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

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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.

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Funding

This work was supported by Grant-in-Aid for Scientific Research (B) from MEXT to K.F.T. (15H03123), Grant-in-Aids for Scientific Research on Innovative Area “Willdynamics” (17H06062) and “Oscillology” (16H01621) from the MEXT to K.F.T.

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Authors and Affiliations

  1. Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, 160-8582, Japan

    Marina Mori, Iku Tsutsui-Kimura, Masaru Mimura & Kenji F. Tanaka

  2. Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, 02138, USA

    Iku Tsutsui-Kimura

  3. JSPS Overseas Research Fellow, Tokyo, 102-0083, Japan

    Iku Tsutsui-Kimura

Authors
  1. Marina Mori
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  2. Iku Tsutsui-Kimura
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Correspondence to Iku Tsutsui-Kimura or Kenji F. Tanaka.

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Mori, M., Tsutsui-Kimura, I., Mimura, M. et al. 5-HT3 antagonists decrease discounting rate without affecting sensitivity to reward magnitude in the delay discounting task in mice. Psychopharmacology 235, 2619–2629 (2018). https://doi.org/10.1007/s00213-018-4954-0

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