Evaluation of Dopamine D3 Receptor Antagonists PG01037, PG01042, and VK4-116 Against D1R-induced Dyskinesia
Parkinson’s Disease (PD) results in motor deficits that can be relieved with L-DOPA, a dopamine (DA) replacement therapy. Unfortunately, chronic treatment often leads to L-DOPA-induced dyskinesia (LID), a debilitating side effect characterized by abnormal involuntary movements (AIMs). Overactivity of the direct striatonigral pathway is seen in LID and is characterized by potent changes in D1 and D3 receptors (D1R, D3R). Further, D1R and D3R may physically and functionally interact to form D1R-D3R heteromer thereby potentiating LID. This D1R-D3R heteromer uniquely switches from G-protein dependent to G-protein independent signaling, allowing for an avenue to manage LID. To uncover the role of these pathways in LID, Sprague-Dawley rats were rendered hemi-parkinsonian and treated daily for 2 weeks with L-DOPA (6 mg/kg; s.c.) to induce stable LID. In a within subjects, counterbalanced design, they were then split into treatment groups that received D3R antagonists: PG01037 (10, 30 mg/kg; i.p.), PG01042 (5, 10 mg/kg; i.p.), or VK4-116 (10, 20 mg/kg; i.p.). PG01037 (PG1) is a mixed D3R antagonist, acting at both the G-protein dependent and independent pathways. PG01042 (PG2) acts as an antagonist on G-protein independent signaling and VK4-116 acts as a G-protein dependent antagonist. All drugs were tested against D1R agonist-induced dyskinesia with SKF38393 (2mg/kg; s.c.). The only effects found were with PG2 which implicates promotion of the D1R G-protein dependent pathway as contributing to D1R-induced dyskinesia. Future studies with these drugs and L-DOPA treatment should unveil the importance of D1R, D3R, and D1R-D3R influences in the presence of the natural ligand DA.
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D’Almeida, Evan; Center, Ashley; Coyle, Mike; Glinski, John; Terry, Michelle; and Cohen, Sophie, "Evaluation of Dopamine D3 Receptor Antagonists PG01037, PG01042, and VK4-116 Against D1R-induced Dyskinesia" (2021). Research Days Posters 2021. 39.