Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning
Barlow, Rebecca L
Nature Publishing Group
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Barlow, R. L., Alsiö, J., Jupp, B., Rabinovich, R., Shrestha, S., Roberts, A., Robbins, T., & et al. (2015). Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning. Neuropsychopharmacology, 40 1619-1630. https://doi.org/10.1038/npp.2014.335
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-hydroxyindoleacetic 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 raphe´ 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.
serotonin, dopamine, striatum, perseveration, monoamine oxidase, tryptophan hydroxylase
This work was supported by Medical Research Council Grants (G0701500; G0802729), a 503 Wellcome Trust Programme Grant (grant number 089589/Z/09/Z), and by a Core Award 504 from the Medical Research Council and the Wellcome Trust to the Behavioural and Clinical 505 21 Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z). RLB was supported 506 by a studentship from the Medical Research Council. JA was supported by a Fellowship from 507 the Swedish Research Council (350-2012-230). BJ was supported by Fellowships from the 508 AXA Research Fund and the National Health and Medical Research Council of Australia. 509 Financial support from the Fredrik and Ingrid Thuring Foundation is also acknowledged.
MEDICAL RESEARCH COUNCIL (G0001354)
Wellcome Trust (089589/Z/09/Z)
Wellcome Trust (093875/Z/10/Z)
WELLCOME TRUST (104631/Z/14/Z)
External DOI: https://doi.org/10.1038/npp.2014.335
This record's URL: https://www.repository.cam.ac.uk/handle/1810/246930