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 α₂ 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 α₂ARs 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 α₂ARs in depression. In particular, the pharmacological properties of the radioligand (e.g. agonist versus antagonist) utilized for determining receptor density are crucial in determining study outcome. Upregulation of α₂AR 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 α₂ARs, which is indicative of enhanced G protein coupling to the receptor. Importantly, this high-affinity state α₂AR upregulation can be normalized with antidepressant treatments. Thus, depressive disorders appear to be associated with increased α₂AR 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 α₂AR accessory proteins in depressive disorders and discuss their potential contribution to α₂AR dysfunction.