title: Imaging Dopamine and Serotonin Systems on MPTP Monkeys: A Longitudinal PET Investigation of Compensatory Mechanisms.
abstract: It is now widely accepted that compensatory mechanisms are involved during the early phase of Parkinson's disease (PD) to delay the expression of motor symptoms. However, the neurochemical mechanisms underlying this presymptomatic period are still unclear. Here, we measured in vivo longitudinal changes of both the dopaminergic and serotonergic systems in seven asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys (when motor symptoms are less apparent) using PET. We used the progressively MPTP-intoxicated monkey model that expresses recovery from motor symptoms to study the changes in dopamine synthesis ([(18)F]DOPA), dopamine D2/D3 receptors ([(11)C]raclopride), and serotonin transporter (11)C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio) benzylamine ([(11)C]DASB) and serotonin 1A receptor ([(18)F]MPPF) levels between four different states (baseline, early symptomatic, full symptomatic and recovered). During the early symptomatic state, we observed increases of [(18)F]DOPA uptake in the anterior putamen, [(11)C]raclopride binding in the posterior striatum, and 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine [(18)F]MPPF uptake in the orbitofrontal cortex and dorsal ACC. After recovery from motor symptoms, the results mainly showed decreased [(11)C]raclopride binding in the anterior striatum and limbic ACC. In addition, our findings supported the importance of pallidal dopaminergic neurotransmission in both the early compensatory mechanisms and the functional recovery mechanisms, with reduced aromatic L-amino acid decarboxylase (AAAD) activity closely related to the appearance or perseveration of motor symptoms. In parallel, this study provides preliminary evidence of the role of the serotonergic system in compensatory mechanisms. Nonetheless, future studies are needed to determine whether there are changes in SERT availability in the early symptomatic state and if [(18)F]MPPF PET imaging might be a promising biomarker of early degenerative changes in PD.
  
  
  CONCLUSIONS
  The present research provides evidence of the potential of combining a multitracer PET imaging technique and a longitudinal protocol applied on a progressively 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated monkey model to further elucidate the nature of the compensatory mechanisms involved in the preclinical period of Parkinson's disease (PD). In particular, by investigating the dopaminergic and serotonergic changes both presynaptically and postsynaptically at four different motor states (baseline, early symptomatic, full symptomatic, and recovered), this study has allowed us to identify putative biomarkers for future therapeutic interventions to prevent and/or delay disease expression. For example, our findings suggest that the external pallidum could be a new target for cell-based therapies to reduce PD symptoms.
authors: Centre de Neurosciences Cognitives, Unité Mixte de Recherche 5229 Centre National de la Recherche Scientifique, Bron 69675, France, Université Claude Bernard Lyon 1, Villeurbanne 69100, France.
authors: Benedicte
authors: B
authors: Ballanger
authors: Centre de Neurosciences Cognitives, Unité Mixte de Recherche 5229 Centre National de la Recherche Scientifique, Bron 69675, France, Université Claude Bernard Lyon 1, Villeurbanne 69100, France.
authors: Maude
authors: http://orcid.org/0000-0002-3056-2384
authors: M
authors: Beaudoin-Gobert
authors: Centre de Neurosciences Cognitives, Unité Mixte de Recherche 5229 Centre National de la Recherche Scientifique, Bron 69675, France, Université Claude Bernard Lyon 1, Villeurbanne 69100, France.
authors: Sara
authors: S
authors: Neumane
authors: Centre de Neurosciences Cognitives, Unité Mixte de Recherche 5229 Centre National de la Recherche Scientifique, Bron 69675, France, Université Claude Bernard Lyon 1, Villeurbanne 69100, France.
authors: Justine
authors: J
authors: Epinat
authors: Centre de Neurosciences Cognitives, Unité Mixte de Recherche 5229 Centre National de la Recherche Scientifique, Bron 69675, France, Université Claude Bernard Lyon 1, Villeurbanne 69100, France.
authors: Elise
authors: http://orcid.org/0000-0001-6868-315X
authors: E
authors: Metereau
authors: Centre de Neurosciences Cognitives, Unité Mixte de Recherche 5229 Centre National de la Recherche Scientifique, Bron 69675, France, Université Claude Bernard Lyon 1, Villeurbanne 69100, France.
authors: Sandra
authors: S
authors: Duperrier
authors: Centre de Neurosciences Cognitives, Unité Mixte de Recherche 5229 Centre National de la Recherche Scientifique, Bron 69675, France, Université Claude Bernard Lyon 1, Villeurbanne 69100, France, Hospices Civils de Lyon, Lyon 69229, France.
authors: Emmanuel
authors: E
authors: Broussolle
authors: Centre de Neurosciences Cognitives, Unité Mixte de Recherche 5229 Centre National de la Recherche Scientifique, Bron 69675, France, Université Claude Bernard Lyon 1, Villeurbanne 69100, France, Hospices Civils de Lyon, Lyon 69229, France.
authors: Stephane
authors: S
authors: Thobois
authors: Centre d'Exploration et de Recherche Médicale par Emission de Positons, Imagerie du vivant, Bron 69677, France.
authors: Frederic
authors: F
authors: Bonnefoi
authors: Centre d'Exploration et de Recherche Médicale par Emission de Positons, Imagerie du vivant, Bron 69677, France.
authors: Christian
authors: C
authors: Tourvielle
authors: Centre d'Exploration et de Recherche Médicale par Emission de Positons, Imagerie du vivant, Bron 69677, France.
authors: Franck
authors: F
authors: Lavenne
authors: Centre d'Exploration et de Recherche Médicale par Emission de Positons, Imagerie du vivant, Bron 69677, France.
authors: Nicolas
authors: N
authors: Costes
authors: Université Claude Bernard Lyon 1, Villeurbanne 69100, France, Centre d'Exploration et de Recherche Médicale par Emission de Positons, Imagerie du vivant, Bron 69677, France, Institut de Chimie et de Biochimie Moléculaires et Supramoléculaires, Unité Mixte de Recherche 5246 Centre National de la Recherche Scientifique, Lyon 69622, France, and Hospices Civils de Lyon, Lyon 69229, France.
authors: Didier
authors: D
authors: Lebars
authors: Université Claude Bernard Lyon 1, Villeurbanne 69100, France, Centre d'Exploration et de Recherche Médicale par Emission de Positons, Imagerie du vivant, Bron 69677, France, Hospices Civils de Lyon, Lyon 69229, France.
authors: Luc
authors: L
authors: Zimmer
authors: Centre de Neurosciences Cognitives, Unité Mixte de Recherche 5229 Centre National de la Recherche Scientifique, Bron 69675, France, Université Claude Bernard Lyon 1, Villeurbanne 69100, France.
authors: Véronique
authors: http://orcid.org/0000-0002-8792-8586
authors: V
authors: Sgambato-Faure
authors: Centre de Neurosciences Cognitives, Unité Mixte de Recherche 5229 Centre National de la Recherche Scientifique, Bron 69675, France, Université Claude Bernard Lyon 1, Villeurbanne 69100, France, leon.tremblay@isc.cnrs.fr.
authors: Léon
authors: http://orcid.org/0000-0001-8370-6903
authors: L
authors: Tremblay
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D008137:Longitudinal Studies; D008252:Macaca fascicularis; D008297:Male; D020734:Parkinsonian Disorders / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000639:trends*; D059326:Serotonergic Neurons / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology
keywords: MPTP; PET imaging; Parkinson's disease; compensatory mechanisms; dopamine; serotonin