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Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia

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Abstract

Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1–D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-l-alanine (l-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or l-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from l-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.

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Abbreviations

6-OHDA:

6-hydroxy dopamine

AIM:

Abnormal involuntary movement

l-DOPA:

3,4-dihydroxyphenyl-l-alanine

7-OH-DPAT:

7-hydroxy-N,N-di-n-propyl-2-aminotetralin

LID:

l-DOPA-induced dyskinesia

7-OH-PIPAT:

7-hydroxy-2-[N-n-propyl-N-(3′-iodo-2′- propenyl)-amino]tetralin

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Acknowledgments

This study was supported by grants SAF2009-07276 and BFU2012-37907, from the Spanish Ministerio de Ciencia y Tecnología (current name: Ministerio de Economía y Competitividad), including FEDER funding (fondo Europeo de desarrollo regional). We acknowledge the critical reading and helpful comments of Dr. Milos Petrovic. We thank Manel Bosch, of the Unitat de Miscroscopia Optica Avançada, Fac. of Biology, University of Barcelona, for the ImageJ macro to analyze PLA results.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Diagonal 645, Prevosti Building, 08028, Barcelona, Spain

    Daniel Farré, Estefanía Moreno, Júlia Canet-Pons, Carme Lluís, Josefa Mallol, Gemma Navarro, Enric I. Canela, Antonio Cortés, Vicent Casadó & Rafael Franco

  2. Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain

    Ana Muñoz & José L. Labandeira-García

  3. Neuroscience Department, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    Irene Reyes-Resina, Iria G. Dopeso-Reyes, Alberto J. Rico, José L. Lanciego & Rafael Franco

  4. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

    Daniel Farré, Ana Muñoz, Estefanía Moreno, Iria G. Dopeso-Reyes, Alberto J. Rico, Carme Lluís, Josefa Mallol, Gemma Navarro, Enric I. Canela, Antonio Cortés, José L. Labandeira-García, Vicent Casadó, José L. Lanciego & Rafael Franco

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Correspondence to Rafael Franco.

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Vicent Casadó, José L. Lanciego and Rafael Franco are Senior authors of the manuscript

Daniel Farré, Ana Muñoz and Estefanía Moreno have contributed equally to this paper.

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Farré, D., Muñoz, A., Moreno, E. et al. Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia. Mol Neurobiol 52, 1408–1420 (2015). https://doi.org/10.1007/s12035-014-8936-x

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  • DOI: https://doi.org/10.1007/s12035-014-8936-x

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