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.

Significance Statement

Lights and sounds signaling reward are used extensively in electronic gaming machines. Recent data indicate that these win-associated cues can increase disadvantageous risky choice. Administering a serotonin 2C receptor antagonist can ameliorate this effect in rats, potentially by increasing flexibility in decision-making. The orbitofrontal cortex (OFC) is critically involved in mediating flexible behavior. Thus, the present study evaluated whether serotonin 2C antagonism in the OFC can reduce disadvantageous risky choice via alterations to behavioral flexibility. Results implicate the OFC as one critical locus, and an increase in flexibility as a potential cognitive mechanism, through which cue-enhanced risky decision-making may improve. This could point to potential therapeutic interventions for problematic gambling that target the control of cues over behavior.