title: Perseveration in a spatial-discrimination serial reversal learning task is differentially affected by MAO-A and MAO-B inhibition and associated with reduced anxiety and peripheral serotonin levels.
abstract: Impairments in behavioral flexibility lie at the core of anxiety and obsessive-compulsive disorders. Few studies, however, have investigated the neural substrates of natural variation in behavioral flexibility and whether inflexible behavior is linked to anxiety and peripheral markers of stress and monoamine function.
  
  
  
  The objective of the study was to investigate peripheral and central markers associated with perseverative behavior on a spatial-discrimination serial reversal learning task.
  
  
  
  Rats were trained on a reversal learning task prior to blood sampling, anxiety assessment, and the behavioral evaluation of selective monoamine oxidase-A (MAO-A) and MAO-B inhibitors, which block the degradation of serotonin (5-HT), dopamine (DA), and noradrenaline (NA).
  
  
  
  Perseveration correlated positively with 5-HT levels in blood plasma and inversely with trait anxiety, as measured on the elevated plus maze. No significant relationships were found between perseveration and the stress hormone corticosterone or the 5-HT precursor tryptophan. Reversal learning was significantly improved by systemic administration of the MAO-A inhibitor moclobemide but not by the MAO-B inhibitor lazabemide. Moclobemide also increased latencies to initiate a new trial following an incorrect response suggesting a possible role in modulating behavioral inhibition to negative feedback. MAO-A but not MAO-B inhibition resulted in pronounced increases in 5-HT and NA content in the orbitofrontal cortex and dorsal raphé nuclei and increased 5-HT and DA content in the basolateral amygdala and dorsomedial striatum.
  
  
  
  These findings indicate that central and peripheral monoaminergic mechanisms underlie inter-individual variation in behavioral flexibility, which overlaps with trait anxiety and depends on functional MAO-A activity.
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Zhukovsky
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.|Department of Neuroscience, University of Uppsala, Uppsala, Sweden.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
authors.forename: Johan
authors.initials: J
authors.lastname: Alsiö
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.|Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
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.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Xia
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giuliano
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Jenner
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Griffiths
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
authors.forename: Errin
authors.initials: E
authors.lastname: Riley
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
authors.forename: Sajeed
authors.initials: S
authors.lastname: Ali
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.|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.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK. jwd20@cam.ac.uk.|Department of Psychiatry, University of Cambridge, Cambridge, UK. jwd20@cam.ac.uk.|Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK. jwd20@cam.ac.uk.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Dalley
mesh_terms: D000818:Animals; D001007:Anxiety / Q000097:blood* / Q000188:drug therapy; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology*; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008995:Monoamine Oxidase / Q000097:blood*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012193:Reversal Learning / Q000187:drug effects / Q000502:physiology*; D012691:Serial Learning / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000097:blood*; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D008996:Monoamine Oxidase Inhibitors; D012701:Serotonin; D008995:Monoamine Oxidase
keywords: Basolateral amygdala; Behavioral flexibility; Endophenotype; Lazabemide; Moclobemide; Orbitofrontal cortex; Striatum