1. ¹Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA
2. ²National Institute of Mental Health, Section on Neuroimaging in Mood and Anxiety Disorders, Bethesda, MD, USA
3. ³Laboratory of Neurogenetics, NIAAA, Rockville, MD, USA
4. ⁴National Institute of Dental and Craniofacial Research, NICDR, Bethesda, MD, USA
5. ⁵PET Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
6. ⁶Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

Correspondence: Dr A Neumeister, Department of Psychiatry, Yale University School of Medicine, Molecular Imaging Program of the Clinical Neuroscience Division, 950 Campbell Avenue, Building 1, Room 9-174, MSC 151E, West Haven, CT 06516, USA. Tel: +1 203 932 5711 ext. 2428; Fax: +1 203 937 3481; E-mail: alexander.neumeister@yale.edu

Received 12 October 2005; Revised 14 November 2005; Accepted 15 November 2005; Published online 11 January 2006.

Abstract

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 _2C-adrenoreceptor (AR) subtype—the deletion of four consecutive amino acids at codons 322–325 of the 2C-AR (2CDel322–325-AR) in medication-free, remitted individuals with MDD (rMDD), and healthy control subjects. After injection of 10 mCi of H₂¹⁵O, 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 2CDel322–325-AR exhibit greater amygdala as well as pregenual and subgenual anterior cingulate gyrus neuronal activity in response to sad faces than healthy 2CDel322–325-AR carriers and rMDD noncarriers. These results suggest that the 2CDel322–325-AR confers a change in brain function implicating this 2-AR subtype into the pathophysiology of MDD.