Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via facilitation of dopamine release

  1. Xiaojie Liu
  2. Casey R Vickstrom
  3. Hao Yu
  4. Shuai Liu
  5. Shana Terai Snarrenberg
  6. Vladislav Friedman
  7. Lianwei Mu
  8. Bixuan Chen
  9. Thomas J Kelly
  10. David A Baker
  11. Qing-song Liu  Is a corresponding author
  1. Medical College of Wisconsin, United States
  2. Marquette University, United States

Abstract

Repeated exposure to drugs of abuse results in an upregulation of cAMP signaling in the mesolimbic dopamine system, a molecular adaptation thought to be critically involved in the development of drug dependence. Exchange protein directly activated by cAMP (Epac2) is a major cAMP effector abundantly expressed in the brain. However, it remains unknown whether Epac2 contributes to cocaine reinforcement. Here, we report that Epac2 in the mesolimbic dopamine system promotes cocaine reinforcement via enhancement of dopamine release. Conditional knockout of Epac2 from midbrain dopamine neurons (Epac2-cKO) and the selective Epac2 inhibitor ESI-05 decreased cocaine self-administration in mice under both fixed-ratio and progressive-ratio reinforcement schedules and across a broad range of cocaine doses. In addition, Epac2-cKO led to reduced evoked dopamine release, whereas Epac2 agonism robustly enhanced dopamine release in the nucleus accumbens in vitro. This mechanism is central to the behavioral effects of Epac2 disruption, as chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons via deschloroclozapine (DCZ)-induced activation of Gs-DREADD increased dopamine release and reversed the impairment of cocaine self-administration in Epac2-cKO mice. Conversely, chemogenetic inhibition of VTA dopamine neurons with Gi-DREADD reduced dopamine release and cocaine self-administration in wild-type mice. Epac2-mediated enhancement of dopamine release may therefore represent a novel and powerful mechanism that contributes to cocaine reinforcement.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for figures 1-7. Custom code used for the analysis of the fiber photometry data is available at https://github.com/xiaojieliu17/Fiber-photometry.

Article and author information

Author details

  1. Xiaojie Liu

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Casey R Vickstrom

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Hao Yu

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shuai Liu

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Shana Terai Snarrenberg

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Vladislav Friedman

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lianwei Mu

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Bixuan Chen

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Thomas J Kelly

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. David A Baker

    Department of Biomedical Sciences, Marquette University, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Qing-song Liu

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    For correspondence
    qsliu@mcw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1858-1504

Funding

National Institute on Drug Abuse (R01DA035217)

  • Qing-song Liu

National Institute on Drug Abuse (R01DA047269)

  • Qing-song Liu

National Institute of Mental Health (F30MH115536)

  • Casey R Vickstrom

National Institute on Drug Abuse (R01DA050180)

  • David A Baker

National Institute on Drug Abuse (F31DA054759)

  • Vladislav Friedman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal maintenance and use were in accordance with protocols (AUA #2420) approved by the Institutional Animal Care and Use Committee of Medical College of Wisconsin. All surgery was performed under ketamine and xylazine anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Jeremy J Day, University of Alabama at Birmingham, United States

Publication history

  1. Received: June 2, 2022
  2. Preprint posted: June 16, 2022 (view preprint)
  3. Accepted: August 21, 2022
  4. Accepted Manuscript published: August 22, 2022 (version 1)
  5. Version of Record published: September 1, 2022 (version 2)

Copyright

© 2022, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Xiaojie Liu
  2. Casey R Vickstrom
  3. Hao Yu
  4. Shuai Liu
  5. Shana Terai Snarrenberg
  6. Vladislav Friedman
  7. Lianwei Mu
  8. Bixuan Chen
  9. Thomas J Kelly
  10. David A Baker
  11. Qing-song Liu
(2022)
Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via facilitation of dopamine release
eLife 11:e80747.
https://doi.org/10.7554/eLife.80747
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