| The D1 and D3 dopamine receptors (D 1R and D3R, respectively) have been implicated in L-DOPA-induced dyskinesia (LID) but have been difficult to manipulate independently. Now, D1R-D3R interactions in the form of a heteromer have emerged as a new target in LID management. This complex has garnered support in vitro but little work has investigated how it may influence behavior and signaling in vivo. Therefore, the current research sought to characterize consequences of putative D1R-D3R. To do so, adult male Sprague-Dawley hemi-parkinsonian rats were given daily L-DOPA (6 mg/kg; s.c.) for 2 weeks to establish stable LID, measured via the abnormal voluntary movements (AIMs) scale. Thereafter, rats underwent within-subjects dose-response AIMs testing for the D1R agonist SKF38393 (vehicle, 0.3, 1.0, 3.0 mg/kg) and the D3R agonist, PD128907 (vehicle, 0.1, 0.3, 1.0 mg/kg). Each agonist induced dyskinesia individually. More importantly, when co-administered, rats displayed synergistic exacerbation of dyskinesia. This potentiation was dyskinesia specific, as agonist co-administration did not improve motor performance in the forepaw adjusting steps test. To illuminate the mechanisms by which D1R-D3R co-stimulation led to in vivo synergy, levels of striatal phosphorylated extracellular regulated kinase1/2 (pERK1/2) were quantified after administration of SKF38393 and/or PD128907. Neither agonist individually influenced pERK1/2 levels, but combined agonist treatment synergistically drove pERK1/2 expression. Together, these results support the presence of a functional, synergistic interaction between D1R and D3R that manifests both behaviorally and biochemically, further implicating the D1R-D 3R heteromer in dyskinesia. |
