Abstract
The dopamine D5 receptor (D5R) is a Gαs-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.
Highlights
The dopamine D5 receptor (D5R) is a Gαs-coupled dopamine receptor belonging to the dopamine D1-like receptor family
The expression ratio of these receptors differs in cell types: The D1 receptor is present in all direct pathway spiny projection neurons but the D5R is not expressed
Since no data exist about the involvement of the D5 receptor in Parkinson’s disease (PD) and L-DOPA-induced dyskinesia (LID), we first wanted to investigate if its striatal expression is altered in response to dopamine depletion and to chronic L-DOPA in the unilateral 6-OHDA PD model
Summary
The dopamine D5 receptor (D5R) is a Gαs-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 is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. 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. The spiny neurons that project directly to the basal ganglia output nuclei are termed ‘direct pathway’ or dSPNs and express D1 receptor (D1R), that signals via the G proteins Gαs/Gαolf to PKA and enhances cAMP production. Memory assessing paradigms (Morris water maze, and cued and contextual fear conditioning) are not altered[17,21], when probed more thoroughly, such as for example in a paired-trial T-maze test and a temporal order object recognition task, the KO mice exhibited reduced performance[22]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
