Dopamine D3 Receptor Modulates l-DOPA-Induced Dyskinesia by Targeting D1 Receptor-Mediated Striatal Signaling

Abstract

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.

Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation

“…The direct MSN constitutes the direct efferent pathway and expresses D1R and D3R, which can potentially form D1R-D3R heteromers [63, 65]. D3R has a lower striatal expression than D1R, but it upregulates in animal models of L-dopa-induced dyskinesia and psychostimulants abuse [91, 92]. Significantly, striatal D3R have also been reported to upregulate in cocaine- and methamphetamine-dependent subjects [86, 93] and D1R-D3R heteromers have been suggested to play a main pathogenetic role in these disorders [94].…”

Current drug treatments targeting dopamine D3 receptor

“…Worthy of note, L-DOPA treatment increases D3R expression more in D1R-than in D2R-containing striatal neurons, supporting the notion that the D3R directly interacts with the D1R in the control of LID (Solis et al, 2015). A number of studies tried to modify LID by using D2R/D3R/D4R ligands.…”

“…A number of studies tried to modify LID by using D2R/D3R/D4R ligands. In some animal studies, D3R blockade seems effective in decreasing LID (Solis et al, 2015;Visanji et al, 2009), but others do not observe the same effect (Mela et al, 2010). This apparent discrepancy may be due to the selectivity of compounds used to target D3R; indeed, they bind to all D2R-like receptors (D2R, D3R and D4R).…”

“…Tardive dyskinesia induced by haloperidol in nonhuman primates correlates with upregulated D3R in striatum (Mahmoudi et al, 2014); moreover, lentiviralinduced D3R overexpression in the dorsal striatum leads to the appearance of dyskinetic behavior (Cote et al, 2014). On the other hand, genetic deletion of the D3R decreases LID without interfering with the antiparkinsonian effect of L-DOPA (Solis et al, 2015), while striatal injection of oligonucleotides antisense targeting D3R blocks the behavioral sensitization to the A C C E P T E D M A N U S C R I P T…”

“…that dyskinesia induced by L-DOPA or DR agonists is characterized by D3R upregulation in striatum (Solis et al, 2015). Table S2 reports clinical trials currently running or recently completed regarding buspirone in different CNS diseases.…”