Simon Loiodice1,2, Poppy Winlow3,4, Sarah Dremier3,5, Etienne Hanon3, David Dardou6, Omar Ouachikh6, Aziz Hafidi6, Andre Nogueira da Costa3, Franck Durif6,7. 1. UFR Medicine, Université d'Auvergne, 28 Place Henri Dunant, 63000, Clermont-Ferrand, France. simon.loiodice@gmail.com. 2. Department of Non-Clinical Development, UCB Biopharma SPRL, Chemin du Foriest 1, 1420, Braine-l'Alleud, Belgium. simon.loiodice@gmail.com. 3. Department of Non-Clinical Development, UCB Biopharma SPRL, Chemin du Foriest 1, 1420, Braine-l'Alleud, Belgium. 4. Faculty of Biological Sciences, University of Leeds, LS29JT, Leeds, UK. 5. Euroscreen SA, 6041, Gosselies, Belgium. 6. UFR Medicine, Université d'Auvergne, 28 Place Henri Dunant, 63000, Clermont-Ferrand, France. 7. Neurology Department, CHU de Clermont-Ferrand, 28 Place Henri Dunant, 63000, Clermont-Ferrand, France.
Abstract
RATIONALE: Impulsive-compulsive disorders (ICD) in patients with Parkinson's disease (PD) have been described as behavioral or substance addictions including hypersexuality, gambling, or compulsive medication use of the dopamine replacement therapy (DRT). OBJECTIVES: A remaining challenge is to understand the neuroadaptations leading to reward bias in PD patients under DRT. METHODS: To this end, the appetitive effect of the D2/D3 agonist pramipexole was assessed after chronic exposure to L-dopa in an alpha-synuclein PD rat model. RESULTS: Association of progressive nigral loss and chronic L-dopa was required to observe a pramipexole-induced place preference. This behavioral outcome was inhibited by metabotropic glutamate receptor 5 (mGluR5) antagonism while transcriptional profiling highlighted regulations potentially related to the context of psychostimulant addiction. CONCLUSION: This study provides evidences strongly suggesting that PD-like lesion and L-dopa therapy were concomitant factors involved in striatal remodeling underlying the pramipexole-induced place preference. Molecular and pharmacological data suggest a key involvement of the glutamatergic pathway in this behavioral outcome.
RATIONALE: Impulsive-compulsive disorders (ICD) in patients with Parkinson's disease (PD) have been described as behavioral or substance addictions including hypersexuality, gambling, or compulsive medication use of the dopamine replacement therapy (DRT). OBJECTIVES: A remaining challenge is to understand the neuroadaptations leading to reward bias in PDpatients under DRT. METHODS: To this end, the appetitive effect of the D2/D3 agonist pramipexole was assessed after chronic exposure to L-dopa in an alpha-synuclein PDrat model. RESULTS: Association of progressive nigral loss and chronic L-dopa was required to observe a pramipexole-induced place preference. This behavioral outcome was inhibited by metabotropic glutamate receptor 5 (mGluR5) antagonism while transcriptional profiling highlighted regulations potentially related to the context of psychostimulant addiction. CONCLUSION: This study provides evidences strongly suggesting that PD-like lesion and L-dopa therapy were concomitant factors involved in striatal remodeling underlying the pramipexole-induced place preference. Molecular and pharmacological data suggest a key involvement of the glutamatergic pathway in this behavioral outcome.
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