The interrelationship of dopamine D2-like receptor availability in striatal and extrastriatal brain regions in healthy humans: A principal component analysis of [18F]fallypride binding

Abstract

Individual differences in dopamine D2-like receptor availability arise across all brain regions expressing D2-like receptors. However, the inter-relationships in receptor availability across brain regions are poorly understood. To address this issue, we examined the relationship between D2-like binding potential (BP ND ) across striatal and extrastriatal regions in a sample of healthy participants. PET imaging was performed with the high affinity D2/D3 ligand [ 18 F]fallypride in 45 participants. BP ND images were submitted to voxel-wise principal components analysis to determine the pattern of associations across brain regions. Individual differences in D2-like BP ND were explained by three distinguishable components. A single component explained almost all of the variance within the striatum, indicating that individual differences in receptor availability vary in a homogenous manner across the caudate, putamen, and ventral striatum. Cortical BP ND was only modestly related to striatal BP ND , and mostly loaded on a distinct component. After controlling for the general level of cortical D2-like BP ND , an inverse relationship emerged between receptor availability in the striatum and the ventral temporal and ventromedial frontal cortices, suggesting possible cross-regulation of D2-like receptors in these regions. The analysis additionally revealed evidence of: 1) a distinct component involving the midbrain and limbic areas; 2) a dissociation between BP ND in the medial and lateral temporal regions; and 3) a dissociation between BP ND in the medial/midline and lateral thalamus. In summary, individual differences in D2-like receptor availability reflect several distinct patterns. This conclusion has significant implications for neuropsychiatric models that posit global or regionally specific relationships between dopaminergic tone and behavior.

Extrastriatal dopamine D2-receptor availability in social anxiety disorder

“…Previous studies of striatal D2-R have reported no differences (Schneier et al, 2009), or lower levels in patients (Schneier et al, 2000), as compared to the present results of elevated extrastriatal D2-R availability. This apparent discrepancy is however in line with observations of low , or even inverse associations (Zald et al, 2010), between striatal and extrastriatal D2-R levels.…”

“…We hypothesized that differences would be found within brain regions highlighted in activation and blood flow studies of SAD (Freitas-Ferrari et al, 2010;Brühl et al, 2014), and subsequently selected regions of interest (ROIs) for the statistical comparison. Since the HRRT system allows for precise examination of the spatially heterogeneous distribution of D2-Rs observed in the human brain (Zald et al, 2010), a voxel-by-voxel analysis of group differences was also performed, using the combined ROIs as search volume. Since D2-R availability shows low correlations between striatal and extrastriatal regions (Zald et al, 2010;, we investigated differences in D2-R availability in both directions.…”

“…Since the HRRT system allows for precise examination of the spatially heterogeneous distribution of D2-Rs observed in the human brain (Zald et al, 2010), a voxel-by-voxel analysis of group differences was also performed, using the combined ROIs as search volume. Since D2-R availability shows low correlations between striatal and extrastriatal regions (Zald et al, 2010;, we investigated differences in D2-R availability in both directions.…”

Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment

“…Extrastriatal VOIs for the hippocampus, amygdala, and thalamus were defined using the FSL software package and a whole striatum VOI was created by combining VOIs of the caudate, putamen, and nucleus accumbens. The functional subdivisions of the striatum (Martinez et al, 2011) and midbrain (Zald et al, 2010) were defined using published guidelines. The cerebellum was selected as an appropriate reference region (Hall et al, 1994;Ishibashi et al, 2013).…”

Selectivity and activation of dopamine D3R from molecular dynamics

“…It has been revealed to be a therapeutic target for antipsychotic and antiparkinsonian drugs. High degrees of sequence identities are within the trans-membrane helices among D 2 -like receptor [2,13,16,[18][19][20][21], especially between D2R and D3R. Importantly, the near-identity of the residues inferred to form the binding site among them produces a formidable challenge to developing D3R-selective compounds with drug-like physicochemical properties.…”