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Dopamine D2 receptors in nucleus accumbens cholinergic interneurons increase impulsive choice

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Abstract

Impulsive choice, often characterized by excessive preference for small, short-term rewards over larger, long-term rewards, is a prominent feature of substance use and other neuropsychiatric disorders. The neural mechanisms underlying impulsive choice are not well understood, but growing evidence implicates nucleus accumbens (NAc) dopamine and its actions on dopamine D2 receptors (D2Rs). Because several NAc cell types and afferents express D2Rs, it has been difficult to determine the specific neural mechanisms linking NAc D2Rs to impulsive choice. Of these cell types, cholinergic interneurons (CINs) of the NAc, which express D2Rs, have emerged as key regulators of striatal output and local dopamine release. Despite these relevant functions, whether D2Rs expressed specifically in these neurons contribute to impulsive choice behavior is unknown. Here, we show that D2R upregulation in CINs of the mouse NAc increases impulsive choice as measured in a delay discounting task without affecting reward magnitude sensitivity or interval timing. Conversely, mice lacking D2Rs in CINs showed decreased delay discounting. Furthermore, CIN D2R manipulations did not affect probabilistic discounting, which measures a different form of impulsive choice. Together, these findings suggest that CIN D2Rs regulate impulsive decision-making involving delay costs, providing new insight into the mechanisms by which NAc dopamine influences impulsive behavior.

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Fig. 1: D2R upregulation in NAc CINs increases delay discounting.
Fig. 2: D2R upregulation in NAc CINs does not alter probabilistic discounting.
Fig. 3: CIN D2R upregulation in NAc does not alter timing.
Fig. 4: Lack of CIN D2Rs decreases delay, but not probabilistic, discounting.

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Acknowledgements

We thank David D’Onofrio, Eric Teboul, Emily Huegler, and Daphne Baker for technical assistance, Katherine Nautiyal for input on behavioral design and analysis, and Christoph Kellendonk and Jonathan Javitch for sharing the D2R viral vector.

Funding

This work was supported by K01 MH107648, R01 DA055018 and Fordham University Faculty Research Grants to EFG; JC was supported by a Len Blavatnik STEM Research Fellowship and Fordham Undergraduate Research Grant; PDB and BA were supported by R01 MH068073.

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  1. These authors contributed equally: Julianna Cavallaro, Jenna Yeisley.

Authors and Affiliations

  1. Department of Biological Sciences, Fordham University, Bronx, NY, USA

    Julianna Cavallaro, Jenna Yeisley, Ronald E. Salazar, Joseph R. Floeder & Eduardo F. Gallo

  2. Department of Psychology, Columbia University, New York, NY, USA

    Başak Akdoǧan & Peter D. Balsam

  3. Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, NY, USA

    Başak Akdoǧan & Peter D. Balsam

  4. Department of Neuroscience and Behavior, Barnard College, New York, NY, USA

    Peter D. Balsam

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JC, JY, RES, JRF and BA and EFG conducted the experiments and data analysis. EFG and JC wrote the manuscript. PDB and BA edited the manuscript. EFG and PDB designed the experiments. EFG supervised the experiments and data analysis.

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Correspondence to Eduardo F. Gallo.

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Cavallaro, J., Yeisley, J., Akdoǧan, B. et al. Dopamine D2 receptors in nucleus accumbens cholinergic interneurons increase impulsive choice. Neuropsychopharmacol. 48, 1309–1317 (2023). https://doi.org/10.1038/s41386-023-01608-1

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