α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.

The poor norepinephrine innervation and high density of Gi/o-coupled α2A- and α2C-adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D2-like receptor ligands, such as the D3 receptor agonist 7-OH-PIPAT and the D4 receptor agonist RO-105824, to α2-adrenoceptors in cortical and striatal tissue, which express α2A-adrenoceptors and both α2A- and α2C-adrenoceptors, respectively. The affinity of dopamine for α2-adrenoceptors was found to be similar to that for D1-like and D2-like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α2A- and α2C-adrenoceptors. Their ability to activate Gi/o proteins through α2A- and α2C-adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α2-adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α2A- and α2C-adrenoceptors was nearly identical to its binding to the crystallized D3 receptor. Therefore, we provide conclusive evidence that α2A- and α2C-adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D2-like receptor ligands, which calls for revisiting previous studies with those ligands.