The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

• Published in: Scientific reports 2020-02, Vol.10 (1), p.2542, Article 2542
• Main Authors: Castello, Julia, Cortés, Marisol, Malave, Lauren, Kottmann, Andreas, Sibley, David R., Friedman, Eitan, Rebholz, Heike
• Format: Article
• Language: English
• Subjects: 13/1; 13/95; 14; 14/19; 38; 38/77; 631/378/1689/1718; 631/378/340; 64; 64/60; 82; 82/51; 96; 96/63; Animals; Basal ganglia; Biochemistry, Molecular Biology; Cell activation; Central nervous system diseases; Cholinergic Neurons - drug effects; Cholinergic Neurons - metabolism; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dihydroxyphenylalanine; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dopamine D1 receptors; Dopamine D2 receptors; Dopamine D5 receptors; Dyskinesia; Dyskinesia, Drug-Induced - genetics; Dyskinesia, Drug-Induced - pathology; Humanities and Social Sciences; Humans; Interneurons; Interneurons - drug effects; Interneurons - metabolism; Levodopa; Levodopa - adverse effects; Life Sciences; MAP Kinase Signaling System - genetics; Mice; Mice, Knockout; Molecular biology; Molecular modelling; Movement disorders; multidisciplinary; Neostriatum; Neurobiology; Neurons and Cognition; Oxidopamine - pharmacology; Parkinson Disease - genetics; Parkinson Disease - pathology; Receptors, Dopamine D5 - genetics; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-59011-5

The dopamine D5 receptor (D5R) is a Gα s -coupled dopamine receptor belonging to the dopamine D1-like receptor family. Together with the dopamine D2 receptor it is highly expressed in striatal cholinergic interneurons and therefore is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. Tonically active cholinergic interneurons become dysregulated during chronic L-DOPA administration and participate in the expression of L-DOPA induced dyskinesia. The molecular mechanisms involved in this process have not been elucidated, however a correlation between dyskinesia severity and pERK expression in cholinergic cells has been described. To better understand the function of the D5 receptor and how it affects cholinergic interneurons in L-DOPA induced dyskinesia, we used D5R knockout mice that were rendered parkinsonian by unilateral 6-OHDA injection. In the KO mice, expression of pERK was strongly reduced indicating that activation of these cells is at least in part driven by the D5 receptor. Similarly, pS6, another marker for the activity status of cholinergic interneurons was also reduced. However, mice lacking D5R exhibited slightly worsened locomotor performance in response to L-DOPA and enhanced LID scores. Our findings suggest that D5R can modulate L-DOPA induced dyskinesia and is a critical activator of CINs via pERK and pS6.