Behavioral and cellular dopamine D1 and D3 receptor-mediated synergy: Implications for L-DOPA-induced dyskinesia

NEUROPHARMACOLOGY

卷:138

Article

Lanza, Kathryn¹  Meadows, Samantha M.¹  Chambers, Nicole E.¹  Nuss, Emily¹  Deak, Molly M.¹  Ferre, Sergi²  Bishop, Christopher¹ 

[1] SUNY Binghamton, Dept Psychol, Behav Neurosci Program, 4400 Vestal Pkwy East, Binghamton, NY 13902 USA

[2] NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, 251 Bayview Blvd 200, Baltimore, MD 21224 USA

关键词: Parkinson's disease;    L-DOPA-Induced dyskinesia;    Abnormal involuntary movements;    D1R-D3R interactions;   

DOI  :  10.1016/j.neuropharm.2018.06.024

来源: Elsevier

【 摘 要 】

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 (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 D1R agonist SKF38393 (0, 0.3,1.0, 3.0 mg/kg) and the D3R 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 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. (C) 2018 Elsevier Ltd. All rights reserved.

【 授权许可】

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