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The Journal of Neuroscience, April 15, 2009, 29(15):4829-4835; doi:10.1523/JNEUROSCI.5884-08.2009

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Neurobiology of Disease
Pharmacological Analysis Demonstrates Dramatic Alteration of D₁ Dopamine Receptor Neuronal Distribution in the Rat Analog of L-DOPA-Induced Dyskinesia

Amandine Berthet,¹ Grégory Porras,¹ Evelyne Doudnikoff,¹ Holger Stark,² Martine Cador,¹ Erwan Bezard,^1 * and Bertrand Bloch^1 *

¹Université Victor Segalen–Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, 33076 Bordeaux Cedex, France, and ²Johann Wolfgang Goethe-Universität, Biozentrum, 60438 Frankfurt am Main, Germany

Correspondence should be addressed to Bertrand Bloch, CNRS UMR 5227, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France. Email: bertrand.bloch{at}u-bordeaux2.fr

We have associated behavioral, pharmacological, and quantitative immunohistochemical study in a rat analog of L-DOPA-induced dyskinesia to understand whether alterations in dopamine receptor fate in striatal neurons may be involved in mechanisms leading to movement abnormalities. Detailed analysis at the ultrastructural level demonstrates specific alterations of dopamine D₁ receptor (D₁R) subcellular localization in striatal medium spiny neurons in L-DOPA-treated 6-hydroxydopamine-lesioned rats with abnormal involuntary movements (AIMs). This includes exaggerated D₁R expression at the plasma membrane. However, D₁R retains ability of internalization, as a challenge with the potent D₁R agonist SKF-82958 induces a strong decrease of labeling at membrane in animals with AIMs. Since a functional cross talk between D₁R and D₃R has been suggested, we hypothesized that their coactivation by dopamine derived from L-DOPA might anchor D₁R at the membrane. Accordingly, cotreatment with L-DOPA and the D₃R antagonist ST 198 restores normal level of membrane-bound D₁R. Together, these results demonstrate that AIMs are related to abnormal D₁R localization at the membrane and intraneuronal trafficking dysregulation, and suggest that strategies aiming at disrupting the D₁R–D₃R cross talk might reduce L-DOPA-induced dyskinesia by reducing D₁R availability at the membrane.

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Received Dec. 11, 2008; revised March 10, 2009; accepted March 11, 2009.

Correspondence should be addressed to Bertrand Bloch, CNRS UMR 5227, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France. Email: bertrand.bloch{at}u-bordeaux2.fr

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