Behavioral and cellular dopamine D1 and D3 receptor-mediated synergy: Implications for L-DOPA-induced dyskinesia. (August 2018)

• Record Type: Journal Article
• Authors: Lanza, Kathryn; Meadows, Samantha M.; Chambers, Nicole E.; Nuss, Emily; Deak, Molly M.; Ferré, Sergi; Bishop, Christopher
• Is Part Of: Neuropharmacology. Volume 138(2018)
• Page Start: 304
• Page End: 314
• Publication Date: 2018-08
• Subjects: Parkinson's disease -- L-DOPA-Induced dyskinesia -- Abnormal involuntary movements -- D1R-D3R interactions; DA Dopamine -- DOPAC Dihydroxyphenylacetic acid -- PD Parkinson's disease -- LID L-DOPA-Induced Dyskinesia -- D1R Dopamine D1 Receptor -- D2R Dopamine D2 Receptor -- D3R Dopamine D3 Receptor -- PLA Proximity ligation assay -- pERK1/2 phosphorylated extracellular signal-regulated kinase -- ERK1/2 Extracellular signal-regulated kinase -- cAMP cyclic adenosine monophosphate -- 6-OHDA 6-hydroxydopamine hydrobromide -- MFB Medial forebrain bundle -- AIMs Abnormal involuntary movements -- ALO Axial limb and orolingual -- FAS Forepaw adjusting steps -- HPLC High performance liquid chromatography -- M.A.D. Mean absolute deviation -- S.E.M. Standard error of the mean; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.06.024
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Individually, D1 and D3 dopamine receptors (D1 R and D3 R, respectively) have been implicated in L-DOPA-induced dyskinesia (LID). Of late, direct D1 R-D3 R interactions have been linked to LID yet remain enigmatic. Therefore, the current research sought to characterize consequences of putative D1 R-D3 R 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 (6 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 D1 R agonist SKF38393 (0, 0.3, 1.0, 3.0 mg/kg) and the D3 R agonist, PD128907 (0, 0.1, 0.3, 1.0 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 D1 R-D3 R 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 D1 R and D3 R that manifests both behaviorally and biochemically to drive dyskinesia in hemi-parkinsonian rats. Highlights: Both D1 R and D3 R agonists dose-dependently elicited dyskinesia in hemi-parkinsonian, L-DOPA primed rats. D1 R and D3 R agonist co-administration synergistically exacerbated dyskinesia expression. D1 R and D3 R agonist co-administration increased expression of extracellular signal-regulated kinase 1/2.