Taar1 gene variants have a causal role in methamphetamine intake and response and interact with Oprm1

  1. Alexandra M Stafford
  2. Cheryl Reed
  3. Harue Baba
  4. Nicole AR Walter
  5. John RK Mootz
  6. Robert W Williams
  7. Kim A Neve
  8. Lev M Fedorov
  9. Aaron J Janowsky
  10. Tamara J Phillips  Is a corresponding author
  1. Oregon Health and Science University, United States
  2. Oregon National Primate Research Center, United States
  3. University of Tennessee Health Sciences Center, United States

Abstract

We identified a locus on mouse chromosome 10 that accounts for 60% of the genetic variance in methamphetamine intake in mice selectively bred for high versus low methamphetamine consumption. We nominated the trace amine-associated receptor 1 gene, Taar1, as the strongest candidate and identified regulation of the mu-opioid receptor 1 gene, Oprm1, as another contributor. This study exploited CRISPR-Cas9 to test the causal role of Taar1 in methamphetamine intake and a genetically-associated thermal response to methamphetamine. The methamphetamine-related traits were rescued, converting them to levels found in methamphetamine-avoiding animals. We used a family of recombinant inbred mouse strains for interval mapping and to examine independent and epistatic effects of Taar1 and Oprm1. Both methamphetamine intake and the thermal response mapped to Taar1 and the independent effect of Taar1 was dependent on genotype at Oprm1. Our findings encourage investigation of the contribution of Taar1 and Oprm1 variants to human methamphetamine addiction.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2 through 8.

Article and author information

Author details

  1. Alexandra M Stafford

    Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4045-1888
  2. Cheryl Reed

    Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Harue Baba

    Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nicole AR Walter

    Division of Neuroscience, Oregon National Primate Research Center, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. John RK Mootz

    Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Robert W Williams

    Department of Genetics, Genomics and Informatics, University of Tennessee Health Sciences Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kim A Neve

    Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0109-7345
  8. Lev M Fedorov

    Transgenic Mouse Models Shared Resource, Knight Cancer Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Aaron J Janowsky

    Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Tamara J Phillips

    Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, United States
    For correspondence
    phillipt@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7350-6323

Funding

National Institute on Drug Abuse (R01 DA046081)

  • Tamara J Phillips

Veterans Affairs Research Career Scientist Program (Career Scientist award)

  • Tamara J Phillips

Veterans Affairs Research Career Scientist Program (Career Scientist award)

  • Aaron J Janowsky

University of Tennessee Center for Integrative and Translational Science (Center support)

  • Robert W Williams

National Institute on Drug Abuse (P50 DA018165)

  • Aaron J Janowsky

National Institute on Drug Abuse (P50 DA018165)

  • Tamara J Phillips

National Institute on Drug Abuse (U01 DA041579)

  • Tamara J Phillips

National Institute on Drug Abuse (P30 DA044223)

  • Robert W Williams

Department of Veterans Affairs (I01BX002106)

  • Tamara J Phillips

Department of Veterans Affairs (I01BX002758)

  • Aaron J Janowsky

Department of Veterans Affairs (I01BX003279)

  • Kim A Neve

Oregon Health & Science University-Pilot Funding to the Transgenic Mouse Models Shared Resource (University Shared Resource award)

  • Kim A Neve

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Reviewing Editor

  1. Jonathan Flint, University of California, Los Angeles, United States

Ethics

Animal experimentation: All experiments were performed in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of the VA Portland Health Care System (VAPORHCS), protocol numbers 3169-14 and 3169-16.

Version history

  1. Received: February 28, 2019
  2. Accepted: July 4, 2019
  3. Accepted Manuscript published: July 5, 2019 (version 1)
  4. Accepted Manuscript updated: July 9, 2019 (version 2)
  5. Version of Record published: August 5, 2019 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Alexandra M Stafford
  2. Cheryl Reed
  3. Harue Baba
  4. Nicole AR Walter
  5. John RK Mootz
  6. Robert W Williams
  7. Kim A Neve
  8. Lev M Fedorov
  9. Aaron J Janowsky
  10. Tamara J Phillips
(2019)
Taar1 gene variants have a causal role in methamphetamine intake and response and interact with Oprm1
eLife 8:e46472.
https://doi.org/10.7554/eLife.46472

Share this article

https://doi.org/10.7554/eLife.46472

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