title: Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning.
abstract: Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid- and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low- vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Barlow
authors.affiliation: 1] Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK [2] Department of Neuroscience, University of Uppsala, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Alsiö
authors.affiliation: 1] Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK [2] Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Bianca
authors.initials: B
authors.lastname: Jupp
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rabinovich
authors.affiliation: NIMH, IRP, Bethesda, MD, USA.
authors.forename: Saurav
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: 1] Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK [2] Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Roberts
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: 1] Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK [2] Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Dalley
mesh_terms: D000818:Animals; D015283:Citalopram / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects / Q000502:physiology*; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D008297:Male; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012054:Reinforcement, Psychology; D012193:Reversal Learning / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013028:Space Perception / Q000187:drug effects / Q000502:physiology*; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D015283:Citalopram; D008995:Monoamine Oxidase; D010879:Piperazines; D012333:RNA, Messenger; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014365:Tryptophan Hydroxylase; C043425:vanoxerine; C504569:tph2 protein, rat