Dissociating the role of prefrontal noradrenaline signaling in cost-benefit decision making and impulsive action

Win-paired stimuli can promote risk taking on 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 risky choice on the cued rat gambling task (crGT), a rodent decision making task in which wins are accompanied by salient audiovisual cues. Both compounds also decreased impulsive premature responding. However, the central mechanisms behind noradrenergic regulation of cue-guided risk taking and impulsivity have not yet been elucidated. Areas of the prefrontal cortex such as the lateral orbitofrontal cortex (lOFC) and prelimbic (PrL) subregion of the medial prefrontal cortex receive dense noradrenergic innervation and are highly implicated in risk assessment, action selection and impulse control. I therefore probed the prefrontal substrates of noradrenaline’s influence over gambling-like behaviour by infusing atomoxetine and guanfacine directly into either the lOFC or PrL prior to task performance. Atomoxetine infused into the lOFC improved decision making score in male rats but did not alter decision making in females. Atomoxetine also improved impulse control when infused into the PrL, yet only in risk preferring animals. Contrastingly, intra-PrL guanfacine exacerbated motor impulsivity in all subjects. Our data reveal a double dissociation such that lOFC noradrenaline importantly guides decision making, at least in males, while PrL noradrenaline signaling regulates motor impulsivity. We also show that noradrenergic manipulations differentially influence behaviour depending on baseline risk preference, suggesting that the noradrenaline system may function differently in subjects that are susceptible to the risk-promoting lure of win cues.Medicine, Faculty ofGraduat