title: Noradrenergic antidepressant responses to desipramine in vivo are reciprocally regulated by arrestin3 and spinophilin.
abstract: Many antidepressant drugs, including the tricyclic antidepressant desipramine (DMI), are broadly understood to function by modulating central noradrenergic neurotransmission. α(2) adrenergic receptors (α(2)ARs) are key regulators of the noradrenergic system, and previous work has implicated α(2)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(2)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(2)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(2A)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(2A)AR-mediated response is reciprocally regulated by arrestin and spinophilin. The characteristic of α(2A)AR-dependence and arrestin3 involvement was shared by the antidepressant effect of the classic α(2)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(2A)AR and arrestin3. Our results implicate arrestin- and spinophilin-mediated regulation of the α(2A)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.
authors.affiliation: Department of Physiology & Biophysics, University of Alabama at Birmingham, 986 MCLM 1918 University Blvd., Birmingham, AL 35294, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cottingham
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects / Q000502:physiology*; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019390:Arrestins / Q000502:physiology*; D003891:Desipramine / Q000494:pharmacology*; D007103:Immobilization / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D013550:Swimming / Q000502:physiology; D000099273:Neurabins
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D019390:Arrestins; D003891:Desipramine; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D018341:Receptors, Adrenergic, alpha-2; D000099273:Neurabins; C082333:arrestin3