The precise physiological effects of antidepressant drugs, and in particular their actions at non-monoamine transporter targets, are largely unknown. We have recently identified the tricyclic antidepressant drug desipramine (DMI) as a direct ligand at the α 2A adrenergic receptor (AR) without itself driving heterotrimeric G protein/downstream effector activation . In this study, we report our novel finding that DMI modulates α 2AAR signaling in response to the endogenous agonist norepinephrine (NE). DMI acted as a signaling potentiator, selectively enhancing NE-induced α 2AAR-mediated ERK1/2 MAPK signaling. This potentiation of ERK1/2 activation was observed as an increase in NE response sensitivity and a prolongation of the activation kinetics. DMI in a physiologically relevant ratio with NE effectively turned on ERK1/2 signaling that is lacking in response to physiological NE alone. Further, the DMI-induced ERK1/2 potentiation relied on heterotrimeric G i/o proteins and was arrestin-independent. This modulatory effect of DMI on NE signaling provides novel insight into the effects of this antidepressant drug on the noradrenergic system which it regulates, insight which enhances our understanding of the therapeutic mechanism for DMI. © 2012 Elsevier Inc.