Characterization of D3 Dopamine Receptor Agonist-Dependent Tolerance Property

Abstract

Among dopamine receptors, the signaling function of D3 dopamine receptor subtype has been particularly difficult to study in vivo. In vivo signaling studies are hampered by the limited expression profile of the D3 receptor and lack of selective ligands. We and others have extensively characterized D3 receptor signaling in heterologous expression systems. These studies have provided insight into properties of the D3 receptor that might explain the difficulty of studying receptor function in vivo. The D3, but not the closely related D2 receptor, exhibits a tolerance property wherein repeated agonist stimulation results in a progressive decrease in signaling response. The D3 receptor also exhibits a slow response termination (SRT) property wherein the termination of D3 receptor-induced signaling response terminates very slowly following the removal of agonist. The role of these D3 dopamine receptor properties in physiology and pathophysiology is not known; however, with an understanding of the mechanisms underlying these properties, new approaches are being developed to clarify the in vivo role of D3 receptor tolerance and SRT properties. We recently showed that the D3 receptor tolerance and SRT properties are agonist dependent. In this chapter we describe tools and methods to study D3 receptor signaling function and properties in vivo. We describe the use of the drd3-EGFP reporter mouse model and novel non-tolerance causing D3 receptor agonist to study D3 receptor signaling function in vivo and the role of its signaling properties on locomotor behavior.