Brain Advance Access originally published online on September 13, 2007
Brain 2007 130(11):2898-2914; doi:10.1093/brain/awm208
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A new model to study compensatory mechanisms in MPTP-treated monkeys exhibiting recovery
1Institut National de la Santé et de la Recherche Médicale, Unité 679, Paris F-75013, 2Université Pierre et Marie Curie-Paris6, Institut Fédératif de Recherche de Neurosciences Unité Mixte de Recherche S679, Paris F-75013, 3Assistance Publique - Hôpitaux de Paris, Groupe Pitié-Salpêtrière, Paris F-75013, 4Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institut des Neurosciences, Equipe Dynamique des Réseaux Neuronaux du Mouvement, Grenoble F-38043, Cedex 09, 5Université Joseph Fourier, 38041 Grenoble F- 38041, Cedex 09 and 6Centre Hospitalier Universitaire de Grenoble, Grenoble F-38043, Cedex 09, France
Correspondence to: Léon Tremblay, INSERM UMR679, 47 boulevard de l’hôpital, 75651 Paris Cedex13, France E-mail: ltremb{at}ccr.jussieu.fr
The cardinal symptoms in Parkinson's disease (PD), akinesia, rigidity and tremor, are only observed when the striatal level of dopamine is decreased by 60–80%. During the preclinical phase of PD, compensatory mechanisms are probably involved in delaying the appearance of motor symptoms. In a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of PD, a spontaneous recovery has been reported after initial intoxication suggesting that compensatory mechanisms are activated in this model as well. Assuming that mechanisms are similar in these phenomena, the study of recovery in monkeys following MPTP intoxication may enable identification of compensatory mechanisms involved in the preclinical phase of PD. In order to maximize the temporal similarity between PD and the MPTP model, we assessed a new progressive monkey model in which spontaneous recovery is expressed systematically and to characterize it based on (1) its behavioural features, and (2) the presence of compensatory mechanisms revealed by an immunohistological approach comparing dopaminergic and serotoninergic innervation between monkeys either exhibiting behavioural recovery or stable motor symptoms. This immunohistological study focused on the substantia nigra, striatum and pallidum, and their anatomical and functional subdivisions: sensorimotor, associative and limbic. The behavioural analysis revealed that with progressive MPTP intoxication motor symptoms were initially expressed in all monkeys. Observable recovery from these symptoms occurred in all monkeys (7/7) within 3–5 weeks after the last MPTP injection, and most exhibited a full recovery. In contrast, acute intoxication induced stable motor symptoms. Despite this obvious behavioural difference, immunohistological methods revealed that the loss of dopaminergic cell bodies in substantia nigra was substantial and similar in both MPTP-treated groups. However, quantification of fibres revealed that recovered monkeys displayed more dopaminergic and serotoninergic fibres than those with stable motor symptoms in sensorimotor and associative territories of striatum and more dopaminergic fibres in internal pallidum. This study provides a new model of PD where all monkeys expressed functional recovery from motor symptoms despite a large dopaminergic neuronal loss. The immunohistological results suggest that both dopamine and serotonin could be implicated in the compensatory mechanisms.
Key Words: parkinson's disease; monkey; MPTP; behaviour; immunohistology; compensation
Abbreviations: TH, tyrosine hydroxylase; DAT = dopamine transporter
Received April 16, 2007. Revised August 5, 2007. Accepted August 8, 2007.
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