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Noradrenergic regulation of cue-guided decision making and impulsivity is doubly dissociable across frontal brain regions.

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Peer-reviewed

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Authors

Hynes, Tristan J 
Schumacher, Jackson D 
Ramaiah, Shrishti 
Avramidis, Dimitrios K 

Abstract

RATIONALE: Win-paired stimuli can promote risk taking in experimental gambling paradigms in both rats and humans. We previously demonstrated that atomoxetine, a noradrenaline reuptake inhibitor, and guanfacine, a selective α2A adrenergic receptor agonist, reduced risk taking on the cued rat gambling task (crGT), a rodent assay of risky choice in which wins are accompanied by salient cues. Both compounds also decreased impulsive premature responding. OBJECTIVE: The key neural loci mediating these effects were unknown. The lateral orbitofrontal cortex (lOFC) and the medial prefrontal cortex (mPFC), which are highly implicated in risk assessment, action selection, and impulse control, receive dense noradrenergic innervation. We therefore infused atomoxetine and guanfacine directly into either the lOFC or prelimbic (PrL) mPFC prior to task performance. RESULTS: When infused into the lOFC, atomoxetine improved decision making score and adaptive lose-shift behaviour in males, but not in females, without altering motor impulsivity. Conversely, intra-PrL atomoxetine improved impulse control in risk preferring animals of both sexes, but did not alter decision making. Guanfacine administered into the PrL, but not lOFC, also altered motor impulsivity in all subjects, though in the opposite direction to atomoxetine. CONCLUSIONS: These data highlight a double dissociation between the behavioural effects of noradrenergic signaling across frontal regions with respect to risky choice and impulsive action. Given that the influence of noradrenergic manipulations on motor impulsivity could depend on baseline risk preference, these data also suggest that the noradrenaline system may function differently in subjects that are susceptible to the risk-promoting lure of win-associated cues.

Description

Acknowledgements: This work was supported by a Canadian Institutes of Health Research project grant awarded to CAW (PJT-162312). CSC was supported by a Canadian Graduate Scholarship- Master’s level, TJH was supported by a Marshall Graduate Scholarship, and JDS was supported by a UBC Four Year Doctoral Fellowship. This work took place at a UBC campus situated on the traditional, ancestral, and unceded land of the xʷməθkʷəy̓əm (Musqueam), sə̓lílwətaʔɬSelilwitulh (Tsleil-Waututh) and Sḵwx̱wú7mesh (Squamish) Peoples. We acknowledge and are grateful for their stewardship of this land for thousands of years.


Funder: IMH Marshall Fellows Program

Keywords

Decision making, Impulsivity, Noradrenaline, Orbitofrontal cortex, Prefrontal cortex, Prelimbic cortex, Rat gambling task, Humans, Male, Female, Rats, Animals, Atomoxetine Hydrochloride, Cues, Guanfacine, Impulsive Behavior, Norepinephrine, Brain, Prefrontal Cortex, Decision Making, Choice Behavior

Journal Title

Psychopharmacology (Berl)

Conference Name

Journal ISSN

0033-3158
1432-2072

Volume Title

241

Publisher

Springer Science and Business Media LLC
Sponsorship
Canadian Institutes of Health Research (PJT-162312)
Natural Sciences and Engineering Research Council of Canada (CGS M)
University of British Columbia Graduate School (4YF)
This work was supported by a Canadian Institutes of Health Research project grant awarded to CAW (PJT-162312). CSC was supported by a Canadian Graduate Scholarship- Master’s level, TJH was supported by a Marshall Graduate Scholarship, and JDS was supported by a UBC Four Year Doctoral Fellowship.