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

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 (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.

• Authors: Kathryn Lanza, Samantha M Meadows, Nicole E Chambers, Emily Nuss, Molly M Deak, Sergi Ferré, Christopher Bishop
• Journal: Neuropharmacology (Neuropharmacology) Vol. 138 Pg. 304-314 (08 2018) ISSN: 1873-7064 [Electronic] England
• PMID: 29936243 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antiparkinson Agents
• Benzopyrans
• Dopamine Agonists
• Drd3 protein, rat
• Oxazines
• Receptors, Dopamine D1
• Receptors, Dopamine D3
• 3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol
• Levodopa
• 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
• Oxidopamine
• Mapk1 protein, rat
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (pharmacology)
• Animals
• Antiparkinson Agents (adverse effects, pharmacology)
• Benzopyrans (pharmacology)
• Corpus Striatum (drug effects, metabolism)
• Dopamine Agonists (pharmacology)
• Dose-Response Relationship, Drug
• Dyskinesia, Drug-Induced (metabolism)
• Functional Laterality
• Levodopa (adverse effects, pharmacology)
• Male
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Motor Activity (drug effects, physiology)
• Oxazines (pharmacology)
• Oxidopamine
• Parkinsonian Disorders (drug therapy, metabolism)
• Rats, Sprague-Dawley
• Receptors, Dopamine D1 (agonists, metabolism)
• Receptors, Dopamine D3 (agonists, metabolism)