Dopamine type-1 receptor binding in major depressive disorder assessed using positron emission tomography and [11C]NNC-112

Abstract

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. 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. 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 women (F=7.33, p=0.01). 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.

Figure 1. Dopamine-D₁ receptor binding potential in healthy control and MDD groups in the left and right hemispheres for the striatal regions-of-interest

*p<0.05: D₁-receptor binding was significantly lower in the left middle caudate (MC) in the MDD group relative to control group. **p<0.05, ***p<0.001: The main effect of hemisphere on BP_ND was significant in the anteroventral striatum (AVS), ventral putamen (VP), dorsal putamen (DP), middle caudate (MC), and dorsal caudate (DC) regions-of-interest

Figure 2. Representative parametric dopamine-D₁ receptor BP_ND images through the striatum in a control subject (left panel) and an MDD subject (right panel)

Within each panel the upper row of images show axial (left) and coronal (right) sections through the anatomical MRI, on which the regions-of-interest (ROI) were defined (Drevets et al. 2001), and the lower row of images show parametric images of the non-displaceable component of the D₁-recetor binding potential (BP_ND) modeled from PET emission images. The MRI and PET images for each subject are co-registered. The axial images show the plane containing both the anterior and posterior commissures. The orthogonal lines locate approximately the center of the caudate head on this bi-commissural plane. The coronal sections pass through the anterior striatum, which at the level shown is composed predominantly of the caudate head. The middle caudate region is evident in the coronal sections, where it is situated immediately above the bicommissural plane (marked by the horizontal line). The D₁-receptor BP_ND consistently was higher in the right caudate than the left in both groups (see figure 1, figure 3), as evinced in these representative images. The mean BP_ND value in the left middle caudate of the MDD group was lower than in the control group (figure 1).

Figure 3. Dopamine-D₁ receptor binding potential in the left and right hemispheres for each striatal region-of-interest showing the consistency of laterality effects. The left- and right-sided values corresponding to a single participant are connected by a line

Main effects of hemisphere on regional binding potentials were significant in all five regions-of-interest (see figure 1 and results section for significance levels).

Figure 4. Relationship between dopamine-D₁ receptor binding potential in the left middle caudate and illness duration in the MDD sample

The D₁-receptor binding potential in the left middle caudate correlated inversely (r=−0.531, p=0.02) with illness duration (calculated as time since illness onset).

Figure 5. Relationships between age and D₁-receptor BP_ND in the middle caudate and ventral putamen for all subjects

Age correlated negatively with [¹¹C]NNC-112 BP_ND in the middle caudate, ventral putamen, and most of other striatal regions examined (ρ=−0.33 to −0.42, p=0.01 to 0.04; see text).

Figure 6. Mean (+/− SEM) binding potential values for the right and left dorsal putamen separated by sex and diagnosis. In females with MDD the difference in D₁-receptor BP_ND between the right and left hemispheres of the dorsal putamen was significantly less than that of the female controls

In the dorsal putamen the group-by-gender-by-hemisphere interaction was significant (F=7.33, p=0.011). Abbreviations: HC, healthy control; MDD, major depressive disorder.