Dopamine Type-1 Receptor Binding in Major Depressive Disorder Assessed using Positron Emission Tomography and [(11)C]NNC-112

INTRODUCTION: The dopamine-type-1 receptor has been implicated in major depressive disorder (MDD) by clinical and preclinical evidence from neuroimaging, post-mortem and behavioral studies. To date, however, selective in vivo assessment of D(1)-receptors has been limited to the striatum in MDD-samples manifesting anger attacks. We employed the PET radioligand, [(11)C]NNC-112, to selectively assess D(1)-receptor binding in extrastriatal and striatal regions in a more generalized sample of MDD-subjects. METHODS: The [(11)C]NNC-112 nondisplaceable binding-potential (BP(ND)) was assessed using PET in 18 unmedicated, currently-depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest analysis. RESULTS: The mean D(1)-receptor BP(ND) was reduced (14%) in the left middle caudate of the MDD group relative to control group (p<0.05). Among the MDD-subjects D(1)-receptor BP(ND) in this region correlated negatively with illness duration (r= −0.53; p=0.02), and the left-to-right BP(ND) ratio correlated inversely with anhedonia ratings (r=−0.65, p=0.0040). The D(1)receptor BP(ND) was strongly lateralized in striatal regions (p<0.002 for main effects of hemisphere in accumbens area, putamen and caudate). In post hoc analyses, a group-by-hemisphere-by-gender interaction was detected in the dorsal putamen, which was accounted for by a loss of the normal asymmetry in depressed females (F=7.33,p=0.01). CONCLUSIONS: These data extended a previous finding of decreased striatal D(1)-receptor binding in an MDD-sample manifesting anger attacks to a sample selected more generally according to MDD criteria. Our data also more specifically localized this abnormality in MDD to the left middle caudate, which is the target of afferent neural projections from the orbitofrontal and anterior cingulate cortices where neuropathological changes have been reported in MDD. Finally, D(1)-receptor binding was asymmetrical across hemispheres in healthy humans, compatible with evidence that dopaminergic function in the striatum is lateralized during reward processing, voluntary movement and self-stimulation behavior.