n =1] √ ne na Oh et al. (2002) [n =12] ne √ na Bédard and Boucher (1989), Gomez-Mancilla and Bedard (1991), Gomez-Mancilla et al. (1992a), Blanchet et al. (1993, 1994), Akai et al. (1995), Grondin et al. (1997), Samadi et al. (2003, 2004,

2005c), Bibbiani et al. (2005b), Hyacinthe et al. (2014) jpet.aspetjournals.org [n =1] ne √ na Greenamyre et al. (1994) Ro-61,8048 [n =6] √ ne na Samadi et al. (2005b), Grégoire et al. (2008), Ouattara et al. (2009), Tamim et al. (2010), Riahi et al. (2012, 2013) Ro 65-6570 [n =1] √ ne na Marti et al. (2012) [n =2] ne √ na Belluzzi et al. (1994), Domino and Ni (1998a) [n =1] √√na Grégoire et al. (2013) [n =2] √ de na Bibbiani et al. (2001), Grégoire et al. (2009) SCH-23,390 [n =3] √ de na Gomez-Mancilla and Bedard (1991), Akai et al. (1995), Grondin

et al. (1999b) at ASPET Journals on September 24, 2021 Simvastatin [n =1] √ ne na Tison et al. (2013) SKF-38,393 [n =6] ne √/ne na Falardeau et al. (1988), Bédard and Boucher (1989), Gagnon et al. (1990), Rouillard et al. (1990), Blanchet et al. (1993), Hyacinthe et al. (2014) SKF-82,958 [n = 18] ne √ na Blanchet et al. (1993, 1994, 1996a,b), Akai et al. (1995), Goulet et al. (1996, 1999), Domino and Ni (1998a), Morissette et al. (1998, 1999), Calon et al. (1999, 2000, 2002), Grondin et al. (1999c), Samadi et al. (2003, 2004, 2005c), Bibbiani et al. (2005b) ST-198 [n =1] √ de na Bézard et al. (2003) [n =3] √ de na Gomez-Mancilla and Bedard (1991), Akai et al. (1995), Grondin et al. (1999b) [n =1] ne √ na McCall et al. (2005) Talampanel [n =1] √√na Konitsiotis et al. (2000) Tamoxifen [n =1] √ ne na Smith et al. (2007) TC-8831 [n =1] √ ne na Johnston et al. (2013b) [n =1] ne √ na Gomez-Mancilla and Bedard (1991) []n =2 ne √ na Domino and Ni (1998a,b) U-91,356-A [n =4] ne √ na Blanchet et al. (1995), Calon et al. (1995), Goulet et al. (1997), Morissette et al. (1997) U-99,194-A [n =1] √ ne na Blanchet et al. (1997) VU-0,476,406 [n =1] √ ne na Shen et al. (2015) [n =1] √ ne na Gomez-Mancilla and Bedard (1993)

de, deleterious; na, not assessed; ne, not effective; √, effective.

number of molecules that did not show effect in the primate wouldbeachievedintheclinic.Forthenegativepredictivevalue (2) (eq. 2), the denominatorwasthenumberofdrugsforwhicha number of clinically 2 ineffective molecules therapeutic effect was not achieved in the clinic, and the numerator was the number of these drugs that did not show efficacy in the Here, we define the false-positive rate of a species as the primate: percentage of cases for which a primate species has incorrectly

number of clinically-ineffective molecules that showed positive effect in the primate (3) number of clinically-ineffective molecules Predictive Value of Parkinsonian Primates in Drug Research 383

TABLE 2 Drugs tested in the MPTP-lesioned marmoset The number (n) of studies reporting the effect of each drug is in brackets.

Drug Dyskinesia Parkinsonism Psychosis References D-(9)-THC ne √ na van Vliet et al. (2008) [n =1] (+)-PHNO ne √ na Nomoto et al. (1987), Close et al. (1990) [n =2] (+)-N-n-propyl-3-(3-hydroxyphenyl)- [(+)-3PPP] ne √ na Close et al. (1990) [n =1] (-)-N-n-propyl-3-(3-hydroxyphenyl)-piperidine (-)-3PPP ne ne Na Close et al. (1990) [n =1] (-)-N-0437 [n =1] ne √ na Löschmann et al. (1989) (-)-OSU-6162 [n =1] √ ne na Ekesbo et al. (1997) 2-amino-5,6-dihydroxytetralin (N,N-dipropyl A-5,6-DTN) ne √ na Close et al. (1990) [n =1] R-(-)-11-OH-NPa [n =1] ne √ na Lincoln et al. (2016) A-66,359 [n = 1] ne de na Gnanalingham et al. (1995c) A-77,636 [n =4] ne √ na Kebabian et al. (1992), Pearce et al. (1995, 1999), Smith et al. (2002a)

A-86,929 [n =3] ne √ na Shiosaki et al. (1996), Pearce et al. (1999), Downloaded from Treseder et al. (2000) ABT-431 [n =1] ne √ na Shiosaki et al. (1996) Amantadine [n =3] √ ne de Hill et al. (2004b), Visanji et al. (2006), Kobylecki et al. (2011) [n =1] ne √ na Jackson et al. (2010) Apomorphine [n =6] ne √ ne Löschmann et al. (1992), Pearce et al. (1995), Fox et al. (2001), Maratos et al. (2003), Visanji et al.

(2006), Lincoln et al. (2016) jpet.aspetjournals.org Atropine [n =2] ne √ ne Close et al. (1990), Jackson et al. (2014) Benztropine [n =1] ne √ na Close et al. (1990) rasofensine [n =1] ne √ na Pearce et al. (2002) Bromocriptine [n =3] ne √ na Close et al. (1990), Pearce et al. (1995, 1998) BTS-74,398 [n =2] ne √/ne na Hansard et al. (2002b, 2004) [n =2] ne √/ne na Hansard et al. (2002b, 2011) Clozapine [n =1] √ ne √ Visanji et al. (2006) CP-101,606 [n =1] ne √ na Nash et al. (2004)

CPP [n =1] ne √ na Löschmann et al. (1991) at ASPET Journals on September 24, 2021 CY-208,243 [n =2] ne √ na Temlett et al. (1988, 1989) [n =1] √ ne ne Henry et al. (2001) Entacapone [n =4] ne √ na Smith et al. (1997, 2003, 2005), Zubair et al. (2007) Fipamezole [n =1] √√na Savola et al. (2003) GBR-12,909 [n =2] ne √ na Hansard et al. (2002a,b) [n =1] √ de √ Visanji et al. (2006) Idazoxan [n =1] √√na Henry et al. (1999) IEM-1460 [n =1] √ ne na Kobylecki et al. (2010) [n =1] ne √ na Nash et al. (2000) Imetit [n =1] √ ne na Gomez-Ramirez et al. (2006) Immepip [n =1] √ ne na Gomez-Ramirez et al. (2006) Istradefylline [n =6] ne √ na Kanda et al. (1998a,b, 2000), Uchida et al. (2014, 2015a,b) J-113,397 [n =1] √ ne na Visanji et al. (2008) JNJ-27,063,699 [n =1] ne √ na Philippens et al. (2014) Levetiracetam [n =3] √ ne na Hill et al. (2003, 2004a,b) LY-141,865 [n =1] ne √ na Nomoto et al. (1985) MDMA [n =1] √√na Iravani et al. (2003) Melanocyte-inhibiting factor [n = 1] ne ne na Katzenschlager et al. (2007) [n =1] √ de √ Hamadjida et al. (2018) [n =1] √ ne √ Hamadjida et al. (2017) [n =2] ne √ na Jenner et al. (2000), van Vliet et al. (2008) N-0437 [n =1] ne √ na Löschmann et al. (1989) N-methyl ne √ na Jackson et al. (2014) [n =1] [n =1] √ ne na Fox et al. (2002) Naltrexone [n =1] √ ne na Henry et al. (2001) Naltrindole [N =1] √ ne na Henry et al. (2001) Neostigmine [n =1] ne √ na Jackson et al. (2014) [n =1] ne √/de na Hansard et al. (2002b) NBQX [n =1] ne √ na Löschmann et al. (1991) [n =2] ne √ na Close et al. (1990), Hansard et al. (2002b) Oxotremorine [n = 1] ne de na Jackson et al. (2014) [n =3] √√na Johnston et al. (2010a), Jones et al. (2010), Tayarani-Binazir et al. (2010a) (continued) 384 Veyres et al.

TABLE 2—Continued

Drug Dyskinesia Parkinsonism Psychosis References [n =5] ne √ na Pearce et al. (1995), Maratos et al. (2003), Fox et al. (2006b), Uchida et al. (2015a,b) Physostigmine [n = 1] ne de na Jackson et al. (2014) [n =4] ne √ na Smith et al. (1996, 2000, 2002b, 2006) [n =4] ne √ na Iravani et al. (2003, 2006), Fox et al. (2006b), Tayarani-Binazir et al. (2010b) Quetiapine [n =1] √ ne √ Visanji et al. (2006) Quinpirole [n =8] ne √ na Nomoto et al. (1988), Close et al. (1990), Löschmann et al. (1992), Gnanalingham et al. (1995a,b), Pearce et al. (1995), Kanda et al. (2000), Treseder et al. (2000) (R)-(+)-OHDPAT [n =1] √ de na Iravani et al. (2006) R-MDMA [n =1] √ ne √ Huot et al. (2011) [n =4] √ de na Löschmann et al. (1992), Gnanalingham et al. (1995c), Ekesbo et al. (1997), Smith et al. (2002a) [n =1] √ ne na Henry et al. (1999) RGFP-109 [n =1] √ ne na Johnston et al. (2013a)

Rimonabant [n =1] √√na van der Stelt et al. (2005) Downloaded from Ro-25,6981 [n =1] ne √ na Löschmann et al. (2004) [n = 13] ne √ na Pearce et al. (1998), Maratos et al. (2001), Hill et al. (2003), Millan et al. (2004), Silverdale et al. (2004), Fox et al. (2006b), Jackson et al. (2007, 2010), Zubair et al. (2007), Stockwell et al. (2008), Johnston et al. (2010a), Uchida et al. (2015a,b)

Rotigotine [n =3] ne √ na Rose et al. (2007), Stockwell et al. (2009, 2010) jpet.aspetjournals.org S-32,504 [n =2] ne √ na Millan et al. (2004), Hill et al. (2006) S-33,084 [n =3] ne √ na Silverdale et al. (2004), Hill et al. (2006), Visanji et al. (2009a) S-MDMA [n =1] de √ ne Huot et al. (2011) S,S- ne √ na Hansard et al. (2011) [n =1] SB-224,289-A [n = 1] ne ne na Jackson et al. (2004) SCH-23,390 [n = 4] ne de na (Temlett et al. (1988), Löschmann et al. (1992),

Gnanalingham et al. (1995c), Smith et al. at ASPET Journals on September 24, 2021 (2002a) Scopolamine [n =2] ne √ na Close et al. (1990), Jackson et al. (2014) [n = 1] ne de na Hansard et al. (2002b) SKF-38,393 [n = 6] ne ne/de na Nomoto et al. (1985, 1988), Close et al. (1990), Löschmann et al. (1992), Gnanalingham et al. (1995a,b) SKF-75,670 [n = 2] ne de na Gnanalingham et al. (1995a,b) SKF-80,723 [n =4] ne √/de na Gnanalingham et al. (1995a,b,c), Kanda et al. (2000) SKF-82,958 [n =2] ne √/de na Gnanalingham et al. (1995a,b) SKF-83,565 [n =1] ne √ na Gnanalingham et al. (1995a) SKF-83,959 [n =3] ne √ na Gnanalingham et al. (1995a,b,c) SKF-99,101-H [n =1] √ ne/de na Jackson et al. (2004) SNC-80 ne √ na Hille et al. (2001) [n =1] ST-1535 ne √ na Rose et al. (2006) [n =1] Sulpiride ne de na Temlett et al. (1988), Jones et al. (2010) [n =2] Terguride [n =1] ne √ na Lange et al. (1992) [n =2] √ ne na Silverdale et al. (2005), Kobylecki et al. (2011) Trihexyphenidyl ne √ na Jackson et al. (2014) [n =1] URB-597 [n = 1] ne ne ne Johnston et al. (2011) UWA-101 []n =2 ne √ ne Huot et al. (2012a), Johnston et al. (2012) UWA-121 [n =1] ne √ ne Huot et al. (2014) UWA-122 [n =1] √√ne Huot et al. (2014) Yohimbine [n =1] √ ne na Henry et al. (1999)

de, deleterious; na, not assessed; ne, not effective; √, effective.

predicted that a lack of antidyskinetic or antiparkinsonian benefit Results would be achieved in the clinic. For the false-positive rate (eq. 3), the denominator was the number of drugs for which a therapeutic Pharmacologic Targets effect was not achieved in the clinic; the numerator was the number Several pharmacologic targets have been modulated in of these clinically ineffective drugs that were deemed to be effective studies performed in the MPTP-lesioned macaque and the in the primate: MPTP-lesioned marmoset. In contrast, only dopaminergic, Predictive Value of Parkinsonian Primates in Drug Research 385

TABLE 3 Drugs tested in the MPTP-lesioned squirrel monkey The number (n) of studies reporting the effect of each drug is in brackets.

Drug Dyskinesia Parkinsonism Psychosis References ABT-089 [n =1] √ ne na Zhang et al. (2014) ABT-107 [n =1] √ ne na Zhang et al. (2013) ABT-126 [n =1] √ ne na Zhang et al. (2015) ABT-894 [n =3] √ ne na Zhang et al. (2013, 2014, 2015) BP-897 [n =1] √ de na Hsu et al. (2004) [n =4] √ ne na Quik et al. (2007, 2013a,b), Zhang et al. (2015) TC-8831 [n =1] √ ne na Zhang et al. (2013) U50-488 [n =1] √ de na Cox et al. (2007) [n =1] √ ne na Zhang et al. (2013)

de, deleterious; na, not assessed; ne, not effective; √, effective. opioidergic and targets have been assessed in Prediction of Antidyskinetic Effect studies conducted in the MPTP-lesioned squirrel monkey (see Of the 64 drugs that were tested in the clinic and in the

Supplemental Table 1 for the pharmacologic profile of all MPTP-lesioned primate, 22 showed antidyskinetic effect in Downloaded from molecules that have been tested in the MPTP-lesioned clinical trials, no antidyskinetic effect was found or reported primate). for 36 drugs, and four drugs showed a deleterious effect on A total of 98 different molecules were assessed in the MPTP- dyskinesia severity (see Supplemental Table 2 for details). lesioned macaque, 97 in the MPTP-lesioned marmoset, and MPTP-Lesioned Macaque. Of the 22 drugs that demon- nine in the MPTP-lesioned squirrel monkey (Fig. 1). Of all the strated an antidyskinetic effect in clinical settings, 16 were

molecules tested in the MPTP-lesioned primate, 64 have been tested in the macaque, and an antidyskinetic effect was jpet.aspetjournals.org assessed at the clinical level or are clinically approved. Of obtained with 14 (87.5% positive predictive value, Fig. 3). Of these, 44 were tested in the macaque, 38 in the marmoset, and the 36 drugs for which no antidyskinetic effect was found or one in the squirrel monkey (Fig. 2). Because very few drugs reported in the clinic, 21 were tested in the macaque. No antidyskinetic effect was encountered or reported with have been tested in the MPTP-lesioned squirrel monkey 13 (61.9% negative predictive efficacy, Fig. 4); an antidyski- compared with the macaque and the marmoset, we do not netic action was found with eight (38.1% false-positive rate, discuss it further in the text, but we have nevertheless

Fig. 5). Of the four drugs that had a deleterious effect on at ASPET Journals on September 24, 2021 included it in the tables. dyskinesia severity in the clinic, two were tested in the We have summarized our research results in tables: macaque, and an exacerbation of dyskinesia could not be • Table 1: drugs tested in the MPTP-lesioned macaque demonstrated in either case. • Table 2: drugs tested in the MPTP-lesioned marmoset MPTP-Lesioned Marmoset. Of the 22 drugs that dem- • Table 3: drugs tested in the MPTP-lesioned squirrel onstrated an antidyskinetic effect in clinical settings, 13 were monkey tested in the marmoset, and an antidyskinetic effect was • Table 4: drugs tested in the MPTP-lesioned primate that obtained with 10 (76.9% positive predictive value, Fig. 3). Of were tested in the clinic or are clinically-available the 36 drugs for which no antidyskinetic effect was found or reported, 22 were tested in the marmoset, and the absence of In each table, the drugs are listed in numerical or - antidyskinetic effect was identified in 19 (86.4% negative betical order. predictive value, Fig. 4), whereas an antidyskinetic action was We have also summarized our results in figures: found with three (15.6% false-positive rates Fig. 5). Of the four • Figure 1: number of drugs tested in the MPTP-lesioned drugs that had a deleterious effect on dyskinesia severity, nonhuman primate three were tested in the marmoset, but an exacerbation of • Figure 2: number of drugs assessed in the clinic or dyskinesia could not be demonstrated in any case. clinically approved that were tested in the MPTP- lesioned nonhuman primate Prediction of Antiparkinsonian Action • Figure 3: antidyskinetic positive predictive value of the Of the 64 drugs that were tested in the clinic and in the MPTP-lesioned nonhuman primate MPTP-lesioned primate, 34 showed an antiparkinsonian • Figure 4: antidyskinetic negative predictive value of the effect in clinical trials; no antiparkinsonian effect was found MPTP-lesioned nonhuman primate or reported for 24 drugs, and five drugs were found to have a • Figure 5: antidyskinetic false positive rate of the MPTP- deleterious effect on parkinsonian disability (see Supplemen- lesioned nonhuman primate tal Table 3 for details). • Figure 6: antiparkinsonian positive predictive value of MPTP-Lesioned Macaque. Of the 34 drugs that showed the MPTP-lesioned nonhuman primate antiparkinsonian effect in clinical trials, 22 were tested in the • Figure 7: antiparkinsonian negative predictive value of macaque, and an antiparkinsonian benefit was obtained with the MPTP-lesioned nonhuman primate 15 (68.2% positive predictive value, Fig. 6). Of the 24 drugs for • Figure 8: antiparkinsonian false positive rate of the which no antiparkinsonian effect was found or reported, MPTP-lesioned nonhuman primate 18 were tested in the macaque, and no antiparkinsonian effect • Figure 9: worsening of parkinsonism positive predictive was encountered or reported with six (33.3% negative pre- value of the MPTP-lesioned nonhuman primate. dictive value, Fig. 7), whereas antiparkinsonian action was 386 Veyres et al.

TABLE 4 Drugs tested in the MPTP-lesioned primate that were tested in the clinic or are clinically available

Drug Dyskinesia Parkinsonism Psychosis References (+)-4-Propyl-9-hydroxynaphthoxazine Ne √ na Stoessl et al. (1985), Grandas et al. (1987), Muenter et al. (1988) ABT-431 Ne √ na Rascol et al. (1999, 2001b) AFQ-056 √/ne ne na Stocchi et al. (2013), Trenkwalder et al. (2016b) Amantadine √√na Parkes et al. (1971), Butzer et al. (1975), Verhagen Metman et al. (1998), Luginger et al. (2000), Del Dotto et al. (2001), Oertel et al. (2017), Pahwa et al. (2017) Apomorphine ne √ na Schwab et al. (1951), Corsini et al. (1979), Stibe et al. (1987) AQW-051 ne ne na Trenkwalder et al. (2016a) Atropine ne √ na Boman and Meurman (1970) Benztropine ne √ na Doshay (1956) ne ne na Frackiewicz et al. (2002) Bromocriptine ne √ na Agid et al. (1979), Quinn et al. (1981), Jellinger (1982), Hely et al. (1994), Montastruc et al. (1994, Castro-Caldas et al. (2006) Bupropion ne √ na Goetz et al. (1984) Cabergoline ne √ na Ahlskog et al. (1996), Rinne et al. (1997), Deuschl et al. (2007) Citalopram √√na Rampello et al. (2002), Pålhagen et al. (2008, 2009) Clonidine na √/de na Shoulson and Chase (1976), Serrano-Dueñas (2000) Clozapine √√√Durif et al. (1997, (2004); The French Clozapine Parkinson Study Downloaded from Group (1999), Parkinson Study Group (1999) CP-101,606 √ ne na Nutt et al. (2008) CY-208,243 ne √ na Tsui et al. (1989), Emre et al. (1992) Diazepam √√na Pourcher et al. (1989) Dipraglurant √ ne na Tison et al. (2016) Eltoprazine √ ne na Svenningsson et al. (2015) Entacapone de √ na Kaakkola et al. (1994), Merello et al. (1994), Fenelon et al. (2003)

Ethosuximide ne ne/de na Pourcher et al. (1992) jpet.aspetjournals.org Famotidine ne ne na Molinari et al. (1995), Mestre et al. (2014) Fipamezole √ ne na Lewitt et al. (2012) Haloperidol √ de na Klawans and Weiner (1974) Idazoxan √/ne ne na Manson et al. (2000), Rascol et al. (2001a) Istradefylline ne √ na Hauser et al. (2003, 2008), LeWitt et al. (2008), Pourcher et al. (2012) L-tryptophan ne ne na Coppen et al. (1972) Levetiracetam √/ne ne ne Wolz et al. (2010), Stathis et al. (2011), Wong et al. (2011) Melanocyte-inhibiting factor ne ne na Gerstenbrand et al. (1975)

Methysergide ne ne na Klawans and Ringel (1973) at ASPET Journals on September 24, 2021 Mianserin na na √ Ikeguchi and Kuroda (1995) Mirtazapine √√√Gordon et al. (2002), Meco et al. (2003), Nagata et al. (2013), Tagai et al. (2013) Modafinil ne ne na Tyne et al. (2007, 2010) Morphine √ de na Berg et al. (1999) Nabilone √ ne na Sieradzan et al. (2001) Naloxone √/ne √/ne na Trabucchi et al. (1982), Fox et al. (2004) Naltrexone √/ne ne na Rascol et al. (1994), Manson et al. (2001) Nicotine na √/ne na Vieregge et al. (2001), Lemay et al. (2004), Villafane et al. (2007) Nomifensine de √ na Teychenne et al. (1976), Bedard et al. (1977), Park et al. (1977, 1981) Pardoprunox ne √ na Bronzova et al. (2010), Sampaio et al. (2011), Rascol et al. (2012) Pergolide ne √ na Lieberman et al. (1986), Wright et al. (1987), Olanow et al. (1994), Mizuno et al. (1995), Oertel et al. (2006) Physostigmine √/ne de na Tarsy et al. (1974), Lindeboom and Lakke (1978), Clough et al. (1984) Pimavanserin ne ne √ Meltzer et al. (2010), Cummings et al. (2014) Pioglitazone ne ne na NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators (2015) Piribedil ne √ na Castro-Caldas et al. (2006), Rascol et al. (2006b) Pramipexole ne √ na Lieberman et al. (1997), Parkinson Study Group (2000b), Poewe et al. (2007) Preladenant de √/ne na Hauser et al. (2011, (2015), Factor et al. (2013), Stocchi et al. (2017) Propranolol √√/ne na Koller and Herbster (1987), Carpentier et al. (1996) Quetiapine √/ne ne/de √/ne Fernandez et al. (1999), (2003), Baron and Dalton (2003), Katzenschlager et al. (2004), Ondo et al. (2005) Remacemide ne ne na Parkinson Study Group (2000a, 2001), Shoulson et al. (2001) Ropinirole ne √ na Rascol et al. (1996, (2000, 2006a), Korczyn et al. (1999) Rotigotine ne √ na Parkinson Study Group (2003), Giladi et al. (2007), LeWitt et al. (2007), Mizuno et al. (2013) Safinamide √√na Borgohain et al. (2014a,b), Cattaneo et al. (2015), Schapira et al. (2017) Sarizotan ne de na Olanow et al. (2004), Goetz et al. (2007, 2008) Scopolamine ne √ na Gruchet (1952), Duvoisin (1967) Sertraline ne ne na Hauser and Zesiewicz (1997), Antonini et al. (2006), Kulisevsky et al. (2008), Marino et al. (2008) Simvastatin ne ne na Tison et al. (2013) SKF-38,393 ne ne na Braun et al. (1987) Sulpiride √ de na Lees et al. (1978) Sumanirole ne √/ne na Barone et al. (2007), Singer et al. (2007) (continued) Predictive Value of Parkinsonian Primates in Drug Research 387

TABLE 4—Continued

Drug Dyskinesia Parkinsonism Psychosis References Terguride ne √ na Filipova et al. (1988), Martignoni et al. (1995) Topiramate ne/de ne na Kobylecki et al. (2014), Goetz et al. (2017) Trihexyphenidyl ne √ na Martin et al. (1974), Lamid and Jenkins (1975) Yohimbine ne √ na Montastruc et al. (1981)

de, deleterious; na, not assessed; ne, not effective; √, effective. found with eight (44.4% false-positive rate, Fig. 8). Of the five primate. No drug that underwent clinical testing or that is drugs that had a deleterious effect on parkinsonian disability, clinically available has demonstrated antipsychotic effect in four were tested in the macaque, and this deleterious effect on the MPTP-lesioned macaque or the MPTP-lesioned squirrel parkinsonism was correctly identified in three (75% predictive monkey. Pimavanserin was not tested in the MPTP-lesioned value, Fig. 9). marmoset, but an antipsychotic benefit was achieved with MPTP-Lesioned Marmoset. Of the 34 drugs that showed clozapine, mianserin, mirtazapine, and quetiapine (100% antiparkinsonian effect in clinical trials, 23 were tested in the positive predictive value).

marmoset; an antiparkinsonian effect was obtained with Downloaded from 20 (86.9% positive predictive value, Fig. 6). Of these, 24 drugs did not find or did not report an antiparkinsonian effect, Discussion 12 were tested in the marmoset, and no antiparkinsonian Here, we have reviewed all the literature published in peer- effect was encountered with six (50.0% negative predictive value, Fig. 7), whereas antiparkinsonian benefit was found reviewed scientific journals that reported the results of with five (41.7% false-positive rate, Fig. 8). Of the five drugs pharmacologic studies conducted in the MPTP-lesioned ma- caque, marmoset, and squirrel monkey in which the effects jpet.aspetjournals.org found to have a deleterious effect on parkinsonian disability, three were tested in the marmoset, all of which hindered of experimental drugs on dyskinesia, parkinsonism, and parkinsonism (100% predictive value, Fig. 9). psychosis was assessed. By comparing the results obtained at the preclinical level with those obtained in clinical settings, we have calculated the predictive value of each Prediction of Antipsychotic Action primate species for these disease manifestations/treat- Of the 64 drugs that were tested in the clinic and in the ment-related complications.

MPTP-lesioned primate, five showed an antipsychotic effect in There are limitations to our analysis that must be men- at ASPET Journals on September 24, 2021 clinical trials/reports (clozapine, mianserin, mirtazapine, tioned. First, as mentioned in the Introduction, the results of pimavanserin, quetiapine). Compared with dyskinesia and several studies, both preclinical and clinical, have not been parkinsonism, the effect of experimental drugs on dopaminer- published; and, although we aimed for exhaustiveness, our gic psychosis has been far less studied in the MPTP-lesioned review is necessarily incomplete, which may have affected the

Fig. 3. The antidyskinetic positive predictive value of the MPTP-lesioned Fig. 4. The antidyskinetic negative predictive value of the MPTP- macaque is 87.5% and 76.9% for the MPTP-lesioned marmoset. lesioned macaque is 61.9% and 86.4% for the MPTP-lesioned marmoset. 388 Veyres et al. Downloaded from

Fig. 5. The antidyskinetic false-positive rate of the MPTP-lesioned Fig. 7. The antiparkinsonian negative predictive value of the MPTP- jpet.aspetjournals.org macaque is 38.1% and 15.6% for the MPTP-lesioned marmoset. lesioned macaque is 33.3% and 50.0% for the MPTP-lesioned marmoset. various rates presented. Second, the methods of the clinical dose administered may be poorly tolerated by patients, which trials cited is highly variable, ranging from observational is why this approach is seldom used in clinical trials. Fourth, reports to randomized controlled trials; they were weighed some clinical trials were performed in early stage PD patients, equally here. Third, the method used in preclinical studies is, whereas the degree of parkinsonism after MPTP administra- at ASPET Journals on September 24, 2021 at times, different from the one used in clinical settings; one tion is severe and would correspond to advanced-stage PD. example is when a low dose of L-DOPA is administered to Finally, as several types of trials are part of our review, in primates in combination with an agent with potential anti- some, PD patients were taking antiparkinsonian , parkinsonian effect as adjunct therapy. Lowering the L-DOPA in addition to L-DOPA, which is generally not the case in

Fig. 6. The antiparkinsonian positive predictive value of the MPTP- Fig. 8. The antiparkinsonian false-positive rate of the MPTP-lesioned lesioned macaque is 68.2% and 86.9% for the MPTP-lesioned marmoset. macaque is 44.4% and 41.7% for the MPTP-lesioned marmoset. Predictive Value of Parkinsonian Primates in Drug Research 389

Authorship Contributions Participated in research design: Veyres, Huot. Performed data analysis: Veyres, Huot. Wrote or contributed to the writing of the manuscript: Veyres, Hamadjida, Huot.

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drug category references

D-(9)-THC cannabinoid (Felder et al., CB1,2 agonist (dronabinol) agonist 1995)

(-)-3-(3- (Arnt et al.,

hydroxyphenyl)-N-n- D2 agonist, s ligand D2 agonist 1983; Iyengar et

propylpiperone al., 1991)

(+)-4-propyl-9- (Martin et al., hydroxynaphthoxazine D2 agonist, a2 ligand D2 agonist 1985) (PHNO)

(+)-N-n-propyl-3-(3- (Close et al., hydroxyphenyl)- D2 agonist D2 agonist 1990) piperidine [(+)-3PPP]

(-)-N-n-propyl-3-(3- (Close et al., hydroxyphenyl)- D2 partial agonist D2 partial agonist 1990) piperidine (-)-3PPP

(Loschmann et (-)-N-0437 D2-like agonist D2 agonist al., 1989)

(Burstein et al., (-)-OSU-6162 (PNU- D2 partial agonist, 5-HT2A D2 partial agonist 2011; Carlsson 96,391) partial agonist et al., 2011)

2-amino-5,6- (Mulder et al., D2 agonist D2 agonist dihydroxytetralin 1980; Gower

1 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther (N,N-dipropyl A-5,6- and Marriott,

DTN) 1982)

(Tricklebank et

5-MDOT (5-MeO- non-selective 5-HT al., 1985; 5-HT agonist DMT) receptor agonist Spencer et al.,

1987)

(Lejeune et al., 8-OH-DPAT 5-HT1A agonist 5-HT1A agonist 1997)

17-alpha-oestradiol oestrogen receptor agonist, (Kuiper et al., oestrogen agonist (alfatradiol) 5a-reductase inhibitor 1997)

(Kuiper et al., 17-beta-oestradiol oestrogen receptor agonist oestrogen agonist 1997)

(Vanover et al., A-66,359 D1 antagonist D1 antagonist 1991)

(Kebabian et al., A-77,636 D1 agonist D1 agonist 1992)

(Michaelides et

al., 1995; A-86,929 D1 agonist D1 agonist Ehrlich et al.,

1997)

(Marks et al., ABT-089 () b2 nACh agonist 2009)

2 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther (Malysz et al., ABT-107 a7 nACh agonist nicotinic agonist 2010)

(Zhang et al.,

ABT-126 (nelonicline) a7 nACh agonist nicotinic agonist 2015; Haig et

al., 2016)

(Shiosaki et al., ABT-431 (adrogolide) D1 agonist D1 agonist 1996)

ABT-894 (sofinicline) a4b2 nACh agonist nicotinic agonist (Ji et al., 2007)

(Koprich et al., ADL-5510 µ antagonist µ antagonist 2011)

AFQ-056 (Vranesic et al., mGlu5 NAM mGlu5 NAM (mavoglurant) 2014)

(Matsubayashi

NMDA antagonist, s1 et al., 1997;

amantadine agonist, a7 nACh NMDA antagonist Peeters et al.,

antagonist 2004; Blanpied

et al., 2005)

(Schlicker et al., anpirtoline 5-HT1B > 5-HT1A agonist 5-HT1B agonist 1992)

dopamine partial (Heinrich et al., aplindore (DAB-452) D2,3 partial agonist agonist 2006)

D1 agonist, D2,3,4 partial (Millan et al., apomorphine dopamine agonist agonist, 5-HT2A,2B, 2002; Newman-

3 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther

antagonist, 5-HT1A partial Tancredi et al.,

agonist, a2A partial agonist, 2002a;

a2B,2C antagonist Newman-

Tancredi et al.,

2002b)

nicotinic partial (Feuerbach et AQW-051 a7 nACh partial agonist agonist al., 2015)

muscarinic (Hirose et al., atropine M1,2,3,4,5 antagonist antagonist 2001)

(Hirst et al., baclofen GABAB agonist GABAB agonist 2003)

benztropine M1,2 antagonist, DAT muscarinic (Newman et al.,

(benzatropine) inhibitor antagonist 1995)

(Bezard et al.,

BP-897 D3 partial agonist D3 partial agonist 2003; Pilleri and

Antonini, 2015)

non-selective brasofensine (NS-2214, DAT, NET, SERT monoamine re- (Singh, 2000) BMS-204,756) inhibitor uptake inhibitor

D2,3-preferential dopamine

bromocriptine (CB- agonist, 5-HT1A,1D partial (Millan et al., dopamine agonist 154) agonist, a2A,2B,2C 2002)

antagonist

4 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther non-selective (Cheetham et DAT, NET, SERT BTS-74,398 monoamine re- al., 1998; Singh, inhibitor uptake inhibitor 2000)

(Carroll et al., dual monoamine bupropion DAT, NET inhibitor 2009; Lapinsky re-uptake inhibitor et al., 2009)

D2,3 partial agonist, 5- (Millan et al., cabergoline HT1A,1D,2A,2B agonist, dopamine agonist 2002) a2A,2C antagonist

cannabinoid (Cao et al., CE CB1 antagonist antagonist 2007)

(Ben-Daniel et citalopram SERT inhibitor SERT inhibitor al., 2008)

(Barton and CI-1041 (, White, 2004; PD-196,860, Co- NR2B antagonist NMDA antagonist Barton et al., 200,461) 2004)

(Ernsberger et

clonidine a2A,2B,2C agonist, I1 agonist a2 agonist al., 1987; Jasper

et al., 1998)

H1 antagonist, 5- (Lahti et al., atypical anti- clozapine HT2A,2B,2C,6,7 antagonist, 1993; Schotte et psychotic a1A,1B,1D antagonist, D4 al., 1996;

5 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther

antagonist, 5-HT1A,1F Yoshio et al.,

agonist 2001; Booth et

al., 2002; Knight

et al., 2004;

Purohit et al.,

2005)

D2 fast-off (Koprich et al., CLR-151 D2 antagonist antagonist 2013)

Co-101,244/PD- (Gill et al., NR2B antagonist NMDA antagonist 174,494 (Ro-631,908) 2002)

(Koe et al., CP-94,253 5-HT1B-preferential agonist 5-HT1B agonist 1992)

(Chenard et al.,

CP-101,606 1995; NR2B antagonist NMDA antagonist () Brimecombe et

al., 1997)

(Feng et al., CPP NR2A,2B,2C,2D antagonist NMDA antagonist 2004)

(Krintel et al., CX-516 (BDP-12) GluA2 PAM 2013)

(Andersen and CY-208,243 D1,2 agonist dopamine agonist Jansen, 1990)

6 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther

5-HT2A,2C,6,7 antagonist, H1 (Leysen et al.,

cyproheptadine antagonist, a1B,1D 5-HT antagonist 1981; Hoyer et

antagonist al., 1994)

(Bergeron et al.,

androgen receptor agonist, 1996; Maurice

a- and b-oestrogen et al., 1997;

DHEA receptor agonist, GABAA androgen agonist Sousa and

NAM, NMDA PAM, s1 Ticku, 1997;

agonist Chen et al.,

2005)

(Pritchett et al., diazepam GABAA PAM GABAA PAM 1989)

dipraglurant (ADX- (Chae et al., mGlu5 NAM mGlu5 NAM 48,621) 2013)

(Lampen et al.,

2001; Itoh et al., FFA1 agonist, RXR-a docosahexaenoic acid RXR agonist 2003; Motter agonist, TRPA1 agonist and Ahern,

2012)

eltoprazine (DU- 5-HT1A,1B agonist, 5-HT2C (Schipper et al., 5-HT1A,1B agonist 28,853) antagonist 1990)

(Lotta et al., entacapone (OR-611) COMT inhibitor COMT inhibitor 1995)

7 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther T-type calcium channel T-type calcium (Gomora et al., ethosuximide antagonist channel antagonist 2001)

(Newman- preferential post-synaptic F-15,599 5-HT1A agonist Tancredi et al., 5-HT1A agonist 2009)

famotidine H2 antagonist H2 antagonist (Chremos, 1987)

(Porter et al., fenobam mGlu5 NAM mGlu5 NAM 2005)

(Johnston et al., fipamezole (JP-1730) a2A,2B,2C antagonist a2 antagonist 2010)

GBR-12,909 (Andersen, DAT inhibitor DAT inhibitor () 1989)

(Abraham et al., GYKI-47,261 AMPA antagonist AMPA antagonist 2000)

(Sunahara et al.,

D2-like antagonist, D1 1991; Tice et al.,

haloperidol antagonist, a1 antagonist, D2 antagonist 1994; Kroeze et

s1 antagonist al., 2003; Cobos

et al., 2007)

(Doxey et al.,

1984; idazoxan a2 antagonist, I2 agonist a2 antagonist Regunathan and

Reis, 1996)

8 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther (Schlesinger et IEM-1460 AMPA antagonist AMPA antagonist al., 2005)

(Reynolds and

Miller, 1989; ifenprodil NR1,2 antagonist NMDA antagonist Korinek et al.,

2011)

(Garbarg et al.,

imetit H3,4 agonist H3,4 agonist 1992; Liu et al.,

2001)

(Liu et al., 2001;

immepip H3,4 agonist H3,4 agonist Kitbunnadaj et

al., 2003)

istradefylline (KW- (Fredholm et al., A2A antagonist A2A antagonist 6002) 2011)

(Kawamoto et

J-113,397 ORL-1 antagonist ORL-1 antagonist al., 1999; Ozaki

et al., 2000)

dopamine (Liegeois et al., JL-18 D2,4 antagonist antagonist 1995)

(Philippens et JNJ-27,063,699 a2C antagonist a2 antagonist al., 2014)

(Patel et al., L-745,870 D4 antagonist D4 antagonist 1997)

9 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther (Fernstrom, L-tryptophan 5-HT precursor 5-HT agonist 1983)

(Lynch et al., levetiracetam SV2A antagonist SV2A antagonist 2004)

(Tsuruta et al., LY-141,865 D2 agonist D2 agonist 1981)

(Schoepp et al., LY-235,959 (active NMDA antagonist NMDA antagonist 1991; Herman et isomer of LY-274,614) al., 1995)

NR2A-preferential (Blanchet et al., MDL-100,453 NMDA antagonist antagonist 1999)

(Battaglia et al.,

DAT inhibitor, SERT 1988; Nash et dual monoamine MDMA inhibitor, 5-HT2A partial al., 1994; re-uptake inhibitor agonist Verrico et al.,

2007)

melanocyte-inhibiting

factor (Pro-Leu-Gly- (Verma et al., NH2, melanostatin, D2,4 PAM, opiate D2 PAM 2005; Pan and MSH release- antagonist Kastin, 2007) inhibiting hormone,

MIF-1)

10 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther (Poulain et al., meperidine () µ > k > d agonist opioid agonist 2001)

(Leysen et al.,

1981; Hoyer et

5-HT1D,1F,2A,2C antagonist, al., 1994; methysergide 5-HT antagonist 5-HT2B agonist Bonhaus et al.,

1997; Rothman

et al., 2000)

(Hyttel, 1982;

de Boer et al.,

5-HT2A,2C,3 antagonist, 1988; Hyttel, atypical anti- mianserin a1,2A,2C antagonist, H1 1994; Kooyman depressant antagonist et al., 1994;

Fernandez et al.,

2005)

(de Boer, 1996;

Tatsumi et al., a2A,2C antagonist, 5- mirtazapine (ORG- atypical anti- 1997; Anttila HT2A,2C,3 antagonist, H1 3770) depressant and Leinonen, antagonist 2001; Fernandez

et al., 2005)

NMDA antagonist, a7 (Amador and MK-801 () NMDA antagonist nACh antagonist Dani, 1991)

11 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther T-type calcium channel T-type calcium (Xiang et al., ML-218 antagonist channel antagonist 2011)

(Seeman et al., D2 partial agonist, DAT non-selective DAT 2009; modafinil inhibitor – not fully inhibitor Zolkowska et characterised al., 2009)

(Poulain et al., morphine µ > k > d agonist opioid agonist 2001)

(Gasparini et al.,

MPEP mGlu5 NAM, mGlu4 PAM mGlu5 NAM 1999; Mathiesen

et al., 2003)

(Cosford et al., MTEP mGlu5 NAM mGlu5 NAM 2003)

(Van der Weide

et al., 1986; Van N-0437 D2-like agonist D2 agonist der Weide et al.,

1988)

(Dowling and

Charlton, 2006; muscarinic N-methyl scopolamine M1,3 antagonist Fruchart- antagonist Gaillard et al.,

2006)

12 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther cannabinoid (Blaazer et al., nabilone CB1,2 agonist agonist 2011)

(Sautel et al.,

D2,3 antagonist, 5-HT1A dopamine 1995; Newman- nafadotride agonist antagonist Tancredi et al.,

1998)

(Poulain et al., nalbuphine µ > k > d agonist opioid agonist 2001)

(Poulain et al., naloxone µ = k > d antagonist opioid antagonist 2001)

(Emmerson et

al., 1994; naltrexone µ > k > d antagonist opioid antagonist Koprich et al.,

2011)

(Portoghese et naltrindole d > µ = k antagonist opioid antagonist al., 1988)

AMPA > kainate (Sheardown et NBQX AMPA antagonist antagonist al., 1990)

(Kavitha et al., neostigmine AChE inhibitor ChE inhibitor 2007)

non-selective nACh (Benowitz, nicotine nicotinic agonist agonist 2009)

13 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther (Wong et al., nisoxetine (LY-94,939) NET inhibitor NET inhibitor 1982)

(Andersen et al.,

1992; Nielsen NNC-01-112 D1 antagonist D1 antagonist and Andersen,

1992)

(Richelson and

Nelson, 1984; nomifensine (HOE- dual monoamine DAT = NET inhibitor, Close et al., 984) re-uptake inhibitor 1990; Tatsumi et

al., 1997)

(Jakubik et al., oxotremorine M1,2,3,4 agonist 1997)

PAMQX (CGP- NMDA antagonist (at (Ametamey et NMDA antagonist 78,608) site) al., 2000)

(Glennon et al., pardoprunox (SLV- D2,3 partial agonist, 5-HT1A dopamine partial 2006; Jones et 308) agonist agonist al., 2010)

(DeWald et al.,

1990; Akunne et

PD-128,907 D2,3 agonist dopamine agonist al., 1995;

Pugsley et al.,

1995)

14 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther

5-HT1A,1D partial agonist,

5-HT2A,2B agonist, D2 pergolide (LY- (Millan et al., agonist, D3,4 partial dopamine agonist 127,809) 2002) agonist, a2A,2B,2C partial

agonist

AChE inhibitor, BuChE (Luo et al., physostigmine ChE inhibitor inhibitor 2006)

pimavanserin (ACP- 5-HT2A inverse (Vanover et al., 5-HT2A,2C inverse agonist 103) agonist 2006)

(Smith, 2001; PPARg > a agonist, pioglitazone PPARg agonist Paddock et al., mitoNEET ligand 2007)

a1A,2A,2C antagonist, D2,3

partial agonist, D4 (Millan et al., piribedil dopamine agonist antagonist, 5-HT1A partial 2002)

agonist

lipid plasmalogen plasmalogen ( et al., PPI-1011 precursor precursor 2011)

(Newman- D2S agonist, D2L,3,4 partial pramipexole dopamine agonist Tancredi et al., agonist 2002a)

(Ford et al., a1A,1B,1C antagonist a1 antagonist 1997)

15 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther preladenant (SCH- (Hodgson et al., A2A antagonist A2A antagonist 420,814) 2009)

(Rupprecht et

al., 1993;

Falkenstein et

al., 1998; Meyer

et al., 1998a;

Meyer et al., nPR agonist, mPR agonist, 1998b; Baulieu PGRMC1 agonist, s1 progesterone PR agonist and agonist, nACh NAM, MR Schumacher, antagonist 2000; Maurice

et al., 2001;

Attardi et al.,

2007;

Johannessen et

al., 2011)

propranolol b1,2 antagonist b antagonist (Baker, 2005)

H1 antagonist, D2 (Schotte et al., antagonist, 5-HT2A atypical anti- 1996; Arnt and quetiapine antagonist, 5-HT1A,1B psychotic Skarsfeldt, agonist, a1A,1B,2C 1998; Richelson antagonist

16 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther and Souder,

2000)

quinpirole (LY- (Millan et al., D2-like agonist D2 agonist 171,555) 2002)

R-(-)-11-OH-NPa (Neumeyer et (apomorphine D1,2 agonist D1,2 agonist al., 1988) derivative)

(Lejeune et al., (R)-(+)-OHDPAT 5-HT1A agonist 5-HT1A agonist 1997)

(Lyon et al.,

1986; Battaglia

et al., 1988; 5-HT2A partial R-MDMA 5-HT2A partial agonist Nash et al., agonist 1994; Verrico et

al., 2007; Huot

et al., 2011)

(Wichmann et raclopride D2,3 antagonist D2,3 antagonist al., 1999)

(Weinshank et rauwolscine (iso- al., 1992; Uhlen yohimbine, a- a2A,2B,2C antagonist, 5- a2 antagonist et al., 1994; yohimbine, HT1D,2D antagonist Wainscott et al., corynanthidine) 1998)

17 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther (Subramaniam

NMDA antagonist, Na+ et al., 1996; remacemide NMDA antagonist channel blocker Santangeli et al.,

2002)

RGFP-109 HDAC1,3 inhibitor HDAC inhibitor (Rai et al., 2010)

(SR- cannabinoid (Seely et al., CB1 antagonist 141,716) antagonist 2012)

(Fischer et al., Ro-25,6981 NR2B antagonist NMDA antagonist 1997)

kynurenine 3- kynurenine 3-hydroxylase (Rover et al., Ro-61,8048 hydroxylase inhibitor 1997) inhibitor

(Wichmann et NOP receptor agonist, µ > Ro 65-6570 opioid ligand al., 1999; Toll et k > d ligand al., 2016)

(Eden et al.,

ropinirole (SKF- 1991; Millan et D2,3,4 agonist dopamine agonist 101,468-A) al., 2002; Millan

et al., 2004b)

D1,2,3,4,5 agonist, a1A,B (Beaulieu et al., rotigotine (N-0427, N- ligand, a2A,2B,2C ligand, 5- dopamine agonist 1984; Belluzzi 0923) HT1A partial agonist, 5- et al., 1994; HT7 ligand

18 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther Scheller et al.,

2009)

(Millan et al.,

S-32,504 D2,3 agonist dopamine agonist 2004a; Millan et

al., 2004b)

(Cussac et al.,

S-33,084 D3 antagonist D3 antagonist 2000; Millan et

al., 2000a)

(Verrico et al., SERT > DAT inhibitor, dual monoamine S-MDMA 2007; Huot et monoamine releaser re-uptake inhibitor al., 2011)

NET > DAT inhibitor, dual monoamine (Damaj et al., S,S-hydroxybupropion a4b2 nACh antagonist re-uptake inhibitor 2004)

MAO-B inhibitor, (Caccia et al.,

safinamide glutamate release inhibitor, MAO-B inhibitor 2006; Fariello,

Na+ channel blocker 2007)

sarizotan (EMD- 5-HT1A agonist, D2,3,4 (Bartoszyk et 5-HT1A agonist 128,130) antagonist al., 2004)

5-HT1B inverse (Selkirk et al., SB-224,289-A 5-HT1B inverse agonist agonist 1998)

D1 antagonist, 5-HT2C (Millan et al., SCH-23,390 D1 antagonist agonist 2001)

19 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther scopolamine muscarinic (Huang et al., M1,2,3,4 antagonist (hyoscine) antagonist 2001)

(Owens et al., sertraline SERT inhibitor SERT inhibitor 2001)

HMG-CoA reductase HMG-CoA (Hartman et al., simvastatin inhibitor reductase inhibitor 1992)

(Andersen and

Jansen, 1990; SKF-38,393 D1,5 partial agonist D1 partial agonist Sunahara et al.,

1991)

(Andersen and

Jansen, 1990; SKF-75,670 D1 partial agonist D1 partial agonist Gnanalingham

et al., 1995)

(Gnanalingham

et al., 1995; SKF-80,723 D1 agonist D1 agonist Kanda et al.,

2000)

(Gnanalingham

et al., 1995; D1 agonist, oestrogen SKF-82,958 D1 agonist Domino and Ni, receptor-a agonist 1998; Walters et

al., 2002)

20 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther (Gnanalingham SKF-83,565 D1 partial agonist D1 partial agonist et al., 1995)

(Gnanalingham D1 agonist, D2 partial et al., 1995; agonist, s1 allosteric Rashid et al., SKF-83,959 ligand, DAT inhibitor, D1 agonist 2007; Fang et NET inhibitor, SERT al., 2013; Guo et inhibitor al., 2013)

5-HT1B,1D > 5-HT1A (Hatcher et al., SKF-99,101-H 5-HT1B,1D agonist agonist 1995)

(Bilsky et al.,

SNC-80 d agonist d agonist 1995; Metcalf et

al., 2012)

(Bezard et al., ST-198 D3 antagonist D3 antagonist 2003)

(Stasi et al., ST-1535 A2A > A1 antagonist A2A antagonist 2006)

(Maitre et al., D2,3 antagonist, carbonic 1994; Burris et sulpiride anhydrase inhibitor, GHB D2,3 antagonist al., 1995; Sethi ligand et al., 2013)

sumanirole (PNU- (McCall et al., D2 agonist D2 agonist 95,666) 2005)

21 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther talampanel (GYKI- (Wang and Niu, GluA2 antagonist AMPA antagonist 537,773, LY-300,164) 2013)

oestrogen receptor a and b oestrogen receptor (Kuiper et al., tamoxifen modulator modulator 1997)

(Johnston et al.,

TC-8831 b2 nACh agonist nicotinic agonist 2013; Quik et

al., 2013)

a1A,2A,2B,2C antagonist, D2,3

partial agonist, D4 terguride (trans- (Millan et al., antagonist, 5-HT1A,1D,2A D2 partial agonist dihydro-lisuride) 2002) partial agonist, 5-HT2B

antagonist

Na+ channel blocker,

GABAA enhancer, AMPA topiramate AMPA antagonist (Perucca, 1997) antagonist, carbonic

anhydrase inhibitor

muscarinic (Giachetti et al., trihexyphenidyl M1 antagonist antagonist 1986)

(Von

U50-488 k agonist opioid agonist Voigtlander and

Lewis, 1982)

(Black et al., U-91,356-A D2 agonist D2 agonist 1997)

22 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther U-99,194-A (PNU- (Audinot et al., D3 antagonist D3 antagonist 99,194-A) 1998)

(Mor et al., URB-597 (KDS-4103) FAAH inhibitor FAAH inhibitor 2004)

UWA-101 (a- dual monoamine (Johnston et al., DAT = SERT inhibitor cyclopropyl-MDMA) re-uptake inhibitor 2012)

dual monoamine (Huot et al., UWA-121 DAT > SERT inhibitor re-uptake inhibitor 2014)

(Huot et al., UWA-122 SERT inhibitor SERT inhibitor 2014)

non-selective nACh (Mihalak et al., varenicline nicotinic agonist agonist/partial agonist 2006)

(Shen et al., VU-0,476,406 M4 PAM muscarinic PAM 2015)

(Bylund et al.,

1992; Adham et

al., 1993;

a2A,2B,2C antagonist, 5- Devedjian et al., yohimbine a2 antagonist HT1A,1B,1D,1F,2B antagonist 1994; Bonhaus

et al., 1999;

Millan et al.,

2000b)

23 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther 5-HT: 5-hydroxytryptamine (serotonin); a: alpha adrenoceptor (except when followed by nACh, where they correspond to a sub-unit); b: beta adrenoceptor (except when followed by nACh, where they correspond to a sub-unit); d: delta opioid receptor; k opioid receptor; µ opiod receptor; s: sigma receptor; A: ; AChE: acetylcholinesterase; AMPA: α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BuChE: butyrylcholinesterase;

CB: ; ChE: ; COMT: catechol-O-methyltransferase; D: dopamine receptor; DAT: ; FAAH: fatty acid amide hydrolase; FFA: free fatty acid receptor; GABA: gamma-aminobutyric acid; GHB: gamma-hydroxybutyric acid;

GluA: AMPA receptor sub-unit; H: ; HDAC: histone deacetylase; HMG-CoA:

3-hydroxy-3-methylglutaryl-coenzyme A; I: imidazoline receptor; M: muscarinic receptor;

MAO-B: ; MDMA: 3,4-methylenedioxymethamphetamine; mGlu: metabotropic glutamate receptor; MPR: membrane progesterone receptor; MR: mineralocorticoid receptor; Na+: ; nACh: nicotinic ; NAM: negative allosteric modulator; NET: noradrenaline transporter; NMDA: N-methyl-D-aspartate; NOP: nociceptin receptor; NPR: natriuretic peptide receptor; NR: NMDA receptor sub-unit; ORL: opioid receptor- like; PAM: positive allosteric modulator; PGRMC1: progesterone receptor membrane component

1; PPAR: peroxisome proliferator-activated receptor; PR: progesterone receptor; RXR: retinoid X receptor; SERT: serotonin transporter; SV: synaptic vesicle glycoprotein; TRPA: transient receptor potential channel ankyrin.

24 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther Table S2: comparison of the anti-dyskinetic action of drugs across species

marmose drug human macaque squirrel monkey t

(+)-4-propyl-9-

hydroxynaphth ne na ne na

oxazine

ABT-431 ne ne ne na

AFQ-056 Ö/ne Ö na na

amantadine Ö Ö Ö na

apomorphine ne ne ne na

AQW051 ne Ö na na

atropine ne ne ne na

benztropine ne na ne na

brasofensine ne na ne na

bromocriptine ne ne ne na

bupropion ne na ne na

cabergoline ne ne na na

citalopram Ö Ö na na

clonidine na Ö na na

clozapine Ö Ö Ö na

CP-101,606 Ö ne ne na

25 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther CY-208,243 ne ne ne na

diazepam Ö Ö na na

dipraglurant Ö Ö na na

eltoprazine Ö Ö na na

entacapone de ne ne na

ethosuximide ne ne na na

famotidine ne Ö na na

fipamezole Ö Ö Ö na

haloperidol Ö na Ö na

idazoxan Ö/ne Ö Ö na

istradefylline ne ne ne na

L-tryptophan na Ö na ne

levetiracetam Ö/ne Ö Ö na

melanocyte- ne na ne na inhibiting factor

methysergide ne Ö na na

mianserin na na Ö na

mirtazapine Ö na Ö na

modafinil ne na na na

morphine Ö Ö na na

nabilone Ö na Ö na

naloxone Ö/ne Ö na na

26 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther naltrexone Ö/ne ne/de Ö na

nicotine na na na Ö

nomifensine de na ne na

pardoprunox ne na Ö na

pergolide ne na ne na

physostigmine Ö/ne Ö ne na

pimavanserin ne Ö na na

pioglitazone ne Ö na na

piribedil ne na ne na

pramipexole ne na ne na

preladenant de ne na na

propranolol Ö Ö na na

quetiapine Ö/ne Ö Ö na

remacemide ne ne na na

ropinirole ne na ne na

rotigotine ne ne ne na

safinamide Ö Ö na na

sarizotan ne Ö na na

scopolamine ne na ne na

sertraline ne na na na

simvastatin ne Ö na na

sulpiride Ö Ö ne na

27 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther sumanirole ne ne na na

terguride ne ne ne na

topiramate de/ne na Ö na

trihexyphenidyl ne ne ne na

yohimbine na Ö Ö na

Ö: effective; ne: not effective; de: deleterious; na: not assessed

28 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther Table S3: comparison of the anti-parkinsonian action of drugs across species

marmose drug human macaque squirrel monkey t

(+)-4-propyl-9-

hydroxynaphth Ö na Ö na

oxazine

ABT-431 Ö Ö Ö na

AFQ-056 ne Ö na na

amantadine Ö/ne ne/de ne na

apomorphine Ö Ö Ö na

AQW-051 ne Ö na na

atropine Ö Ö Ö na

benztropine Ö na Ö na

brasofensine ne na Ö na

bromocriptine Ö Ö Ö na

bupropion Ö na Ö na

cabergoline Ö Ö na na

citalopram Ö/ne de na na

clonidine Ö Ö/de na na

clozapine Ö ne ne na

CP-101,606 ne Ö Ö na

29 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther CY-208,243 Ö Ö Ö na

diazepam Ö ne na na

dipraglurant ne ne na na

eltoprazine ne de na na

entacapone Ö Ö Ö na

ethosuximide ne/de Ö na na

famotidine ne Ö na na

fipamezole ne Ö Ö na

haloperidol de na de na

idazoxan ne Ö Ö na

istradefylline Ö Ö Ö na

L-tryptophan ne de na na

levetiracetam ne ne ne na

melanocyte- ne na ne na inhibiting factor

methysergide ne de na na

mianserin na na de na

mirtazapine Ö na ne na

modafinil ne na Ö na

morphine de Ö na na

nabilone ne na ne na

naloxone Ö/ne ne na na

30 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther naltrexone ne ne ne na

nicotine Ö/ne na na ne

nomifensine Ö na Ö na

pardoprunox Ö na Ö na

pergolide Ö na Ö na

physostigmine de de de na

pimavanserin ne ne na na

pioglitazone ne de na na

piribedil Ö na Ö na

pramipexole Ö na Ö na

preladenant Ö Ö na na

propranolol Ö/ne de na na

quetiapine ne/de ne ne na

remacemide ne Ö na na

ropinirole Ö na Ö na

rotigotine Ö Ö Ö na

safinamide Ö Ö na na

sarizotan de de na na

scopolamine Ö na Ö na

sertraline ne na de na

simvastatin ne ne na na

sulpiride de de de na

31 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther sumanirole Ö Ö na na

terguride Ö Ö Ö na

topiramate ne na ne na

trihexyphenidyl Ö Ö Ö na

yohimbine Ö ne ne na

Ö: effective; ne: not effective; de: deleterious; na: not assessed

32 Veyres N, Hamadjida A, Huot P. Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey. J Pharmacol Exp Ther Supplementary references

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