Regional and source-based patterns of [ 11 C]-(+)-PHNO binding potential reveal concurrent alterations in dopamine D 2 and D 3 receptor availability in cocaine-use disorder.

Dopamine type 2 and type 3 receptors (D2 R/D3 R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2 R availability and greater D3 R availability in regions primarily expressing D2 R or D3 R concentrations, respectively. However, these CUD-related alterations in D2 R and D3 R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2 R/D3 R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2 R and D3 R availability using regional and source-based analyses of [11 C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BPND ) in CUD in the midbrain, consistent with prior [11 C]-(+)-PHNO research, and lower BPND in CUD in the dorsal striatum, consistent with research using non-selective D2 R/D3 R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BPND (striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D2 R-related proportions of BPND (calculated using independent reports of [11 C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D3 R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2 R/D3 R research in CUD, demonstrating both lower BPND in the D2 R-rich dorsal striatum and greater BPND in the D3 R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11 C]-(+)-PHNO BPND that were correlated with regional estimates of D2 R-related and D3 R-related proportions of BPND , were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D2 R/D3 R concentration.