Noradrenergic antidepressant responses to desipramine in vivo are reciprocally regulated by arrestin3 and spinophilin

Academic Article

Abstract

  • Many antidepressant drugs, including the tricyclic antidepressant desipramine (DMI), are broadly understood to function by modulating central noradrenergic neurotransmission. α adrenergic receptors (α ARs) are key regulators of the noradrenergic system, and previous work has implicated α ARs in mediating the antidepressant activity of DMI in the rodent forced swim test (FST). However, little is known about intracellular regulators of antidepressant drug action. α AR function is tightly regulated by its intracellular interacting partners arrestin and the dendritic protein spinophilin. We have previously established the competitive and reciprocal nature of these interacting proteins at the α AR in the context of classic agonist effects, and have shown DMI to be a direct arrestin-biased ligand at the receptor. In the present study, we report that mice deficient in the α AR subtype lack DMI-induced antidepressant behavioral effects in the FST. As well, mice deficient in arrestin3 lack antidepressant response to DMI, while spinophilin-null mice have enhanced antidepressant response to DMI compared with wild-type controls, indicating that this α AR-mediated response is reciprocally regulated by arrestin and spinophilin. The characteristic of α AR-dependence and arrestin3 involvement was shared by the antidepressant effect of the classic α AR agonist clonidine but not the non-tricyclic norepinephrine reuptake inhibitor reboxetine, supporting a model whereby DMI exerts its antidepressant effect through direct engagement of the α AR and arrestin3. Our results implicate arrestin- and spinophilin-mediated regulation of the α AR in the pharmacology of the noradrenergic antidepressant DMI, and suggest that manipulation of this mode of receptor regulation may represent a novel and viable therapeutic strategy. © 2011 Elsevier Ltd. All rights reserved. 2 2 2 2 2 2A 2A 2A 2 2A 2A
  • Authors

    Published In

  • Neuropharmacology  Journal
  • Digital Object Identifier (doi)

    Author List

  • Cottingham C; Li X; Wang Q
  • Start Page

  • 2354
  • End Page

  • 2362
  • Volume

  • 62
  • Issue

  • 7