Striatal dopamine D₂/D₃ receptors mediate response inhibition and related activity in frontostriatal neural circuitry in humans

Abstract

Impulsive behavior is thought to reflect a traitlike characteristic that can have broad consequences for an individual's success and well-being, but its neurobiological basis remains elusive. Although striatal dopamine D₂-like receptors have been linked with impulsive behavior and behavioral inhibition in rodents, a role for D₂-like receptor function in frontostriatal circuits mediating inhibitory control in humans has not been shown. We investigated this role in a study of healthy research participants who underwent positron emission tomography with the D₂/D₃ dopamine receptor ligand [¹⁸F]fallypride and BOLD fMRI while they performed the Stop-signal Task, a test of response inhibition. Striatal dopamine D₂/D₃ receptor availability was negatively correlated with speed of response inhibition (stop-signal reaction time) and positively correlated with inhibition-related fMRI activation in frontostriatal neural circuitry. Correlations involving D₂/D₃ receptor availability were strongest in the dorsal regions (caudate and putamen) of the striatum, consistent with findings of animal studies relating dopamine receptors and response inhibition. The results suggest that striatal D₂-like receptor function in humans plays a major role in the neural circuitry that mediates behavioral control, an ability that is essential for adaptive responding and is compromised in a variety of common neuropsychiatric disorders.

Figures

Figure 1.

Correlations between striatal dopamine D2/D3 receptor availability (BPND) and SSRT (n = 18). Participants who stopped more quickly showed greater D2/D3 receptor availability in caudate and putamen. A, B, Results from voxelwise nonparametric regression of BPND on SSRT. TFCE probability maps (corrected for multiple comparisons) are overlaid on the MPRAGE anatomical image. Maps show SSRT was negatively correlated with BPND in caudate and putamen but not nucleus accumbens. Voxelwise height threshold is set at p < 0.1 for illustration purposes. Images are presented in radiological orientation (right = left). C–E, Scatterplots indicating relationship between SSRT and BPND extracted from anatomically defined caudate (p = 0.02), putamen (p = 0.04), and nucleus accumbens (p = 0.47) VOIs. Because left and right BPND values were highly correlated (all r > 0.71 and all p < 0.001), volume-weighted averages of left and right values were used.

Figure 2.

Successful Stop versus Go fMRI contrast and negative correlation with SSRT. Z-statistic map for Stop versus Go is represented by hot colors, and negative correlation of Stop versus Go and SSRT is represented by cool colors. Stop versus Go activations were found in regions typically reported in fMRI studies of the task, including right inferior frontal gyrus, pre-SMA, anterior cingulate, and the insula (Table 3 for list of regions). Clusters corresponding to the negative correlation between Stop versus Go and SSRT were found in the right caudate, putamen, superior frontal gyrus, and left orbitofrontal cortex (see Table 3 for full list of regions). No regions showed significant clusters for positive correlation with SSRT. Z-statistic maps were whole-brain, cluster-corrected (voxel height threshold, Z > 1.96; cluster-forming threshold, p < 0.05). Z-statistic maps are overlaid on the group mean high-resolution anatomical image. Numbers to the side of images represent Z-coordinates in MNI standard space. Images are presented in radiological orientation (right = left).

Figure 3.

Correlations between caudate D2/D3 receptor availability (BPND) and fMRI contrast of Successful Stop versus Go (n = 18). Participants with greater caudate receptor D2/D3 receptor availability had greater activation in frontostriatal brain regions. Image shows Z-statistic map thresholded at Z > 1.96 (whole-brain, cluster-corrected threshold of p < 0.05) overlaid on the mean, spatially normalized anatomical image. A, C, D, Bilateral caudate (A), right inferior frontal cortex/lateral occipital cortex (C, D), and rostral anterior cingulate/superior frontal (medial portion) (D) regions of activation (see Table 4 for full list of regions). Images are presented in radiological orientation (right = left). MNI coordinates: transverse slice, Z = 4 (A); sagittal slice, X = 50 (C); and coronal slice, Y = 34 (D). R, Right. Color bar indicates Z-statistic range. B, Scatterplot shows relationship between dopamine D2/D3 receptor availability and Successful Stop versus Go parameter estimates in anatomically defined caudate VOI (r = 0.82, p = 0.00002; without outlier: r = 0.70, p = 0.002). A weighted average of left and right caudate parameter estimates was used because the two were highly correlated (r = 0.82, p < 0.0001).