title: Regional and source-based patterns of [11C]-(+)-PHNO binding potential reveal concurrent alterations in dopamine D2and D3receptor availability in cocaine-use disorder.
abstract: Dopamine type 2 and type 3 receptors (D2R/D3R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2R availability and greater D3R availability in regions primarily expressing D2R or D3R concentrations, respectively. However, these CUD-related alterations in D2R and D3R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2R/D3R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2R and D3R availability using regional and source-based analyses of [11C]-(+)-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 [11C]-(+)-PHNO research, and lower BPNDin CUD in the dorsal striatum, consistent with research using non-selective D2R/D3R 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 D2R-related proportions of BPND(calculated using independent reports of [11C]-(+)-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 D3R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2R/D3R research in CUD, demonstrating both lower BPNDin the D2R-rich dorsal striatum and greater BPNDin the D3R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11C]-(+)-PHNO BPNDthat were correlated with regional estimates of D2R-related and D3R-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 D2R/D3R concentration.
authors.affiliation: Department of Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. Electronic address: patrick.worhunsky@yale.edu.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Worhunsky
authors.affiliation: Department of Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
authors.forename: David
authors.initials: D
authors.lastname: Matuskey
authors.affiliation: Department of Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Gallezot
authors.affiliation: Department of Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Gaiser
authors.affiliation: Department of Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Angarita
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Electrical & Computer Engineering, University of New Mexico, Albuquerque, NM, USA; The Mind Research Network, Albuquerque, NM, USA.
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Malison
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Child Study Center, Yale School of Medicine, New Haven, CT, USA; Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA; National Center on Addiction and Substance Abuse, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Marc N
authors.initials: MN
authors.lastname: Potenza
authors.affiliation: Department of Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001931:Brain Mapping; D019970:Cocaine-Related Disorders / Q000000981:diagnostic imaging* / Q000378:metabolism; D018450:Disease Progression; D015259:Dopamine Agents / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D010078:Oxazines / Q000378:metabolism* / Q000494:pharmacology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000187:drug effects / Q000378:metabolism*
chemical_list: C581293:DRD2 protein, human; C493593:DRD3 protein, human; D015259:Dopamine Agents; D010078:Oxazines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C042631:naxagolide
keywords: Addiction; Cocaine use disorder; Dopamine; Independent component analysis; Striatum; [(11)C]-(+)-PHNO