Differential dopamine receptor occupancy underlies L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Gurdal Sahin; Lachlan H Thompson; Sonia Lavisse; Merve Ozgur; Latifa Rbah-Vidal; Frédéric Dollé; Philippe Hantraye; Deniz Kirik

doi:10.1371/journal.pone.0090759

Differential dopamine receptor occupancy underlies L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

PLoS One. 2014 Mar 10;9(3):e90759. doi: 10.1371/journal.pone.0090759. eCollection 2014.

Authors

Gurdal Sahin¹, Lachlan H Thompson², Sonia Lavisse³, Merve Ozgur¹, Latifa Rbah-Vidal³, Frédéric Dollé⁴, Philippe Hantraye³, Deniz Kirik¹

Affiliations

¹ Brain Repair And Imaging in Neural Systems (BRAINS) Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
² Brain Repair And Imaging in Neural Systems (BRAINS) Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
³ Commissariat à l'énergie atomique (CEA), Institut d'imagerie biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), Fontenay aux Roses, France.
⁴ Commissariat à l'énergie atomique (CEA), Institut d'imagerie biomédicale (I2BM), Service Hospitalier Frédéric Joliot, Orsay, France.

Abstract

Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzamides
Disease Models, Animal
Dopamine / metabolism
Dyskinesia, Drug-Induced / metabolism*
Dyskinesia, Drug-Induced / pathology
Extracellular Space / metabolism
Female
Levodopa / administration & dosage
Levodopa / adverse effects*
Levodopa / pharmacology
Levodopa / therapeutic use
Microdialysis
Neostriatum / drug effects
Neostriatum / metabolism
Nomifensine / therapeutic use
Parkinson Disease / diagnostic imaging
Parkinson Disease / drug therapy*
Parkinson Disease / metabolism*
Positron-Emission Tomography
Proto-Oncogene Proteins c-fos / metabolism
Pyrrolidines
Rats, Sprague-Dawley
Receptors, Dopamine / metabolism*
Serotonin / metabolism

Substances

Benzamides
Fosb protein, rat
N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide
Proto-Oncogene Proteins c-fos
Pyrrolidines
Receptors, Dopamine
Nomifensine
Serotonin
Levodopa
Dopamine

Grants and funding

The authors would like to acknowledge the Swedish Research Council (K2009-61P-20945-03-1), Swedish Parkinson Foundation (grant no. 334/10), the European Research Council (ERC) Starting Grant (TreatPD, 242932) and European Union 6th Framework Program project Diagnostic Molecular Imaging (DiMI, LSHB-CT-2005-512146). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.