Abstract
Dopamine type 2 and type 3 receptors (D(2)R/D(3)R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D(2)R availability and greater D(3)R availability in regions primarily expressing D(2)R or D(3)R concentrations, respectively. However, these CUD-related alterations in D(2)R and D(3)R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D(2)R/D(3)R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D(2)R and D(3)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 (BP(ND)) in CUD in the midbrain, consistent with prior [(11)C]-(+)-PHNO research, and lower BP(ND) in CUD in the dorsal striatum, consistent with research using non-selective D(2)R/D(3)R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BP(ND) (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 D(2)R-related proportions of BP(ND) (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 D(3)R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D(2)R/D(3)R research in CUD, demonstrating both lower BP(ND) in the D(2)R-rich dorsal striatum and greater BP(ND) in the D(3)R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [(11)C]-(+)-PHNO BP(ND) that were correlated with regional estimates of D(2)R-related and D(3)R-related proportions of BP(ND), were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D(2)R/D(3)R concentration.