Characterization of D3 dopamine receptor signaling in a PD mouse model

Abstract

The dopamine D3 receptor is known to couple to many signal transduction pathways and has been implicated in Parkinson's disease (PD). The D3 receptor exhibits a tolerance property wherein repeated stimulation elicits a progressively decreasing response. In vitro studies have shown that among others, the tolerance is observed in the D3 receptor‐Mitogen Activated Protein Kinase (MAPK) signal transduction pathway. PD patients on chronic levodopa treatment develop Levodopa Induced Dyskinesia (LID). In this study our objective was to test whether the D3 tolerance property exists in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of PD. Drd3‐EGFP mice that report the expression of endogenous D3 receptor were used in this study. D3 receptor induced activation of the MAPK kinase pathway was determined in the striatum of control mice or mice treated chronically with levodopa, MPTP or MPTP + levodopa. MPTP treated mice exhibited increased MAPK phosphorylation when challenged with a D3 selective dose of PD128907. However, the MPTP group chronically treated with L‐dopa showed a decrease in phospho‐MAPK after administration of PD128907. These results suggest that in the mouse PD model chronically treated with levodopa, the tolerance property of D3 receptor might be involved.Supported by: Parkinson's Disease Foundation, NIH (MH82376) and the FM Kirby foundation grants