α₂ adrenergic receptor trafficking as a therapeutic target in antidepressant drug action

Antidepressant drugs remain poorly understood, especially with respect to pharmacological mechanisms of action. This lack of knowledge results from the extreme complexity inherent to psychopharmacology, as well as to a corresponding lack of knowledge regarding depressive disorder pathophysiology. While the final analysis is likely to be multifactorial and heterogeneous, compelling evidence exists for upregulation of brain α₂ adrenergic receptors (ARs) in depressed patients. This evidence has sparked a line of research into actions of a particular antidepressant drug class, the tricyclic antidepressants (TCAs), as direct ligands at α_2AARs. Our findings, as outlined herein, demonstrate that TCAs function as arrestin-biased ligands at α_2AARs. Importantly, TCA-induced α_2AAR/arrestin recruitment leads to receptor endocytosis and downregulation of α_2AAR expression with prolonged exposure. These findings represent a novel mechanism linking α₂AR trafficking with antidepressant pharmacology.