Concurrently upregulated and downregulated D2/D3 receptor systems in cocaine use disorder using [11C]PHNO

Objectives PET imaging of dopamine type 2 and type 3 receptors (D2R/D3R) in cocaine use disorder (CUD) demonstrate lower binding potential (BPND) in the dorsal striatum using [11C]raclopride1,2, which primarily reflects D2R availability, and greater BPND in the D3R-rich midbrain using [11C]PHNO3,4, a D3R-preferring agonist. However, [11C]PHNO studies of CUD have been unable to replicate [11C]raclopride findings of reduced binding in D2R-rich dorsal striatum, where [11C]PHNO BPND largely reflects D2R availability5. The current study aimed to further investigate regional alterations in D2R/D3R availability in CUD and age- and gender-matched healthy comparison (HC) participants using [11C]PHNO.

Methods 26 recently abstinent (< 21 days) individuals with CUD and 26 HC participants completed [11C]PHNO PET scans (Siemens High Resolution Research Tomograph; HRRT) and MR imaging (Siemens 3T Trio). Dynamic PET data were reconstructed with corrections using the MOLAR algorithm. Parametric images of [11C]PHNO BPND were computed using a simple reference tissue model (SRTM2) with the cerebellum as reference, registered into standard space using unified segmentation of the MR image in SPM12 (Wellcome Trust Centre for Neuroimaging), and smoothed with a 4mm FWHM Gaussian kernel. Seven regions of interest (ROIs) were examined: dorsal caudate (DCA), dorsal putamen (DPU), globus pallidus, hypothalamus, substantia nigra (SN), ventral pallidum and ventral striatum. In addition, independent component analysis (ICA) was performed to explore D2R/D3R systems using a network-based approach. ICA is a data-driven computational procedure that identifies the component ‘sources’ comprising a measured signal, and the unique mixed-signal nature of [11C]PHNO strongly implicates the utility of mixture-separating analyses like ICA6. Repeated measures analyses were performed to examine group differences in ROI values (group x ROI) and ICA outputs (group x source).

Results There was a main effect of group across ROIs (F7,44=3.87, p=0.002), with CUD relative to HC displaying greater BPND in the SN (t50=2.91, p=0.005) and reduced BPND in the DPU (t50=2.14, p=0.037), while a group difference in the DCA did not reach significance (t50=1.79, p=0.080). Results survived correction for age-related differences in BPND. Whole-brain analysis confirmed reduced dorsal striatal and greater midbrain BPND in CUD relative to HC participants. ICA identified three sources of [11C]PHNO BPND (striatopallidal, pallidonigral, and mesoaccumbal networks) that represent systems of brain regions displaying coherent variation in receptor availability. There was a main effect of group on source intensities (an indication of a source’s relative contribution to a subject’s aggregate BPND mixture) (F3,48=4.28, p=0.009). Consistent with regional findings, CUD participants displayed reduced intensity of the striatopallidal network (t50=2.58, p=0.013) and greater intensity of the pallidonigral network (t50=2.03, p=0.047).

Conclusions The current study extends previous research of D2R/D3R availability in CUD measured with [11C]PHNO, detecting both lower BPND the dorsal striatum greater BPND in the midbrain, and demonstrates the utility of ICA in exploring concurrently upregulated and downregulated dopamine receptor systems in CUD. Research Support. NIDA: P20-DA027844 (MNP), R03-DA027456 (RTM), T32-DA022975 (PDW); NCATS: UL1 TR000142 (REC); CT-DMHAS, CASAColumbia.