Effects of a α_2C-adrenoreceptor gene polymorphism on neural responses to facial expressions in depression

Alterations in processing of emotionally salient information have been reported in individuals with major depressive disorder (MDD). Evidence suggests a role for noradrenaline in the regulation of a cortico-limbic-striatal circuit that has also been implicated in the pathophysiology of MDD. Herein, we studied the physiological consequences of a common coding polymorphism of the gene for the α_2C-adrenoreceptor (AR) subtype - the deletion of four consecutive amino acids at codons 322-325 of the α2C-AR (α2CDel322-325-AR) in medication-free, remitted individuals with MDD (rMDD), and healthy control subjects. After injection of 10 mCi of H ₂¹⁵O, positron emission tomography (PET) measures of neural activity were acquired while subjects were viewing unmasked sad, happy, and fearful faces. The neural responses to sad facial expressions were increased in the amygdala and decreased in the left ventral striatum in rMDD patients relative to healthy control subjects. Furthermore, we report that rMDD carriers of one or two copies of the α2CDel322-325-AR exhibit greater amygdala as well as pregenual and subgenual anterior cingulate gyrus neuronal activity in response to sad faces than healthy α2CDel322-325-AR carriers and rMDD noncarriers. These results suggest that the α2CDel322-325-AR confers a change in brain function implicating this α2-AR subtype into the pathophysiology of MDD.