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Pramipexole reverses Parkinson's disease-related motivational deficits in rats

Authors

  • Mathieu Favier MSc,

    1. Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institute of Neuroscience, Dynamic and Pathophysiology of Basal Ganglia, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
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    • Drs. Favier and Duran contributed equally to this study.

  • Theo Duran MSc,

    1. Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institute of Neuroscience, Dynamic and Pathophysiology of Basal Ganglia, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
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    • Drs. Favier and Duran contributed equally to this study.

  • Carole Carcenac PhD,

    1. Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institute of Neuroscience, Dynamic and Pathophysiology of Basal Ganglia, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
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  • Guillaume Drui PhD,

    1. Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institute of Neuroscience, Dynamic and Pathophysiology of Basal Ganglia, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
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  • Marc Savasta PhD,

    1. Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institute of Neuroscience, Dynamic and Pathophysiology of Basal Ganglia, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
    3. Centre Hospitalier Universitaire de Grenoble, Grenoble, France
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    • Drs. Savasta and Carnicella are cosenior authors.

  • Sebastien Carnicella PhD

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institute of Neuroscience, Dynamic and Pathophysiology of Basal Ganglia, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
    • Correspondence to: Dr. Sebastien Carnicella, INSERM U836, Grenoble Institute of Neuroscience, Dynamic and Pathophysiology of Basal Ganglia, University Joseph Fourier, Site Santé La Tronche, BP 170, 38042 Grenoble, Cedex 09, France; sebastien.carnicella@inserm.fr

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    • Drs. Savasta and Carnicella are cosenior authors.


  • Funding agencies: This work was supported by the Institut National de la Santé et de la Recherche Médicale, Fondation NeuroDis, Association France Parkinson, Région Rhône-Alpes (ARC no. 2), and Université Joseph Fourier.

  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • Full financial disclosures and author roles may be found in the online version of this article.

ABSTRACT

Recent evidence suggests that Parkinson's disease affects not only movement, but also cognitive and psychiatric functions. Among these nonmotor complications, apathy, which is defined as a lack of motivation and operationalized as a quantitative reduction in goal-directed behavior, may even precede motor impairments, disappearing with the introduction of dopaminergic (DA) therapies and possibly reappearing with its discontinuation, suggesting a causal role of DA. We recently developed a lesion-based model, with stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into precise areas of the rat SNc or ventral tegmental area and showed, in several operant tasks, that a partial denervation of the nigrostriatal, but not of the mesocorticolimbic, DA system induced profound motivational deficits during instrumental action. We investigated the time course of the effects of nigrostriatal DA denervation on motivation in rats, by assessing the negative effect of SNc bilateral 6-OHDA infusion on preacquired operant behavior, and determining whether the induced deficits were sensitive to the introduction and withdrawal of a clinically relevant PD treatment, the DA D2/D3 receptor agonist, pramipexole (PRA). Partial nigrostriatal DA denervation was accompanied by a significant reduction in operant behavior. This deficit, indicative of a decrease in motivation, was fully reversed by PRA and reappeared after treatment withdrawal. This longitudinal preclinical study provides evidence for the implication of the DA nigrostriatal system in PD-associated apathy. Moreover, by showing a good isomorphy and predictive value, our model highlights the relevance of D2/D3 receptors as potential targets for alleviating apathy in PD. © 2014 International Parkinson and Movement Disorder Society

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