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Pramipexole induced place preference after L-dopa therapy and nigral dopaminergic loss: linking behavior to transcriptional modifications

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.

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Acknowledgments

This work was funded by grants from the Fondation de France and the Fédération Française des Groupements de Parkinsoniens. Authors thank The Michael J. Fox Foundation for providing the AAV vectors.

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Correspondence to Simon Loiodice.

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All experiments were approved by the Animal Ethics Committee of the University of Auvergne (CEMEA Auvergne) and the ethics committee for animal use in experimental research of the French Research Ministry (authorization number B6311315).

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The authors declare that there is no conflict of interest.

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Loiodice, S., Winlow, P., Dremier, S. et al. Pramipexole induced place preference after L-dopa therapy and nigral dopaminergic loss: linking behavior to transcriptional modifications. Psychopharmacology 234, 15–27 (2017). https://doi.org/10.1007/s00213-016-4430-7

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  • DOI: https://doi.org/10.1007/s00213-016-4430-7

Keywords

  • Parkinson’s disease
  • Impulsive/compulsive disorders
  • l-dopa
  • Pramipexole
  • Transcriptional profiling
  • Alpha-synuclein