Effect of D3 Dopamine Receptor Signaling Properties on Rodent Locomotion

The dopaminergic system is known to be involved in locomotion, and has been implicated in Parkinson's disease. The D3 dopamine receptor (D3R) exhibits a tolerance property wherein repeated agonist stimulation elicits a progressively decreasing response. In vitro studies have shown that among others, the tolerance property is observed in the D3R‐Mitogen Activated Protein Kinase (MAPK) signal transduction pathway. Previous in vitro and computer modeling studies have shown that D3R tolerance is agonist dependent. However, it is not known if these tolerance and non‐tolerance inducing D3R agonists elicit different effects in vivo . In this study our objective was to test whether the D3R tolerance property affects rodent locomotion, since it is known that D3R stimulation leads to a decrease in locomotor activity (LMA). Drd3‐ EGFP mice that report expression of endogenous D3R were administered one or multiple doses of tolerance causing (PD128907) or non‐tolerance causing (ES609) agonists and LMA measured. D3R‐induced activation of MAPK signaling was also determined. Mice administered ES609 exhibited decreased LMA after each administration. In contrast, while mice administered a single dose of PD128907 showed decreased LMA, a second administration did not significantly reduce LMA. At the signaling level, D3R‐MAPK tolerance occurred in mice administered multiple doses of PD128907 but not ES609. Immunohistochemical analyses of Drd3‐EGFP brain slices from mice administered ES609 or PD128907 showed that the tolerance‐induced changes in phosphorylated MAPK occur in D3R positive cells and their post‐synaptic targets. These results suggest that agonists that modulate D3R tolerance property have distinct signaling and behavioral effects in vivo .