All ETDs from UAB

Advisory Committee Chair

Qin Wang

Advisory Committee Members

Mark O Bevensee

Xiaohua Li

Lori L McMahon

J Michael Wyss

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Depressive disorders carry relatively high lifetime risks of greater than 10%, and the antidepressant drugs used in the pharmacotherapy of these mood/cognitive disorders are among the most-prescribed pharmacological agents. However, a detailed understanding of both depressive etiology and the pharmacological mechanisms of action for antidepressant drugs remain elusive. The overall goal of this dissertation research is to provide novel in-sights through a detailed study of the neuropharmacology of the α2A adrenergic receptor (AR). α2ARs, as key regulators of noradrenergic neurotransmission, have been broadly understood to have some ill-defined role in both the neurobiology and neuropharmacology of depressive disorders. The studies contained within this dissertation have been aimed at investigating the role of the α2AAR in antidepressant neuropharmacology, focusing on the tricyclic antidepressant drug desipramine (DMI) as a model compound. I have studied the actions of DMI at the α2AAR on several levels. First, I have demonstrated that the in vivo antidepressant behavioral effects of DMI in the rodent forced swim test model are dependent on α2AARs (Cottingham et al., 2012, Neuropharmacology, doi:10.1016/j.neuropharm.2012.02.011). Further, this study has indicated that DMI achieves these antidepressant effects through direct engagement of the α2AAR and arrestin, with reciprocal regulation by the dendritic protein spinophilin. Secondly, I have characterized the pharmacological and functional properties of the interaction of DMI with the α2AAR (Cottingham et al., J. Biol. Chem. 286: 36063-75), finding DMI to be the first example of an arrestin-biased ligand at the α2AAR. This interaction does not drive receptor signaling, but rather arrestin-dependent downregulation of central receptors with chronic DMI exposure in vitro and in vivo. These data provide extremely novel insight into previously unexplained neuroadaptive changes in receptor expression associated with antidepressant drugs. Finally, my findings on modulation of endogenous agonist-induced α2AAR signaling by DMI provide evidence that has implications for both the depressive role of α2AARs and the molecular pharmacology of these physiologically important receptors (Cottingham et al., BBRC, doi:10.1016/j.bbrc.02.2012.135). Overall, my findings have validated the importance of the α2AAR in depressive disorders, and identified direct biased targeting of the receptor and its interacting regulators as a novel therapeutic antidepressant strategy.

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