Serotonin 2C Antagonism in the Lateral Orbitofrontal Cortex Ameliorates Cue-Enhanced Risk Preference and Restores Sensitivity to Reinforcer Devaluation in Male Rats

Abstract

Previous research has indicated that reward-paired cues can enhance disadvantageous risky choice in both humans and rodents. Systemic administration of a serotonin 2C receptor antagonist can attenuate this cue-induced risk preference in rats. However, the neurocognitive mechanisms mediating this effect are currently unknown. We therefore assessed whether the serotonin 2C receptor antagonist RS 102221 is able to attenuate cue-enhanced risk preference via its actions in the lateral orbitofrontal cortex (lOFC) or prelimbic (PrL) area of the medial prefrontal cortex (mPFC). A total of 32 male Long–Evans rats were trained on the cued version of the rat gambling task (rGT), a rodent analog of the human Iowa gambling task, and bilateral guide cannulae were implanted into the lOFC or PrL. Intra-lOFC infusions of the 5-HT 2C antagonist RS 102221 reduced risky choice in animals that showed a preference for the risky options of the rGT at baseline. This effect was not observed in optimal decision-makers, nor those that received infusions targeting the PrL. Given prior data showing that 5-HT 2C antagonists also improve reversal learning through the same neural locus, we hypothesized that reward-concurrent cues may amplify risky decision-making through cognitive inflexibility. We therefore devalued the sugar pellet rewards used in the cued rGT (crGT) through satiation and observed that decision-making patterns did not shift unless animals also received intra-lOFC RS 102221. Collectively, these data suggest that the lOFC is one critical site through which reward-concurrent cues promote risky choice patterns that are insensitive to reinforcer devaluation, and that 5-HT 2C antagonism may optimize choice by facilitating exploration.

Audiovisual cues must be predictable and win-paired to drive risky choice

“…While differences in reinforcer devaluation tests in risky versus optimal rats have not been previously observed on the rGT, the cohort sizes of the present study far exceed previous reports, which may have been underpowered to detect such differences. The results from risk-preferring rats corroborate previous studies demonstrating that rats trained on the uncued task are sensitive to this manipulation, whereas rats trained on the cued task are not (Zeeb & Winstanley, 2013; Hathaway et al, 2021). This could be due to either enhanced habit formation or hypoactive, or otherwise maladaptive, goal-directed control.…”

“…This could be due to either enhanced habit formation or hypoactive, or otherwise maladaptive, goal-directed control. Altering serotonergic signaling in the lateral orbitofrontal cortex (OFC) can restore sensitivity to reinforcer devaluation in rats trained on the cued rGT, indicating that prefrontal cortices, and presumably impaired goal-directed control, play a role in inflexibility induced by reward-paired cues (Hathaway et al, 2021). Indeed, given the role of the lateral OFC in updating stored action-outcome contingencies, cue-guided learning, and in the acquisition of uncued rGT (Izquierdo, 2017; Amodeo et al, 2017, Zeeb & Winstanley, 2011), this region could be mediating both the differential processing of rewards and punishments across different variants of the rGT and cue-induced inflexibility.…”

“…A similar effect of reward-paired cues on risky decision making has been observed in humans (Cherkasova et al, 2018). Such cues also appear to lead to inflexibility in decision-making patterns, as indicated by insensitivity to reinforcer devaluation in the cued but not the uncued rGT (Hathaway et al, 2021; Zeeb & Winstanley, 2013).…”

Dopamine activity in the nigrostriatal pathway alters cue‐induced risky choice patterns in female rats

“…We also note that decision-making effects were constrained to a subset of rats that preferred the risky options by the end of training, whereas reduced premature responding was apparent in all rats, further suggesting that different mechanisms are at play. Indeed, other studies have demonstrated that the neural mechanisms of risky choice and motor impulsivity can be dissociated on the rGT (Barrus & Winstanley, 2016;Betts et al, 2021;Chernoff et al, 2021;Hathaway et al, 2021). By contrast, others have found that denervation of this pathway can impair response inhibition when the time required to withhold responses is 20 s (Engeln et al, 2016).…”

“…Recent evidence suggests that choice patterns on the cued rGT, at least in males, are less goal-directed than choice on the uncued rGT (Hathaway et al, 2021). More specifically, choice is insensitive to reinforcer devaluation when rats are trained on cue-outcome schedules that promote risky choice.…”