5-HT3 antagonists decrease discounting rate without affecting sensitivity to reward magnitude in the delay discounting task in mice.

ABSTRACT

RATIONALE Impulsive choice has often been evaluated in rodents according to the proportion of choices for the delayed large magnitude reinforcer (%large choice) in a delay-discounting task (DDT). However, because %large choice is influenced by both sensitivity to reinforcer magnitude and sensitivity to delayed reinforcement (i.e., discounting rate), distinctively evaluating such discounting parameters represents a critical issue demanding methods to determine each parameter in rats. The serotonin (5-HT) system is well known to be involved in impulsive choice; nevertheless, only a few studies have distinguished discounting parameters and investigated how 5-HT modulators affect discounting rate. OBJECTIVE: Here, we performed a discounting parameter analysis in mice and examined the effects of various 5-HT modulators on discounting rate. METHODS: We set up DDTs with different delay schedules to determine which schedule could address delay-discounting rates in mice. We examined the effect of the following drugs on impulsive choice a 5-HT reuptake inhibitor (paroxetine), a 5-HT1A receptor agonist (8-OH-DPAT), and two 5-HT3 receptor antagonists (granisetron and ondansetron). RESULTS: Mice showed typical delay discounting at the shorter delay schedules (up to 4 s delay). The %large choice under shorter, but not longer, schedules followed an exponential function and allowed us to derive discounting rates. We selected a DDT with a 4-s delay schedule for further experiments. Granisetron and ondansetron, but not paroxetine or 8-OH-DPAT, decreased discounting rates without affecting sensitivity to reinforcer magnitude. CONCLUSION: We found that a method to calculate discounting rates in rats is also applicable to mouse models. We also provided evidence that 5-HT3 antagonism controls impulsive choice in mice.