α2 adrenergic receptor dysregulation in depressive disorders: Implications for the neurobiology of depression and antidepressant therapy

Dysfunction in noradrenergic neurotransmission has long been theorized to occur in depressive disorders. The alpha(2) adrenergic receptor (AR) family, as a group of key players in regulating the noradrenergic system, has been investigated for involvement in the neurobiology of depression and mechanisms of antidepressant therapies. However, a clear picture of the alpha(2)ARs in depressive disorders has not been established due to the existence of apparently conflicting findings in the literature. In this article, we report that a careful accounting of methodological differences within the literature can resolve the present lack of consensus on involvement of alpha(2)ARs in depression. In particular, the pharmacological properties of the radio-ligand (e.g. agonist versus antagonist) utilized for determining receptor density are crucial in determining study outcome. Upregulation of alpha(2)AR density detected by radiolabeled agonists but not by antagonists in patients with depressive disorders suggests a selective increase in the density of high-affinity conformational state alpha(2)ARs, which is indicative of enhanced G protein coupling to the receptor. Importantly, this high-affinity state alpha(2)AR upregulation can be normalized with antidepressant treatments. Thus, depressive disorders appear to be associated with increased alpha(2)AR sensitivity and responsiveness, which may represent a physiological basis for the putative noradrenergic dysfunction in depressive disorders. In addition, we review changes in some key alpha(2)AR accessory proteins in depressive disorders and discuss their potential contribution to alpha(2)AR dysfunction. (C) 2012 Elsevier Ltd. All rights reserved.