© 2015 Elsevier Inc. All rights reserved. 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 α2AARs. Our findings, as outlined herein, demonstrate that TCAs function as arrestin-biased ligands at α2AARs. Importantly, TCA-induced α2AAR/arrestin recruitment leads to receptor endocytosis and downregulation of α2AAR expression with prolonged exposure. These findings represent a novel mechanism linking α2AR trafficking with antidepressant pharmacology.