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

Peter Zhukovsky,Johan Alsiö,Trevor W Robbins,Jeffrey W Dalley,Chiara Guiliano,Lucy Jenner,Bianca Jupp,Angela C Roberts,Errin Riley,Sajeed Ali,Jessica Griffiths,Jing Xia

doi:10.1007/s00213-017-4569-x

Abstract

RationaleImpairments 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.ObjectiveThe objective of the study was to investigate peripheral and central markers associated with perseverative behavior on a spatial-discrimination serial reversal learning task.MethodsRats 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).ResultsPerseveration 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.ConclusionsThese 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.

Highlights

Behavioral inflexibly is common to a range of compulsive and anxiety-related brain disorders, including addiction, obsessive-compulsive disorder (OCD), and schizophrenia (Fineberg et al 2010; Robbins et al 2012; Voon et al 2015)
monoamine oxidase-A (MAO-A) but not MAO-B inhibition resulted in pronounced increases in 5-HT A inhibition profoundly increased 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

Summary

Introduction

Behavioral inflexibly is common to a range of compulsive and anxiety-related brain disorders, including addiction, obsessive-compulsive disorder (OCD), and schizophrenia (Fineberg et al 2010; Robbins et al 2012; Voon et al 2015). Elucidating the neural and psychological mechanisms of behavioral inflexibility is important to facilitate the diagnosis and treatment of a range of mental disorders. Based on selective brain intervention studies, much is known about the neural mechanisms underlying one aspect of impaired behavioral flexibility, namely excessive perseveration. Few studies have investigated the neural mechanisms of inter-individual differences in behavioral flexibility and how these relate to anxiety and other traits present in OCD and related disorders. Selective 5-HT2A and 5-HT2C receptor antagonists, respectively, impair and improve reversal learning (Boulougouris et al 2008) with the orbitofrontal cortex (OFC) an important locus for the latter beneficial effects (Boulougouris and Robbins 2010), consistent with much previous evidence implicating the OFC in reversal learning (Boulougouris et al 2007; Dias et al 1996; Schoenbaum et al 2009; Stalnaker et al 2009). 5-HT in this region is hypothesized to inhibit actions to previously rewarded stimuli when aversive or negative outcomes are expected (Cools et al 2011; Roberts 2011)

Methods

Results

Conclusion