Sex-Specific Effects of the Atypical Antipsychotic Risperidone on Performance in a Risky Decision-making Task

Risperidone is an atypical antipsychotic that exerts widespread effects on cognitive functioning. Antipsychotics are most often administered to individuals with schizophrenia, providing relief from positive symptoms primarily through antagonism of the D₂ dopamine receptor. One behavior that is often abnormal in schizophrenia and is partially mediated by the D₂ receptor is risky decision-making. Therefore, it is critical to understand how antipsychotics impact risky decision-making in healthy subjects to disentangle the influence of schizophrenia and antipsychotics. Here, the effects of risperidone were examined in rats trained in the Risky Decision-making Task (RDT), in which subjects choose between a small, safe reward and a large reward accompanied by escalating risk of mild footshock. Both daily and acute administration of low to medium doses of risperidone induced a female-specific decrease in choice of options associated with risk, even when the risk was no longer present. High-dose risperidone reduced risky choice in both sexes, which likely reflected risk aversion in males and cognitive or motivational disruption in females. Moreover, daily risperidone caused a stark reduction in total trials completed and weight in female but not male rats. Shock threshold testing revealed that risperidone-driven avoidance of risky options was unrelated to altered shock sensitivity, but reduced responding on a progressive ratio schedule suggested that risperidone may reduce risky choice by attenuating appetitive motivation. These findings align with emerging evidence of increased sensitivity to cognitive effects of antipsychotics in females.