title: Dopamine D3 Receptor Availability Is Associated with Inflexible Decision Making.
abstract: Dopamine D2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D2, D3, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [(11)C]-(+)-PHNO was used to quantify individual differences in putative D3 receptor availability in rodents trained on a novel three-choice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [(11)C]-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [(11)C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D3-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D3 receptor in decision-making processes that are altered in psychiatric disorders.
  
  
  
  Flexible decision-making behavior is dependent upon dopamine D2/3 signaling in corticostriatal brain regions. However, the role of D3 receptors in adaptive, goal-directed behavior has not been thoroughly investigated. By combining PET imaging with the D3-preferring radioligand [(11)C]-(+)-PHNO, pharmacology, a novel three-choice probabilistic discrimination and reversal task and computational modeling of behavior in rats, we report that naturally occurring variation in [(11)C]-(+)-PHNO receptor availability relates to specific aspects of flexible decision making. We confirm these relationships using a D3-preferring agonist, thus identifying a unique role of midbrain D3 receptors in decision-making processes.
authors.affiliation: Departments of Psychiatry.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Groman
authors.affiliation: Departments of Psychiatry.
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Smith
authors.affiliation: Biomedical Engineering, and Department of Diagnostic Radiology.
authors.forename: J Ryan
authors.initials: JR
authors.lastname: Petrullli
authors.affiliation: Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06511.
authors.forename: Bart
authors.initials: B
authors.lastname: Massi
authors.affiliation: Departments of Psychiatry.
authors.forename: Lihui
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Diagnostic Radiology.
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.affiliation: Department of Diagnostic Radiology.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Neurobiology.
authors.forename: Daeyeol
authors.identifier: 0000-0003-3474-019X
authors.initials: D
authors.lastname: Lee
authors.affiliation: Departments of Psychiatry, Biomedical Engineering, and Department of Diagnostic Radiology, Positron Emission Tomography Center, and.
authors.forename: Evan D
authors.initials: ED
authors.lastname: Morris
authors.affiliation: Departments of Psychiatry, jane.taylor@yale.edu.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Taylor
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D001931:Brain Mapping; D003198:Computer Simulation; D003216:Conditioning, Operant / Q000187:drug effects; D003657:Decision Making / Q000187:drug effects / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D005508:Food Deprivation; D008297:Male; D008954:Models, Biological; D010078:Oxazines / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D012193:Reversal Learning / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D015259:Dopamine Agents; D010078:Oxazines; D050637:Receptors, Dopamine D3; C042631:naxagolide
keywords: PET; addiction; computational analyses; decision-making; dopamine D3 receptors; reinforcement learning