Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol. However, whether the sigma-2 receptor, recently cloned and identified as transmembrane protein 97 (σ2R/TMEM97), plays a role in alcohol-related behaviors is currently unknown. Using a Caenorhabditis elegans model, we identified two novel, selective σ2R/Tmem97 modulators that reduce alcohol withdrawal behavior via an ortholog of σ2R/TMEM97. We then show that one of these compounds blunted withdrawal-induced excessive alcohol drinking in a well-established rodent model of alcohol dependence. These discoveries provide the first evidence that σ2R/TMEM97 is involved in alcohol withdrawal behaviors and that this receptor is a potential new target for treating alcohol use disorder.

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We thank the CGC for certain worm strains and the UNC Psychoactive Drug Screening Program (Bryan Roth and XP Huang) for receptor binding assays. This work was supported by The Robert A. Welch Foundation (F-0652) (SFM), the Dell Medical School’s Texas Health Catalyst program (SFM and JJS), donations from Tom Calhoon and Hornraiser (JTP), and NIAAA grants AA024439 (VS) and AA020992 (LS and JTP). Drs. Martin, Sahn, Hodges, Scott and Pierce and Mr. Wood report being co-inventors on pending patent applications related to work described in this article.

Author contributions

Conception and design: LLS, JJS, SFM, JTP, and VS. Design and synthesis of σ2R/Tmem97 ligands: JJS. Re-synthesis of JVW-1034: JJS, MDW, and TRH. Collection and analysis of data: LLS, JJS, AF, RCY, PNS, TS, BAP, KMF, and AS. Interpretation of data: LLS, JJS, AF, VS, JTP, and SFM. SFM, JTP, VS, AF, JJS, and LLS wrote the paper.

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Author notes

  1. These authors contributed equally: Luisa L. Scott, James J. Sahn, Antonio Ferragud.


  1. Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, 78712, USA

    • Luisa L. Scott
    • , Jonathan T. Pierce
    •  & Stephen F. Martin
  2. Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA

    • James J. Sahn
    • , Michael D. Wood
    • , Timothy R. Hodges
    •  & Stephen F. Martin
  3. Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, USA

    • Antonio Ferragud
    •  & Valentina Sabino
  4. Department of Neuroscience, University of Texas at Austin, Austin, TX, 78712, USA

    • Rachel C. Yen
    • , Praveen N. Satarasinghe
    • , Ted Shi
    • , Brooke A. Prakash
    • , Kaitlyn M. Friese
    • , Angela Shen
    •  & Jonathan T. Pierce


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Competing interests

Drs. Martin and Sahn also report being co-founders of NuvoNuro, LLC. Drs. Sabino and Ferragud as well as Yen, Satarasinghe, Shi, Prakash, Friese, and Shen report no biomedical financial interests or potential competing interests.

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Correspondence to Stephen F. Martin.

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