title: Orbitofrontal dopamine depletion upregulates caudate dopamine and alters behavior via changes in reinforcement sensitivity.
abstract: Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia.
authors.affiliation: Departments of Physiology, Development and Neuroscience, Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom, hfc23@cam.ac.uk.
authors.forename: H F
authors.initials: HF
authors.lastname: Clarke
authors.affiliation: Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom, Department of Psychiatry and Liaison Psychiatry Service, Cambridge and Peterborough NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom.
authors.forename: R N
authors.initials: RN
authors.lastname: Cardinal
authors.affiliation: Psychology, and Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Rygula
authors.affiliation: Wolfson Brain Imaging Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom, and.
authors.forename: Y T
authors.initials: YT
authors.lastname: Hong
authors.affiliation: Wolfson Brain Imaging Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom, and.
authors.forename: T D
authors.initials: TD
authors.lastname: Fryer
authors.affiliation: Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom, Wolfson Brain Imaging Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom, and.
authors.forename: S J
authors.initials: SJ
authors.lastname: Sawiak
authors.affiliation: Wolfson Brain Imaging Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom, and.
authors.forename: V
authors.initials: V
authors.lastname: Ferrari
authors.affiliation: Departments of Physiology, Development and Neuroscience, Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
authors.forename: G
authors.initials: G
authors.lastname: Cockcroft
authors.affiliation: Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom, Wolfson Brain Imaging Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom, and.
authors.forename: F I
authors.initials: FI
authors.lastname: Aigbirhio
authors.affiliation: Psychology, and Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
authors.forename: T W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: Departments of Physiology, Development and Neuroscience, Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
authors.forename: A C
authors.initials: AC
authors.lastname: Roberts
mesh_terms: D000818:Animals; D002144:Callithrix; D002421:Caudate Nucleus / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D007858:Learning / Q000502:physiology*; D008297:Male; D012054:Reinforcement, Psychology; D015854:Up-Regulation / Q000235:genetics* / Q000502:physiology
chemical_list: D004298:Dopamine
keywords: PET; behavior; caudate nucleus; dopamine; orbitofrontal cortex; schizophrenia