Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8516409 | Neuropharmacology | 2018 | 11 Pages |
Abstract
Individually, D1 and D3 dopamine receptors (D1R and D3R, respectively) have been implicated in L-DOPA-induced dyskinesia (LID). Of late, direct D1R-D3R interactions have been linked to LID yet remain enigmatic. Therefore, the current research sought to characterize consequences of putative D1R-D3R interactions in dyskinesia expression and in LID-associated downstream cellular signaling. To do so, adult male Sprague-Dawley hemi-parkinsonian rats were given daily L-DOPA (6â¯mg/kg; s.c.) for 2 weeks to establish stable LID, as measured via the abnormal voluntary movements (AIMs) scale. Thereafter, rats underwent dose-response AIMs testing for the D1R agonist SKF38393 (0, 0.3, 1.0, 3.0â¯mg/kg) and the D3R agonist, PD128907 (0, 0.1, 0.3, 1.0â¯mg/kg). Each agonist dose-dependently induced dyskinesia, implicating individual receptor involvement. More importantly, when threshold doses were co-administered, rats displayed synergistic exacerbation of dyskinesia. Interestingly, this observation was not mirrored in general locomotor behaviors, highlighting a potentially dyskinesia-specific effect. To illuminate the mechanisms by which D1R-D3R co-stimulation led to in vivo synergy, levels of striatal phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) were quantified after administration of SKF38393 and/or PD128907. Combined agonist treatment synergistically drove striatal pERK1/2 expression. Together, these results support the presence of a functional, synergistic interaction between D1R and D3R that manifests both behaviorally and biochemically to drive dyskinesia in hemi-parkinsonian rats.
Keywords
D1RMFB6-OHDAALODOPACD2RLIDPLAD3RFASS.E.M.cAMPERK1/2pERK1/2Cyclic adenosine monophosphateProximity ligation assayAIMSmedial forebrain bundleParkinson's diseaseabnormal involuntary movementsstandard error of the meanDopaminedihydroxyphenylacetic acidL-DOPA-induced dyskinesiaMean absolute deviationhigh performance liquid chromatographyHPLCphosphorylated extracellular signal-regulated kinaseextracellular signal-regulated kinaseDopamine D1 receptordopamine D2 receptorDopamine D3 receptor
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Authors
Kathryn Lanza, Samantha M. Meadows, Nicole E. Chambers, Emily Nuss, Molly M. Deak, Sergi Ferré, Christopher Bishop,