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Title: Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey i

Authors: Nicolas Veyres, Adjia Hamadjida, Philippe Huot

Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada NV Montreal Neurological Institute, Montreal, QC, Canada HA,PH Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada PH

Downloaded from jpet.aspetjournals.org at ASPET Journals on October 1, 2021

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Running title: Predictive value of parkinsonian primates in drug research

Text pages: 11 Word count abstract: 253 Word count introduction: 290 Word count discussion: 534 Word count manuscript: 2808 Number of figures: 9 Number of tables: 4 Number of references: 364 Number of supplementary tables: 3 Number of supplementary references: 231

Corresponding Author: Philippe Huot: Montreal Neurological Institute, 3801 University St, BT Downloaded from 209, Montreal, QC, Canada, H3A 2B4, Tel: +1-514-398-5957; Fax: +1-514-398-6644; Email: [email protected]

List of non-standard abbreviations jpet.aspetjournals.org AADC: L-aromatic amino acid decarboxylase L-DOPA: L-3,4-dihydroxyphenylalanine MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Financial disclosure: There are no conflicts of interest.

at ASPET Journals on October 1, 2021

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Abstract

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate is the gold- standard animal model of Parkinson’s disease (PD) and has been used to assess the effectiveness of experimental drugs on dyskinesia, parkinsonism and psychosis. Three species have been used in the majority of studies, the macaque, marmoset and squirrel monkey, the latter much less so than the first 2 species. However, the predictive value of each species at forecasting clinical efficacy, or lack thereof, is poorly documented. Here, we have reviewed all the published literature detailing Downloaded from pharmacological studies that assessed the effects of experimental drugs on dyskinesia, parkinsonism and psychosis in each of these species and have calculated their predictive value of jpet.aspetjournals.org success and failure at the clinical level. We found that, for dyskinesia, the macaque has a positive predictive value of 87.5% and a false positive rate of 38.1%, while the marmoset has a positive predictive value of 76.9% and a false positive rate of 15.6%. For parkinsonism, the macaque has a at ASPET Journals on October 1, 2021 positive predictive value of 68.2% and a false positive rate of 44.4%, while the marmoset has a positive predictive value of 86.9% and a false positive rate of 41.7%. No drug that alleviates psychosis in the clinic has shown efficacy at doing so in the macaque, while the marmoset has

100% positive predictive value. The small number of studies conducted in the squirrel monkey precluded us from calculating its predictive efficacy. We hope that our results will help in the design of pharmacological experiments and will facilitate the drug discovery and development process in PD.

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Introduction

Since its accidental discovery (Davis et al., 1979; Langston et al., 1983), 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been used extensively to model Parkinson’s disease

(PD) in a breadth of non-human primates, enabling the investigation of anatomical (Jan et al., 2000;

Zeng et al., 2008), behavioural (Pessiglione et al., 2004a; Pessiglione et al., 2004b), neuro-chemical

(Soghomonian et al., 1994; Huot et al., 2008), etc. aspects of the disease. The MPTP-lesioned primate has also been invaluable in the search of effective anti-dyskinetic and anti-parkinsonian Downloaded from agents. A review article previously examined the translational predictive value of the MPTP- lesioned primate for the development of anti-dyskinetic drugs, but it was published over a decade jpet.aspetjournals.org ago (Fox et al., 2006a), and many drug have since then been tested both in the primate and in clinical settings. This previous review did not examine the translational predictive value of the

MPTP-lesioned primate when it relates to the effect of drugs on parkinsonian disability or at ASPET Journals on October 1, 2021 dopaminergic psychosis, nor did it look at differences between different primate species when it comes to predict the clinical effectiveness of an experimental molecule.

We have therefore conducted a thorough and unbiased review of the literature in order to compare the predictive effectiveness of different MPTP-lesioned primate species on the clinical effectiveness of potential anti-dyskinetic, anti-parkinsonian and anti-psychotic agents.

We believe that this Review comes at a critical time, given that it has recently been suggested that some primate species might be more suited than other to conduct behavioural pharmacological research (Porras et al., 2012), and that there have been several failures of high- profile drugs in clinical trials (Cook et al., 2014; Bespalov et al., 2016), emphasising the need to use the best animal model possible in pre-clinical settings, to maximise chances of success when translating to the clinic.

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Methods

Three non-human primate species have been used in the majority of experiments to determine the anti-dyskinetic, anti-parkinsonian and anti-psychotic effect of experimental drugs: the macaque (both cynomolgus (Di Paolo et al., 1986) and rhesus (Burns et al., 1983), Macaca fascicularis and Macaca mulatta, respectively), common marmoset (Jenner et al., 1984) (Callithrix jacchus) and common squirrel monkey (Langston et al., 1984) (Saimiri sciureus). For each of these

3 primate species, we have reviewed all the studies that reported their effect, or lack thereof, on Downloaded from each of dyskinesia, parkinsonism and psychosis. We then sought which of these drugs tested in the non-human primate underwent clinical testing and compared their pre-clinical and clinical effects jpet.aspetjournals.org and calculated different predictive values (see “Endpoints” below).

Inclusion criteria at ASPET Journals on October 1, 2021 The literature search spans from 1983, time at which the first MPTP-lesioned non-human primate was engineered (Burns et al., 1983), until 10th December 2017. Studies published after this date, either online or in print format, are not included.

Only drugs whose pre-clinical and clinical efficacy, or lack thereof, was reported in peer- reviewed articles are included in this article. Results disseminated solely through abstracts or conference proceedings are therefore not reported in this article. We are aware that not all studies conducted on parkinsonian primates have been published, and that results of some clinical trials have not been disseminated through peer-reviewed journals; by choosing to include only studies and reports that were published in peer-reviewed journals, we may be introducing a selection bias in our analysis. For instance, whereas it has been studied in human (NCT00034814,

NCT00108667), the clinical effectiveness of talampanel will not be discussed here, as the results of the clinical trials where it was assessed were not published in peer-reviewed scientific journals.

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In addition, we have excluded L-3,4-dihydroxyphenylalanine (L-DOPA) and inhibitors of L- aromatic amino acid decarboxylase (AADC, e.g. benserazide (Rinne et al., 1975) and carbidopa

(Marsden et al., 1973)) from our analysis, as these were used in almost all studies cited here, to reverse parkinsonism and induce dyskinesia.

Research methodology

Literature review was conducted primarily through the United States National Library of Downloaded from

Medicine (NLM) database, accessed via PubMed. The search engine Google was used to complete the literature review and to access articles not indexed in the NLM database. The following terms jpet.aspetjournals.org were used to perform the literature search: abnormal involuntary movements, chorea, cynomolgus, dyskinesia, dyskinetic, dystonia, hallucinations, hyperactivity, hyperkinesia, L-DOPA, levodopa, macaque, marmoset, monkey, at ASPET Journals on October 1, 2021 MPTP, non-human primate, Parkinson’s disease, parkinsonian, parkinsonism, primate, psychosis, rhesus, squirrel monkey, visual hallucinations.

Definition of “efficacy”

Throughout our literature search, a reduction of dyskinesia/psychosis was considered such only if statistical significance was reached; trends were not considered. A drug was deemed to have anti-parkinsonian benefit if it alleviated parkinsonism as monotherapy or as adjunct to L-DOPA.

Impulse-control disorders (Weintraub et al., 2010) were not considered as a psychotic manifestation.

Several studies, especially in the macaque, were performed that administered drugs, e.g. cabergoline, to reduce the development of dyskinesia and then conducted post-mortem experiments; we have included these studies in our analysis, even if their primary end-point was

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JPET #247171 not determination of pharmacological efficacy. Studies reporting the effects of experimental drugs on rotational behaviour in the hemi-MPTP-lesioned primate, e.g. (Vermeulen et al., 1995), were not included.

In some instances, conflicting results were obtained with some drugs, e.g. studies encountered a therapeutic benefit, while others did not reach similar conclusions; whenever this happened, we calculated the predictive values using “best result”, i.e. the one that showed a therapeutic effect, weighing in the methodology of the studies (2009), if applicable. For instance, Downloaded from in the case of preladenant, Phase II studies have found anti-parkinsonian efficacy (Hauser et al.,

2011; Factor et al., 2013), while Phase III studies did not (Hauser et al., 2015; Stocchi et al., 2017), jpet.aspetjournals.org but in one instance, the active comparator, rasagiline (Hauser et al., 2015), was also ineffective, despite proven anti-parkinsonian benefit in randomised-controlled trials (ParkinsonStudyGroup,

2005; Rascol et al., 2005), somewhat casting doubt on study conclusions; in this case, we at ASPET Journals on October 1, 2021 considered that preladenant exerted anti-parkinsonian benefit.

Endpoints

By comparing the outcomes of the primate studies on each of dyskinesia, parkinsonism and psychosis, we have calculated, for each species, the positive predictive value, the negative predictive value and the false positive rate.

Here, we define the positive predictive value of a species as the percentage of cases for which a primate species has correctly predicted that an anti-dyskinetic or anti-parkinsonian benefit would be achieved in the clinic. For the positive predictive value, the denominator was the number of drugs for which a therapeutic effect was achieved in the clinic, while the numerator was the number of these drugs that showed efficacy in the primate, i.e.

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Here, we define the negative predictive value of a species as the percentage of cases for which a primate species has correctly predicted that a lack of anti-dyskinetic or anti-parkinsonian benefit would be achieved in the clinic. For the negative predictive value, the denominator was the number of drugs for which a therapeutic effect was not achieved in the clinic, while the numerator was the number of these drugs that did not show efficacy in the primate, i.e. Downloaded from ������ �� ��������� �ℎ�� ��� ��� �ℎ�� ������ �� �ℎ� �������

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Here, we define the false positive rate of a species as the percentage of cases for which a jpet.aspetjournals.org primate species has incorrectly predicted that a lack of anti-dyskinetic or anti-parkinsonian benefit would be achieved in the clinic. For the false positive rate, the denominator was the number of drugs for which a therapeutic effect was not achieved in the clinic, while the nuemrator was the at ASPET Journals on October 1, 2021 number of these clinically-ineffective drugs that were deemed to be effective in the primate, i.e.

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Results

Pharmacological targets

Several pharmacological targets have been modulated in studies performed in the MPTP- lesioned macaque and the MPTP-lesioned marmoset. In contrast, only dopaminergic, opioidergic and cholinergic targets have been assessed in studies conducted in the MPTP-lesioned squirrel monkey (see Supplementary Table 1 for the pharmacological profile of all molecules that have been tested in the MPTP-lesioned primate).

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A total of 98 different molecules were assessed in the MPTP-lesioned macaque, 97 in the

MPTP-lesioned marmoset and 9 in the MPTP-lesioned squirrel monkey (Figure 1). Of all the molecules tested in the MPTP-lesioned primate, 64 have been assessed at the clinical level or are clinically-approved. Of these, 44 were tested in the macaque, 38 in the marmoset and 1 in the squirrel monkey (Figure 2). Because very few drugs have been tested in the MPTP-squirrel monkey compared to the macaque and the marmoset, we will not discuss it further in the text, but we have nevertheless included it in the Tables. Downloaded from

We have summarised our research results in Tables:

• Table 1: drugs tested in the MPTP-lesioned macaque; jpet.aspetjournals.org • Table 2: drugs tested in the MPTP-lesioned marmoset;

• Table 3: drugs tested in the MPTP-lesioned squirrel monkey;

• Table 4: drugs tested in the MPTP-lesioned primate that were tested in the clinic or are at ASPET Journals on October 1, 2021 clinically-available;

In each Table, the drugs are listed in numerical/alphabetical order.

We have also summarised our results in Figures:

• Figure 1: number of drugs tested in the MPTP-lesioned non-human primate;

• Figure 2: number of drugs assessed in the clinic or clinically-approved that were tested in the

MPTP-lesioned non-human primate;

• Figure 3: anti-dyskinetic positive predictive value of the MPTP-lesioned non-human primate;

• Figure 4: anti-dyskinetic negative predictive value of the MPTP-lesioned non-human primate;

• Figure 5: anti-dyskinetic false positive rate of the MPTP-lesioned non-human primate;

• Figure 6: anti-parkinsonian positive predictive value of the MPTP-lesioned non-human

primate;

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• Figure 7: anti-parkinsonian negative predictive value of the MPTP-lesioned non-human

primate;

• Figure 8: anti-parkinsonian false positive rate of the MPTP-lesioned non-human primate;

• Figure 9: worsening of parkinsonism positive predictive value of the MPTP-lesioned non-

human primate.

Prediction of anti-dyskinetic effect Downloaded from

Of the 64 drugs that were tested in the clinic and in the MPTP-lesioned primate, 22 showed anti-dyskinetic effect in clinical trials, no anti-dyskinetic effect was found or reported for 36 drugs, jpet.aspetjournals.org and 4 drugs were found to have a deleterious effect on dyskinesia severity (see Supplementary

Table 2 for details).

MPTP-lesioned macaque at ASPET Journals on October 1, 2021 Of the 22 drugs that demonstrated an anti-dyskinetic effect in clinical settings, 16 were tested in the macaque, and an anti-dyskinetic effect was obtained with 14 (87.5% positive predictive value, Figure 3).

Of the 36 drugs for which no anti-dyskinetic effect was found or reported in the clinic, 21 were tested in the macaque. No anti-dyskinetic effect was encountered or reported with 13 (61.9% negative predictive efficacy, Figure 4), while an anti-dyskinetic action was found with 8 (38.1% false positive rate, Figure 5).

Of the 4 drugs that were found to have a deleterious effect on dyskinesia severity in the clinic, 2 were tested in the macaque and an exacerbation of dyskinesia could not be demonstrated in either case.

MPTP-lesioned marmoset

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Of the 22 drugs that demonstrated an anti-dyskinetic effect in clinical settings, 13 were tested in the marmoset and anti-dyskinetic effect was obtained with 10 (76.9% positive predictive value, Figure 3).

Of the 36 drugs for which no anti-dyskinetic effect was found or reported, 22 were tested in the marmoset and the absence of anti-dyskinetic effect was identified in 19 (86.4% negative predictive value, Figure 4), while anti-dyskinetic an action was found with 3 (15.6% false positive rate, Figure 5). Downloaded from

Of the 4 drugs that were found to have a deleterious effect on dyskinesia severity, 3 were tested in the marmoset and an exacerbation of dyskinesia could not be demonstrated in any case. jpet.aspetjournals.org

Prediction of anti-parkinsonian action

Of the 64 drugs that were tested in the clinic and in the MPTP-lesioned primate, 34 showed at ASPET Journals on October 1, 2021 anti-parkinsonian effect in clinical trials, no anti-parkinsonian effect was found or reported for 24 drugs, and 5 drugs were found to have a deleterious effect on parkinsonian disability (see

Supplementary Table 3 for details).

MPTP-lesioned macaque

Of the 34 drugs that showed anti-parkinsonian effect in clinical trials, 22 were tested in the macaque and anti-parkinsonian benefit was obtained with 15 (68.2% positive predictive value,

Figure 6).

Of the 24 drugs for which no anti-parkinsonian effect was found or reported, 18 were tested in the macaque and no anti-parkinsonian effect was encountered or reported with 6 (33.3% negative predictive value, Figure 7), while anti-parkinsonian action was found with 8 (44.4% false positive rate, Figure 8).

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Of the 5 drugs that were found to have a deleterious effect on parkinsonian disability, 4 were tested in the macaque and this deleterious effect on parkinsonism was correctly identified in

3 (75% predictive value, Figure 9).

MPTP-lesioned marmoset

Of the 34 drugs that showed anti-parkinsonian effect in clinical trials, 23 were tested in the marmoset and anti-parkinsonian effect was obtained with 20 (86.9% positive predictive value,

Figure 6). Downloaded from

Of these, 24 drugs did not find or did not report an anti-parkinsonian effect, 12 were tested in the marmoset and no anti-parkinsonian effect was encountered with 6 (50.0% negative predictive jpet.aspetjournals.org value, Figure 7), while anti-parkinsonian benefit was found with 5 (41.7% false positive rate,

Figure 8).

Of the 5 drugs that were found to have a deleterious effect on parkinsonian disability, 3 at ASPET Journals on October 1, 2021 were tested in the marmoset, all of which hindered parkinsonism (100% predictive value, Figure

9).

Prediction of anti-psychotic action

Of the 64 drugs that were tested in the clinic and in the MPTP-lesioned primate, 5 showed anti-psychotic effect in clinical trials/reports (clozapine, mianserin, mirtazapine, pimavanserin, quetiapine).

In comparison to dyskinesia and parkinsonism, the effect of experimental drugs on dopaminergic psychosis has been far less studied in the MPTP-lesioned primate. No drug that underwent clinical testing or that is clinically-available has demonstrated anti-psychotic effect in the MPTP-lesioned macaque or the MPTP-lesioned squirrel monkey. Pimavanserin was not tested

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JPET #247171 in the MPTP-lesioned marmoset, but an anti-psychotic benefit was achieved with each of clozapine, mianserin, mirtazapine and quetiapine (100% positive predictive value).

Discussion

Here, we have reviewed all the literature published in peer-reviewed scientific journals that reported the results of pharmacological studies conducted in the MPTP-lesioned macaque, Downloaded from marmoset and squirrel monkey where the effects of experimental drugs on dyskinesia, parkinsonism and psychosis was assessed. By comparing the results obtained at the pre-clinical jpet.aspetjournals.org level with those obtained in clinical settings, we have calculated the predictive value of each primate species for these disease manifestations/treatment-related complications.

There are limitations to our analysis that have to be mentioned. Firstly, as we mentioned in at ASPET Journals on October 1, 2021 the Introduction, the results of several studies, both pre-clinical and clinical, have not been published and, although we aimed for exhaustiveness, our Review is necessarily incomplete, which may have affected the various rates presented. Secondly, the methodology of the clinical trials cited is highly-variable, ranging from observational reports to randomised controlled trials; they were weighed equally here. Thirdly, the methodology used in pre-clinical studies is, at times, different to the one used in clinical settings; one example is when a low dose of L-DOPA is administered to primates, in combination with an agent with potential anti-parkinsonian effect as adjunct therapy.

Lowering the L-DOPA dose administered may be poorly tolerated by patients, which is why this approach is seldom used in clinical trials. Fourthly, some clinical trials were performed in early- stage PD patients, while the degree of parkinsonism following MPTP administration is severe and would correspond to advanced-stage PD. Lastly, as several types of trials are part of our Review, in some of them, PD patients were taking anti-parkinsonian medication in addition to L-DOPA,

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JPET #247171 which is generally not the case in primate studies, and the extent to which these molecules affected the results is undetermined.

Keeping these limitations in mind, the following general conclusions can be drawn:

• Relatively to the anti-dyskinetic effect of drugs, the macaque has higher positive predictive

value than the marmoset, but the marmoset has fewer false positive results than the macaque.

Both the macaque and the marmoset appear limited when it comes to predicting a detrimental

effect of experimental drugs on dyskinesia; Downloaded from

• Relatively to the anti-parkinsonian action of drugs, the marmoset has higher positive predictive

value and fewer false positive results than the macaque than the macaque, both species have jpet.aspetjournals.org high predictive values when it comes to forecasting a potentially deleterious effect of drugs on

parkinsonism;

• Relatively to the anti-psychotic effect of drugs, comments can be made only for the marmoset, at ASPET Journals on October 1, 2021 which has high positive predictive value;

• In comparison to the macaque and the marmoset, the squirrel monkey has been used in a small

number of studies and very few pharmacological targets have been assessed in this primate

species, which makes it impossible to calculate its predictive value.

At a time when the discovery and development process for drugs acting at the central nervous system level is facing challenges and has been marred by failures of high-profile candidates, it is our hope that this Review will help in the planning and design of pre-clinical experiments aimed at testing the effects of drugs on L-DOPA-induced dyskinesia, parkinsonian disability and dopaminergic psychosis, by helping experimenters and sponsors to plan their experiments in the animal model of PD with the highest translational potential for their specific end-point.

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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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jpet.aspetjournals.org at ASPET Journals on October 1, 2021

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Footnotes

i iFunding: PH holds research support from Parkinson Canada, Fonds de Recherche Québec –

Santé, Natural Sciences and Engineering Research Council of Canada and the Weston Brain

Institute.

Downloaded from jpet.aspetjournals.org at ASPET Journals on October 1, 2021

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Figure legends

Figure 1 A total of 98 experimental drugs were tested in the MPTP-lesioned macaque, 97 in the MPTP- lesioned marmoset and 9 in the MPTP-lesioned squirrel monkey.

Figure 2 A total of 44 drugs that are either clinically-approved or that underwent clinical testing in PD were tested in the MPTP-lesioned macaque, 38 in the MPTP-lesioned marmoset and 1 in the MPTP-lesioned squirrel monkey.

Figure 3 The anti-dyskinetic positive predictive value of the MPTP-lesioned macaque is 87.5%, while it is 76.9% for the MPTP-lesioned marmoset. Downloaded from

Figure 4 The anti-dyskinetic negative predictive value of the MPTP-lesioned macaque is 61.9%, while it is 86.4% for the MPTP-lesioned marmoset. jpet.aspetjournals.org

Figure 5 The anti-dyskinetic false positive rate of the MPTP-lesioned macaque is 38.1%, while it is 15.6% for the MPTP-lesioned marmoset.

Figure 6 at ASPET Journals on October 1, 2021 The anti-parkinsonian positive predictive value of the MPTP-lesioned macaque is 68.2%, while it is 86.9% for the MPTP-lesioned marmoset.

Figure 7 The anti-parkinsonian negative predictive value of the MPTP-lesioned macaque is 33.3%, while it is 50.0% for the MPTP-lesioned marmoset.

Figure 8 The anti-parkinsonian false positive rate of the MPTP-lesioned macaque is 44.4%, while it is 41.7% for the MPTP-lesioned marmoset.

Figure 9 The worsening of parkinsonism positive predictive value of the MPTP-lesioned macaque is 75.0%, while it is 100.0% for the MPTP-lesioned marmoset.

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Figure 1

number of drugs tested in the MPTP-lesioned non-human primate

100

90

80

70

60 Downloaded from 50

num be r of dr ugs 40

30 jpet.aspetjournals.org 20

10

0 macaque marmoset squirrel monkey

at ASPET Journals on October 1, 2021

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Figure 2

number of drugs assessed in the clinic or clinically-approved that were tested in the MPTP-lesioned non-human primate

45

40

35

30 Downloaded from 25

20 num be r of dr ugs

15 jpet.aspetjournals.org 10

5

0 macaque marmoset squirrel monkey

at ASPET Journals on October 1, 2021

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Figure 3

anti-dyskinetic positive predictive value of the MPTP- lesioned non-human primate

100

90

80

70

60 Downloaded from

50

40 pr e di c t i ve va l ue ( % )

30 jpet.aspetjournals.org 20

10

0 macaque marmoset

at ASPET Journals on October 1, 2021

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Figure 4

anti-dyskinetic negative predictive value of the MPTP- lesioned non-human primate

100

90

80

70

60 Downloaded from

50

40 pr e di c t i ve va l ue ( % )

30 jpet.aspetjournals.org 20

10

0 macaque marmoset

at ASPET Journals on October 1, 2021

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Figure 5

anti-dyskinetic false positive rate of the MPTP-lesioned non-human primate

50

40

30 Downloaded from r a t e ( % ) 20 jpet.aspetjournals.org 10

0 macaque marmoset

at ASPET Journals on October 1, 2021

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Figure 6

anti-parkinsonian positive predictive value of the MPTP- lesioned non-human primate

100

90

80

70

60 Downloaded from

50

40 pr e di c t i ve va l ue ( % )

30 jpet.aspetjournals.org 20

10

0 macaque marmoset

at ASPET Journals on October 1, 2021

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Figure 7

anti-parkinsonian negative predictive value of the MPTP- lesioned non-human primate

50

40

30 Downloaded from

20 pr e di c t i ve va l ue ( % ) jpet.aspetjournals.org 10

0 macaque marmoset

at ASPET Journals on October 1, 2021

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Figure 8

anti-parkinsonian false positive rate of the MPTP-lesioned non-human primate

50

45

40

35

30 Downloaded from

25 r a t e ( % ) 20

15 jpet.aspetjournals.org 10

5

0 macaque marmoset

at ASPET Journals on October 1, 2021

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Figure 9

worsening of parkinsonism positive predictive value of the MPTP-lesioned non-human primate

100

90

80

70

60 Downloaded from

50

40 pr e di c t i ve va l ue ( % )

30 jpet.aspetjournals.org 20

10

0 macaque marmoset

at ASPET Journals on October 1, 2021

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Table 1: Drugs tested in the MPTP-lesioned macaque

drug dyskinesia parkinsonism psychosis references

17-alpha-oestradiol (Gomez-Mancilla ne ne na [N=1] and Bedard, 1992b)

(Gomez-Mancilla

17-beta-oestradiol and Bedard, 1992b; Ö Ö na [N=2] Belanger et al., Downloaded from

2003a)

(-)-3-(3-

(Gomez-Mancilla jpet.aspetjournals.org hydroxyphenyl)-N-n- ne Ö na and Bedard, 1991) propylpiperone [N=1]

(Gomez-Mancilla at ASPET Journals on October 1, 2021 and Bedard, 1991;

Gomez-Mancilla

and Bedard, 1992a; (+)-4-propyl-9- Luquin et al., 1992; hydroxynaphthoxazine ne Ö na Blanchet et al., [N=7] 1993; Luquin et al.,

1993b; Belluzzi et

al., 1994; Blanchet

et al., 1994)

(Hadj Tahar et al., (-)-OSU-6162 [N=1] Ö ne na 2001)

82 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Gomez-Mancilla 5-MDOT [N=1] Ö de na and Bedard, 1993)

(Munoz et al., 8-OH-DPAT [N=1] Ö ne na 2008)

(Blanchet et al.,

A-77,636 [N=2] Ö na 1993; Blanchet et

al., 1996b) Downloaded from

(Grondin et al., A-86,929 [N=1] Ö na 1997) jpet.aspetjournals.org (Koprich et al., ADL-5510 [N=1] Ö na 2011)

(Gregoire et al., AFQ-056 [N=1] Ö Ö na at ASPET Journals on October 1, 2021 2011)

(Blanchet et al.,

1998; Bibbiani et

al., 2005b; Rylander

et al., 2010; Bezard

amantadine [N=7] Ö de na et al., 2013b;

Gregoire et al.,

2013; Ko et al.,

2014b; Shen et al.,

2015)

83 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Bezard et al., anpirtoline [N=1] Ö de na 2013a)

(Filion et al., 1991;

Luquin et al.,

1993a; Akai et al.,

1995; Blanchet et

al., 1997; Doan et Downloaded from apomorphine [N=8] ne Ö na al., 1999; Silverdale

et al., 2002; jpet.aspetjournals.org Bibbiani et al.,

2003; Bibbiani et

al., 2005a) at ASPET Journals on October 1, 2021 (Di Paolo et al., AQW-051 [N=1] Ö Ö na 2014)

(Gomez-Mancilla et atropine [N=1] ne Ö na al., 1991)

(Gomez-Mancilla baclofen [N=1] ne de na and Bedard, 1993)

(Bezard et al., BP-897 [N=1] Ö ne na 2003)

(Bedard et al.,

bromocriptine [N=9] ne Ö na 1986; Falardeau et

al., 1988; Gagnon et

84 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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al., 1990; Rouillard

et al., 1990;

Gomez-Mancilla

and Bedard, 1991;

Blanchet et al.,

1993; Gomez-

Mancilla et al., Downloaded from

1993; Belluzzi et

al., 1994; Gagnon et jpet.aspetjournals.org al., 1995)

(Grondin et al.,

1996; Morissette et at ASPET Journals on October 1, 2021 al., 1998; Calon et

al., 1999; Goulet et

al., 1999;

Morissette et al.,

cabergoline [N=20] ne Ö na 1999; Calon et al.,

2000; Goulet et al.,

2000; Hadj Tahar et

al., 2000b; Calon et

al., 2002; Belanger

et al., 2003b;

Samadi et al.,

85 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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2008a; Samadi et

al., 2008b; Samadi

et al., 2008c;

Ouattara et al.,

2009; Morissette et

al., 2010; Ouattara

et al., 2010; Samadi Downloaded from

et al., 2010;

Ouattara et al., jpet.aspetjournals.org 2011; Riahi et al.,

2011)

CE [N=1] ne Ö na (Cao et al., 2007) at ASPET Journals on October 1, 2021 (Fidalgo et al., citalopram [N=1] Ö de na 2015)

(Hadj Tahar et al.,

2004; Morissette et

al., 2006a;

Morissette et al.,

CI-1041 [N=14] Ö ne na 2006b; Samadi et

al., 2008a; Samadi

et al., 2008b;

Samadi et al.,

2008c; Ouattara et

86 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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al., 2009;

Morissette et al.,

2010; Ouattara et

al., 2010; Samadi et

al., 2010; Tamim et

al., 2010; Ouattara

et al., 2011; Riahi et Downloaded from

al., 2011)

(Gomez-Mancilla et jpet.aspetjournals.org al., 1991; Gomez- clonidine [N=2] Ö Ö na Mancilla and

Bedard, 1993) at ASPET Journals on October 1, 2021 (Grondin et al., clozapine [N=1] Ö ne na 1999b)

(Koprich et al., CLR-151 [N=1] Ö de Ö 2013)

Co-101,244/PD-174,494 (Blanchet et al., Ö ne na [N=1] 1999)

(Munoz et al., CP-94,253 [N=1] ne ne na 2008)

(Steece-Collier et CP-101,606 [N=1] ne Ö na al., 2000)

87 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Konitsiotis et al., CX-516 [N=1] de ne na 2000)

(Gomez-Mancilla

and Bedard, 1991;

Gomez-Mancilla

and Bedard, 1992a;

Gomez-Mancilla et Downloaded from

al., 1992a; Blanchet CY-208,243 [N=8] ne Ö na et al., 1993; Gagnon jpet.aspetjournals.org et al., 1993;

Gomez-Mancilla et

al., 1993; Luquin et at ASPET Journals on October 1, 2021 al., 1993b; Gagnon

et al., 1995)

(Belanger et al.,

DHEA [N=2] ne Ö na 2003a; Belanger et

al., 2006)

(Gomez-Mancilla diazepam [N=1] Ö ne na and Bedard, 1993)

(Bezard et al., dipraglurant [N=1] Ö ne na 2014)

docosahexaenoic acid (Samadi et al., Ö ne na [N=5] 2006; Mahmoudi et

88 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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al., 2009; Tamim et

al., 2010; Riahi et

al., 2012; Gregoire

et al., 2015)

(Bezard et al.,

2013b; Pinna et al., eltoprazine [N=3] Ö de na 2016; Ko et al., Downloaded from

2017)

entacapone [N=1] ne Ö na (Huot et al., 2013) jpet.aspetjournals.org (Gomez-Mancilla et ethosuximide [N=1] ne Ö na al., 1992b)

F-15,599 [N=1] Ö ne na (Huot et al., 2015b) at ASPET Journals on October 1, 2021

(Johnston et al., famotidine [N=1] Ö Ö na 2010d)

(Rylander et al.,

fenobam [N=2] Ö Ö na 2010; Ko et al.,

2014b)

(Johnston et al., fipamezole [N=1] Ö Ö na 2010c)

(Bibbiani et al., GYKI-47,261 [N=1] Ö ne na 2005b)

89 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Bezard et al., 1999;

idazoxan [N=2] Ö Ö na Grondin et al.,

2000)

(Grondin et al.,

1999a; Bibbiani et istradefylline [N=3] ne/de Ö na al., 2003; Ko et al.,

2016) Downloaded from

(Hadj Tahar et al., JL-18 [N=1] Ö de na 2000a) jpet.aspetjournals.org L-745,870 [N=1] Ö ne na (Huot et al., 2012b)

L-tryptophan [N=1] Ö de na (Ko et al., 2014a)

(Bezard et al., levetiracetam [N=1] Ö ne na at ASPET Journals on October 1, 2021 2004)

(Papa and Chase, LY-235,959 [N=1] Ö ne na 1996)

(Blanchet et al., MDL-100,453 [N=1] Ö ne na 1999)

(Gomez-Mancilla meperidine [N=1] Ö ne na and Bedard, 1993)

(Gomez-Mancilla methysergide [N=1] Ö de na and Bedard, 1993)

(Gomez-Mancilla MK-801 [N=1] Ö de na and Bedard, 1993)

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(Galvan et al., ML-218 [N=1] ne ne na 2016)

(Samadi et al.,

morphine [N=2] Ö Ö na 2004; Yan et al.,

2014)

(Morin et al., 2010;

Morin et al., 2013a; Downloaded from

Morin et al., 2013b;

MPEP [N=7] Ö de na Morin et al., 2015a; jpet.aspetjournals.org Morin et al., 2015b;

Morissette et al.,

2016) at ASPET Journals on October 1, 2021 (Johnston et al.,

MTEP [N=2] Ö de na 2010b; Morin et al.,

2010)

(Bezard et al., nafadotride [N=1] Ö de na 2003)

nalbuphine [N=1] Ö ne na (Potts et al., 2015)

(Gomez-Mancilla

naloxone [N=2] ne ne na and Bedard, 1993;

Samadi et al., 2003)

(Samadi et al., naltrexone [N=5] ne/de ne na 2003; Samadi et al.,

91 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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2005a; Samadi et

al., 2005c; Tamim

et al., 2010;

Koprich et al.,

2011)

(Klockgether et al.,

NBQX [N=2] ne Ö na 1991; Luquin et al., Downloaded from

1993b)

(Grondin et al.,

NNC-01-112 [N=1] Ö de na jpet.aspetjournals.org 1999b)

PAMQX [N=1] na Ö na (Papa et al., 2004)

(Blanchet et al., PD-128,907 [N=1] ne Ö na at ASPET Journals on October 1, 2021 1997)

(Gomez-Mancilla physostigmine [N=1] Ö de na and Bedard, 1993)

(Vanover et al., pimavanserin [N=1] Ö ne na 2008)

pioglitazone [N=1] Ö de na (Huot et al., 2015a)

(Gregoire et al., PPI-1011 [N=1] Ö ne na 2015)

(Visanji et al., prazosin [N=1] ne ne na 2009b)

92 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Hodgson et al.,

2010; Pinna et al., preladenant [N=3] ne Ö na 2016; Ko et al.,

2017)

(Gomez-Mancilla progesterone [N=1] ne ne na and Bedard, 1992b)

(Gomez-Mancilla Downloaded from propranolol [N=1] Ö de na and Bedard, 1993)

quetiapine [N=1] Ö ne na (Oh et al., 2002) jpet.aspetjournals.org (Bedard and

Boucher, 1989;

Gomez-Mancilla at ASPET Journals on October 1, 2021 and Bedard, 1991;

Gomez-Mancilla et

al., 1992a; Blanchet

et al., 1993; quinpirole [N=12] ne Ö na Blanchet et al.,

1994; Akai et al.,

1995; Grondin et

al., 1997; Samadi et

al., 2003; Samadi et

al., 2004; Bibbiani

et al., 2005b;

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Samadi et al.,

2005c; Hyacinthe et

al., 2014)

(Greenamyre et al., remacemide [N=1] ne Ö na 1994)

(Samadi et al.,

2005b; Gregoire et Downloaded from

al., 2008; Ouattara

Ro-61,8048 [N=6] Ö ne na et al., 2009; Tamim jpet.aspetjournals.org et al., 2010; Riahi et

al., 2012; Riahi et

al., 2013) at ASPET Journals on October 1, 2021 Ro 65-6570 [N=1] Ö ne na (Marti et al., 2012)

(Belluzzi et al.,

rotigotine [N=2] ne Ö na 1994; Domino and

Ni, 1998a)

(Gregoire et al., safinamide [N=1] Ö Ö na 2013)

(Bibbiani et al.,

sarizotan [N=2] Ö de na 2001; Gregoire et

al., 2009)

(Gomez-Mancilla SCH-23,390 [N=3] Ö de na and Bedard, 1991;

94 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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Akai et al., 1995;

Grondin et al.,

1999b)

simvastatin [N=1] Ö ne na (Tison et al., 2013)

(Falardeau et al.,

1988; Bedard and

Boucher, 1989; Downloaded from

Gagnon et al., 1990; SKF-38,393 [N=6] ne Ö/ne na Rouillard et al., jpet.aspetjournals.org 1990; Blanchet et

al., 1993; Hyacinthe

et al., 2014) at ASPET Journals on October 1, 2021 (Blanchet et al.,

1993; Blanchet et

al., 1994; Akai et

al., 1995; Blanchet

et al., 1996a;

SKF-82,958 [N=18] ne Ö na Blanchet et al.,

1996b; Goulet et

al., 1996; Domino

and Ni, 1998a;

Morissette et al.,

1998; Calon et al.,

95 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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1999; Goulet et al.,

1999; Grondin et

al., 1999c;

Morissette et al.,

1999; Calon et al.,

2000; Calon et al.,

2002; Samadi et al., Downloaded from

2003; Samadi et al.,

2004; Bibbiani et jpet.aspetjournals.org al., 2005b; Samadi

et al., 2005c)

(Bezard et al.,

ST-198 [N=1] Ö de na at ASPET Journals on October 1, 2021 2003)

(Gomez-Mancilla

and Bedard, 1991;

sulpiride [N=3] Ö de na Akai et al., 1995;

Grondin et al.,

1999b)

(McCall et al., sumanirole [N=1] ne Ö na 2005)

(Konitsiotis et al., talampanel [N=1] Ö Ö na 2000)

tamoxifen [N=1] Ö ne na (Smith et al., 2007)

96 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Johnston et al., TC-8831 [N=1] Ö ne na 2013b)

(Gomez-Mancilla terguride [N=1] ne Ö na and Bedard, 1991)

(Domino and Ni,

trihexyphenidyl [N=2] ne Ö na 1998b; Domino and

Ni, 1998a) Downloaded from

(Blanchet et al.,

1995; Calon et al., jpet.aspetjournals.org U-91,356-A [N=4] ne Ö na 1995; Goulet et al.,

1997; Morissette et

al., 1997) at ASPET Journals on October 1, 2021 (Blanchet et al., U-99,194-A [N=1] Ö ne na 1997)

VU-0,476,406 [N=1] Ö ne na (Shen et al., 2015)

(Gomez-Mancilla yohimbine [N=1] Ö ne na and Bedard, 1993)

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

The number of studies reporting the effect of each drug is in brackets.

97 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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Table 2: drugs tested in the MPTP-lesioned marmoset

drug dyskinesia parkinsonism psychosis references

D-(9)-THC (van Vliet et al., ne Ö na [N=1] 2008)

(Nomoto et al., (+)-PHNO ne Ö na 1987; Close et [N=2]

al., 1990) Downloaded from

(+)-N-n-propyl-

3-(3-

(Close et al., jpet.aspetjournals.org hydroxyphenyl) ne Ö na 1990) -piperidine [(+)-

3PPP] [N=1] at ASPET Journals on October 1, 2021 (-)-N-n-propyl-

3-(3- (Close et al., hydroxyphenyl) ne ne na 1990) -piperidine (-)-

3PPP [N=1]

(-)-N-0437 (Loschmann et ne Ö na [N=1] al., 1989)

(-)-OSU-6162 (Ekesbo et al., Ö ne na [N=1] 1997)

2-amino-5,6- (Close et al., ne Ö na dihydroxytetral 1990)

98 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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in (N,N-

dipropyl A-5,6-

DTN) [N=1]

R-(-)-11-OH- (Lincoln et al., ne Ö na NPa [N=1] 2016)

(Gnanalingham A-66,359 [N=1] ne de na et al., 1995c) Downloaded from

(Kebabian et al.,

1992; Pearce et jpet.aspetjournals.org al., 1995; Pearce A-77,636 [N=4] ne Ö na et al., 1999;

Smith et al., at ASPET Journals on October 1, 2021 2002a)

(Shiosaki et al.,

1996; Pearce et

A-86,929 [N=3] ne Ö na al., 1999;

Treseder et al.,

2000)

(Shiosaki et al., ABT-431 [N=1] ne Ö na 1996)

(Hill et al., amantadine Ö ne de 2004b; Visanji et [N=3] al., 2006;

99 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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Kobylecki et al.,

2011)

(Jackson et al., aplindore [N=1] ne Ö na 2010)

(Loschmann et

al., 1992; Pearce

et al., 1995; Fox Downloaded from

et al., 2001; apomorphine ne Ö ne Maratos et al.,

[N=6] jpet.aspetjournals.org 2003; Visanji et

al., 2006;

Lincoln et al., at ASPET Journals on October 1, 2021 2016)

(Close et al.,

atropine [N=2] ne Ö ne 1990; Jackson et

al., 2014)

benztropine (Close et al., ne Ö na [N=1] 1990)

brasofensine (Pearce et al., ne Ö na [N=1] 2002)

bromocriptine (Close et al., ne Ö na [N=3] 1990; Pearce et

100 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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al., 1995; Pearce

et al., 1998)

(Hansard et al., BTS-74,398 ne Ö/ne na 2002b; Hansard [N=2] et al., 2004)

(Hansard et al., bupropion ne Ö/ne na 2002b; Hansard Downloaded from [N=2] et al., 2011)

(Visanji et al.,

clozapine [N=1] Ö ne Ö jpet.aspetjournals.org 2006)

CP-101,606 (Nash et al., ne Ö na [N=1] 2004) at ASPET Journals on October 1, 2021 (Loschmann et CPP [N=1] ne Ö na al., 1991)

(Temlett et al., CY-208,243 ne Ö na 1988; Temlett et [N=2] al., 1989)

cyproheptadine (Henry et al., Ö ne ne [N=1] 2001)

(Smith et al.,

entacapone 1997; Smith et ne Ö na [N=4] al., 2003; Smith

et al., 2005;

101 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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Zubair et al.,

2007)

fipamezole (Savola et al., Ö Ö na [N=1] 2003)

(Hansard et al., GBR-12,909 ne Ö na 2002b; Hansard [N=2] et al., 2002a) Downloaded from

haloperidol (Visanji et al., Ö de Ö [N=1] 2006) jpet.aspetjournals.org (Henry et al., idazoxan [N=1] Ö Ö na 1999)

IEM-1460 (Kobylecki et Ö ne na at ASPET Journals on October 1, 2021 [N=1] al., 2010)

ifenprodil (Nash et al., ne Ö na [N=1] 2000)

(Gomez-

imetit [N=1] Ö ne na Ramirez et al.,

2006)

(Gomez-

immepip [N=1] Ö ne na Ramirez et al.,

2006)

istradefylline (Kanda et al., ne Ö na [N=6] 1998a; Kanda et

102 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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al., 1998b;

Kanda et al.,

2000; Uchida et

al., 2014; Uchida

et al., 2015a;

Uchida et al.,

2015b) Downloaded from

(Visanji et al., J-113,397 [N=1] Ö ne na 2008) jpet.aspetjournals.org JNJ-27,063,699 (Philippens et ne Ö na [N=1] al., 2014)

(Hill et al., 2003; at ASPET Journals on October 1, 2021 levetiracetam Hill et al., Ö ne na [N=3] 2004a; Hill et

al., 2004b)

LY-141,865 (Nomoto et al., ne Ö na [N=1] 1985)

(Iravani et al., MDMA [N=1] Ö Ö na 2003)

melanocyte- (Katzenschlager inhibiting ne ne na et al., 2007) factor [N=1]

103 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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mianserin (Hamadjida et Ö de Ö [N=1] al., 2018)

mirtazapine (Hamadjida et Ö ne Ö [N=1] al., 2017)

(Jenner et al.,

modafinil [N=2] ne Ö na 2000; van Vliet

et al., 2008) Downloaded from

(Loschmann et N-0437 [N=1] ne Ö na al., 1989) jpet.aspetjournals.org N-methyl (Jackson et al., scopolamine ne Ö na 2014) [N=1] at ASPET Journals on October 1, 2021 nabilone [N=1] Ö ne na (Fox et al., 2002)

naltrexone (Henry et al., Ö ne na [N=1] 2001)

naltrindole (Henry et al., Ö ne na [N=1] 2001)

neostigmine (Jackson et al., ne Ö na [N=1] 2014)

nisoxetine (Hansard et al., ne Ö/de na [N=1] 2002b)

(Loschmann et NBQX [N=1] ne Ö na al., 1991)

104 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Close et al., nomifensine ne Ö na 1990; Hansard et [N=2] al., 2002b)

oxotremorine (Jackson et al., ne de na [N=1] 2014)

(Johnston et al.,

2010a; Jones et Downloaded from pardoprunox Ö Ö na al., 2010; [N=3] Tayarani-Binazir jpet.aspetjournals.org et al., 2010a)

(Pearce et al.,

1995; Maratos et at ASPET Journals on October 1, 2021 al., 2003; Fox et

pergolide [N=5] ne Ö na al., 2006b;

Uchida et al.,

2015a; Uchida et

al., 2015b)

physostigmine (Jackson et al., ne de na [N=1] 2014)

(Smith et al.,

1996; Smith et piribedil [N=4] ne Ö na al., 2000; Smith

et al., 2002b;

105 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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Smith et al.,

2006)

(Iravani et al.,

2003; Fox et al.,

pramipexole 2006b; Iravani et ne Ö na [N=4] al., 2006;

Tayarani-Binazir Downloaded from

et al., 2010b)

quetiapine (Visanji et al.,

Ö ne Ö jpet.aspetjournals.org [N=1] 2006)

(Nomoto et al.,

1988; Close et at ASPET Journals on October 1, 2021 al., 1990;

Loschmann et

al., 1992;

quinpirole Gnanalingham et ne Ö na [N=8] al., 1995a;

Gnanalingham et

al., 1995b;

Pearce et al.,

1995; Kanda et

al., 2000;

106 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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Treseder et al.,

2000)

(R)-(+)- (Iravani et al., OHDPAT Ö de na 2006) [N=1]

R-MDMA (Huot et al., Ö ne Ö [N=1] 2011) Downloaded from

(Loschmann et

al., 1992; jpet.aspetjournals.org Gnanalingham et raclopride Ö de na al., 1995c; [N=4] Ekesbo et al., at ASPET Journals on October 1, 2021 1997; Smith et

al., 2002a)

rauwolscine (Henry et al., Ö ne na [N=1] 1999)

RGFP-109 (Johnston et al., Ö ne na [N=1] 2013a)

rimonabant (van der Stelt et Ö Ö na [N=1] al., 2005)

Ro-25,6981 (Loschmann et ne Ö na [N=1] al., 2004)

107 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Pearce et al.,

1998; Maratos et

al., 2001; Hill et

al., 2003; Millan

et al., 2004;

Silverdale et al.,

2004; Fox et al., Downloaded from

2006b; Jackson

ropinirole et al., 2007; ne Ö na jpet.aspetjournals.org [N=13] Zubair et al.,

2007; Stockwell

et al., 2008; at ASPET Journals on October 1, 2021 Jackson et al.,

2010; Johnston

et al., 2010a;

Uchida et al.,

2015a; Uchida et

al., 2015b)

(Rose et al.,

2007; Stockwell

rotigotine [N=3] ne Ö na et al., 2009;

Stockwell et al.,

2010)

108 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Millan et al.,

S-32,504 [N=2] ne Ö na 2004; Hill et al.,

2006)

(Silverdale et al.,

2004; Hill et al., S-33,084 [N=3] ne Ö na 2006; Visanji et

al., 2009a) Downloaded from

S-MDMA (Huot et al., de Ö ne [N=1] 2011) jpet.aspetjournals.org S,S- (Hansard et al., hydroxybuprop ne Ö na 2011) ion [N=1] at ASPET Journals on October 1, 2021 SB-224,289-A (Jackson et al., ne ne na [N=1] 2004)

(Temlett et al.,

1988;

Loschmann et SCH-23,390 ne de na al., 1992; [N=4] Gnanalingham et

al., 1995c; Smith

et al., 2002a)

109 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Close et al., scopolamine ne Ö na 1990; Jackson et [N=2] al., 2014)

(Hansard et al., sertraline [N=1] ne de na 2002b)

(Nomoto et al.,

1985; Nomoto et Downloaded from

al., 1988; Close

et al., 1990; jpet.aspetjournals.org SKF-38,393 Loschmann et ne ne/de na [N=6] al., 1992;

Gnanalingham et at ASPET Journals on October 1, 2021 al., 1995a;

Gnanalingham et

al., 1995b)

(Gnanalingham

SKF-75,670 et al., 1995a; ne de na [N=2] Gnanalingham et

al., 1995b)

(Gnanalingham

SKF-80,723 et al., 1995a; ne Ö/de na [N=4] Gnanalingham et

al., 1995b;

110 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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Gnanalingham et

al., 1995c;

Kanda et al.,

2000)

(Gnanalingham

SKF-82,958 et al., 1995a; ne Ö/de na [N=2] Gnanalingham et Downloaded from

al., 1995b)

SKF-83,565 (Gnanalingham

ne Ö na jpet.aspetjournals.org [N=1] et al., 1995a)

(Gnanalingham

et al., 1995a; at ASPET Journals on October 1, 2021 SKF-83,959 Gnanalingham et ne Ö na [N=3] al., 1995b;

Gnanalingham et

al., 1995c)

SKF-99,101-H (Jackson et al., Ö ne/de na [N=1] 2004)

(Hille et al., SNC-80 [N=1] ne Ö na 2001)

(Rose et al., ST-1535 [N=1] ne Ö na 2006)

111 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Temlett et al.,

sulpiride [N=2] ne de na 1988; Jones et

al., 2010)

(Lange et al., terguride [N=1] ne Ö na 1992)

(Silverdale et al., topiramate Ö ne na 2005; Kobylecki Downloaded from [N=2] et al., 2011)

trihexyphenidyl (Jackson et al.,

ne Ö na jpet.aspetjournals.org [N=1] 2014)

(Johnston et al., URB-597 [N=1] ne ne ne 2011) at ASPET Journals on October 1, 2021 (Huot et al., UWA-101 ne Ö ne 2012a; Johnston [N=2] et al., 2012)

UWA-121 (Huot et al., ne Ö ne [N=1] 2014)

UWA-122 (Huot et al., Ö Ö ne [N=1] 2014)

yohimbine (Henry et al., Ö ne na [N=1] 1999)

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

The number of studies reporting the effect of each drug is in brackets.

112 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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Table 3: Drugs tested in the MPTP-lesioned squirrel monkey

drug dyskinesia parkinsonism psychosis references

(Zhang et al., ABT-089 [N=1] Ö ne na 2014)

(Zhang et al., ABT-107 [N=1] Ö ne na 2013)

(Zhang et al., Downloaded from ABT-126 [N=1] Ö ne na 2015)

(Zhang et al., jpet.aspetjournals.org 2013; Zhang et ABT-894 [N=3] Ö ne na al., 2014; Zhang

et al., 2015) at ASPET Journals on October 1, 2021 (Hsu et al., BP-897 [N=1] Ö de na 2004)

(Quik et al.,

2007; Quik et

al., 2013a; Quik nicotine [N=4] Ö ne na et al., 2013b;

Zhang et al.,

2015)

(Zhang et al., TC-8831 [N=1] Ö ne na 2013)

113 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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(Cox et al., U50-488 [N=1] Ö de na 2007)

varenicline (Zhang et al., Ö ne na [N=1] 2013)

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

The number of studies reporting the effect of each drug is in brackets.

Downloaded from jpet.aspetjournals.org at ASPET Journals on October 1, 2021

114 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

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Table 4: drugs tested in the MPTP-lesioned primate that were tested in the clinic or are

clinically-available

drug dyskinesia parkinsonism psychosis references

(Stoessl et al., (+)-4-propyl-9- 1985; Grandas et hydroxynaphth ne Ö na al., 1987; Muenter oxazine Downloaded from et al., 1988)

(Rascol et al.,

ABT-431 ne Ö na 1999; Rascol et al., jpet.aspetjournals.org

2001b)

(Stocchi et al., at ASPET Journals on October 1, 2021 AFQ-056 Ö/ne ne na 2013; Trenkwalder

et al., 2016b)

(Parkes et al.,

1971; Butzer et al.,

1975; Verhagen

Metman et al.,

amantadine Ö Ö na 1998; Luginger et

al., 2000; Del

Dotto et al., 2001;

Oertel et al., 2017;

Pahwa et al., 2017)

115 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

JPET #247171

(Schwab et al.,

1951; Corsini et apomorphine ne Ö na al., 1979; Stibe et

al., 1987)

(Trenkwalder et al., AQW-051 ne ne na 2016a)

(Boman and Downloaded from atropine ne Ö na Meurman, 1970)

benztropine ne Ö na (Doshay, 1956) jpet.aspetjournals.org (Frackiewicz et al., brasofensine ne ne na 2002)

(Agid et al., 1979; at ASPET Journals on October 1, 2021 Quinn et al., 1981;

Jellinger, 1982;

bromocriptine ne Ö na Hely et al., 1994;

Montastruc et al.,

1994; Castro-

Caldas et al., 2006)

bupropion ne Ö na (Goetz et al., 1984)

(Ahlskog et al.,

1996; Rinne et al., cabergoline ne Ö na 1997; Deuschl et

al., 2007)

116 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

JPET #247171

(Rampello et al.,

2002; Palhagen et citalopram Ö Ö na al., 2008; Palhagen

et al., 2009)

(Shoulson and

Chase, 1976; clonidine na Ö/de na Serrano-Duenas, Downloaded from

2000)

(Durif et al., 1997; jpet.aspetjournals.org FrenchClozapinePa

rkinsonStudyGroup

clozapine Ö Ö Ö , 1999; at ASPET Journals on October 1, 2021 ParkinsonStudyGro

up, 1999; Durif et

al., 2004)

CP-101,606 Ö ne na (Nutt et al., 2008)

(Tsui et al., 1989; CY-208,243 ne Ö na Emre et al., 1992)

(Pourcher et al., diazepam Ö Ö na 1989)

dipraglurant Ö ne na (Tison et al., 2016)

(Svenningsson et eltoprazine Ö ne na al., 2015)

117 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

JPET #247171

(Kaakkola et al.,

1994; Merello et entacapone de Ö na al., 1994; Fenelon

et al., 2003)

(Pourcher et al., ethosuximide ne ne/de na 1992)

(Molinari et al., Downloaded from

famotidine ne ne na 1995; Mestre et al.,

2014) jpet.aspetjournals.org (Lewitt et al., fipamezole Ö ne na 2012)

(Klawans and haloperidol Ö de na at ASPET Journals on October 1, 2021 Weiner, 1974)

(Manson et al.,

idazoxan Ö/ne ne na 2000; Rascol et al.,

2001a)

(Hauser et al.,

2003; Hauser et al.,

istradefylline ne Ö na 2008; LeWitt et al.,

2008; Pourcher et

al., 2012)

(Coppen et al., L-tryptophan ne ne na 1972)

118 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

JPET #247171

(Wolz et al., 2010;

levetiracetam Ö/ne ne ne Stathis et al., 2011;

Wong et al., 2011)

melanocyte- (Gerstenbrand et ne ne na inhibiting factor al., 1975)

(Klawans and methysergide ne ne na Ringel, 1973) Downloaded from

(Ikeguchi and mianserin na na Ö Kuroda, 1995) jpet.aspetjournals.org (Gordon et al.,

2002; Meco et al.,

mirtazapine Ö Ö Ö 2003; Nagata et al., at ASPET Journals on October 1, 2021 2012; Tagai et al.,

2013)

(Tyne et al., 2007; modafinil ne ne na Tyne et al., 2010)

morphine Ö de na (Berg et al., 1999)

(Sieradzan et al., nabilone Ö ne na 2001)

(Trabucchi et al.,

naloxone Ö/ne Ö/ne na 1982; Fox et al.,

2004)

119 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

JPET #247171

(Rascol et al.,

naltrexone Ö/ne ne na 1994; Manson et

al., 2001)

(Vieregge et al.,

2001; Lemay et al., nicotine na Ö/ne na 2004; Villafane et

al., 2007) Downloaded from

(Teychenne et al.,

1976; Bedard et al., jpet.aspetjournals.org nomifensine de Ö na 1977; Park et al.,

1977; Park et al.,

1981) at ASPET Journals on October 1, 2021 (Bronzova et al.,

2010; Sampaio et pardoprunox ne Ö na al., 2011; Rascol et

al., 2012)

(Lieberman et al.,

1986; Wright et al.,

1986; Olanow et pergolide ne Ö na al., 1994; Mizuno

et al., 1995; Oertel

et al., 2006)

120 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

JPET #247171

(Tarsy et al., 1974;

Lindeboom and

physostigmine Ö/ne de na Lakke, 1978;

Clough et al.,

1984)

(Meltzer et al.,

pimavanserin ne ne Ö 2010; Cummings et Downloaded from

al., 2014)

(Investigators,

pioglitazone ne ne na jpet.aspetjournals.org 2015)

(Castro-Caldas et

piribedil ne Ö na al., 2006; Rascol et at ASPET Journals on October 1, 2021 al., 2006b)

(Lieberman et al.,

1997;

pramipexole ne Ö na ParkinsonStudyGro

up, 2000b; Poewe

et al., 2007)

(Hauser et al.,

2011; Factor et al.,

preladenant de Ö/ne na 2013; Hauser et al.,

2015; Stocchi et

al., 2017)

121 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

JPET #247171

(Koller and

Herbster, 1987; propranolol Ö Ö/ne na Carpentier et al.,

1996)

(Fernandez et al.,

1999; Baron and

Dalton, 2003; Downloaded from

Fernandez et al., quetiapine Ö/ne ne/de Ö/ne 2003; jpet.aspetjournals.org Katzenschlager et

al., 2004; Ondo et

al., 2005) at ASPET Journals on October 1, 2021 (ParkinsonStudyGr

oup, 2000a;

remacemide ne ne na ParkinsonStudyGro

up, 2001; Shoulson

et al., 2001)

(Rascol et al.,

1996; Korczyn et

ropinirole ne Ö na al., 1999; Rascol et

al., 2000; Rascol et

al., 2006a)

122 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version.

JPET #247171

(ParkinsonStudyGr

oup, 2003; Giladi

et al., 2007; LeWitt rotigotine ne Ö na et al., 2007;

Mizuno et al.,

2013)

(Borgohain et al., Downloaded from

2014a; Borgohain

et al., 2014b;

safinamide Ö Ö na jpet.aspetjournals.org Cattaneo et al.,

2015; Schapira et

al., 2017) at ASPET Journals on October 1, 2021 (Olanow et al.,

2004; Goetz et al., sarizotan ne de na 2007; Goetz et al.,

2008)

(Gruchet, 1952; scopolamine ne Ö na Duvoisin, 1967)

(Hauser and

Zesiewicz, 1997;

sertraline ne ne na Antonini et al.,

2006; Kulisevsky

et al., 2008;

123 JPET #247171

Marino et al.,

2008)

simvastatin ne ne na (Tison et al., 2013)

SKF-38,393 ne ne na (Braun et al., 1987)

sulpiride Ö de na (Lees et al., 1978)

(Barone et al.,

sumanirole ne Ö/ne na 2007; Singer et al.,

2007)

(Filipova et al.,

terguride ne Ö na 1988; Martignoni

et al., 1995)

(Kobylecki et al.,

topiramate ne/de ne na 2014; Goetz et al.,

2017)

(Martin et al.,

trihexyphenidyl ne Ö na 1974; Lamid and

Jenkins, 1975)

(Montastruc et al., yohimbine ne Ö na 1981)

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

124 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 S1: pharmacological profile of the drugs assessed in the MPTP-lesioned primate

drug mechanism of action 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 (pozanicline) b2 nACh agonist nicotinic 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,2C 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 (besonprodil, 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 (traxoprodil) 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 AMPAkine 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 (vanoxerine) 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 (pethidine) 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 (dizocilpine) 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 muscarinic agonist 1997)

PAMQX (CGP- NMDA antagonist (at (Ametamey et NMDA antagonist 78,608) glycine 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

ether lipid plasmalogen plasmalogen (Wood 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., prazosin 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)

rimonabant (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: adenosine receptor; AChE: acetylcholinesterase; AMPA: α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BuChE: butyrylcholinesterase;

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

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

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

MAO-B: monoamine oxidase B; MDMA: 3,4-methylenedioxymethamphetamine; mGlu: metabotropic glutamate receptor; MPR: membrane progesterone receptor; MR: mineralocorticoid receptor; Na+: sodium; nACh: nicotinic acetylcholine receptor; 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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