TY - JOUR
T1 - α2 adrenergic receptor dysregulation in depressive disorders
T2 - Implications for the neurobiology of depression and antidepressant therapy
AU - Cottingham, Christopher
AU - Wang, Qin
N1 - Funding Information:
This work has been supported by the UAB Training Program in Neurobiology of Cognition and Cognitive Disorders ( National Institutes of Health T32 grant NS061788-03 , CC) and the National Institute of Mental Health (grant MH081917 , QW).
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Antidepressant
KW - Depressive disorder
KW - Locus coeruleus
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U2 - 10.1016/j.neubiorev.2012.07.011
DO - 10.1016/j.neubiorev.2012.07.011
M3 - Review article
C2 - 22910678
AN - SCOPUS:84867607910
SN - 0149-7634
VL - 36
SP - 2214
EP - 2225
JO - Neuroscience and Biobehavioral Reviews
JF - Neuroscience and Biobehavioral Reviews
IS - 10
ER -