Dopamine D3 Receptor Modulates l-DOPA-Induced Dyskinesia by Targeting D1 Receptor-Mediated Striatal Signaling.
The dopamine D3 receptor (D3R) belongs to the dopamine D2-like receptor family and is principally located in the ventral striatum. However, previous studies reported D3R overexpression in the dorsal striatum following l-DOPA treatment in parkinsonian animals. This fact has drawn attention in the importance of D3R in l-DOPA-induced dyskinesia (LID). Here, we used D3R knockout mice to assess the role of D3R in LID and rotational sensitization in the hemiparkinsonian model. Mice lacking D3R presented a reduction in dyskinesia without interfering with the antiparkinsonian l-DOPA effect and were accompanied by a reduction in the l-DOPA-induced rotations. Interestingly, deleting D3R attenuated important molecular markers in the D1R-neurons such as FosB, extracellular signal-regulated kinase, and histone-3 (H3)-activation. Colocalization studies in D1R-tomato and D2R-green fluorescent protein BAC-transgenic mice indicated that l-DOPA-induced D3R overexpression principally occurs in D1R-containing neurons although it is also present in the D2R-neurons. Moreover, D3R pharmacological blockade with PG01037 reduced dyskinesia and the molecular markers expressed in D1R-neurons. In addition, this antagonist further reduced dyskinetic symptoms in D1R heterozygous mice, indicating a direct interaction between D1R and D3R. Together, our results demonstrate that D3R modulates the development of dyskinesia by targeting D1R-mediated intracellular signaling and suggest that decreasing D3R activity may help to ameliorate LID.
Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid 28002, Spain.|CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
Oscar
O
Solís
Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid 28002, Spain.|CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
Jose Ruben
JR
Garcia-Montes
Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid 28002, Spain.
Aldo
A
González-Granillo
Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL, USA.
Ming
M
Xu
Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid 28002, Spain.|CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
Rosario
R
Moratalla
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D015259:Dopamine Agents / Q000633:toxicity*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D007980:Levodopa / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D020734:Parkinsonian Disorders / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*
D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D007980:Levodopa
Parkinson disease; abnormal involuntary movements; basal ganglia; behavioral sensitization; striatonigral